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High Dose or High Dose Frequency Study of Alglucosidase Alfa

Primary Purpose

Pompe Disease, Glycogen Storage Disease Type II (GSD-II), Glycogenesis 2 Acid Maltase Deficiency

Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
alglucosidase alfa
Sponsored by
Genzyme, a Sanofi Company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pompe Disease

Eligibility Criteria

6 Months - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • The patient or patient's legal guardian must provide signed, informed consent prior to performing any study-related procedures;
  • The patient must have a clinical diagnosis of Pompe disease as defined by documented GAA deficiency in skin fibroblasts or blood;
  • The patient must have been compliant with the standard dosing regimen of alglucosidase alfa (20 mg/kg every other week) for a minimum of 6 months immediately prior to study entry

  • The patient must have clinical decline or sub-optimal improvement in at least one of the following parameters as compared to their condition prior to the beginning alglucosidase alfa treatment:

    1. Cardiac: Left Ventricular Mass (LVM) Z-score ≥6 or LVM index ≥150 g/m2 after a minimum of 6 months of regular treatment with alglucosidase alfa; OR
    2. Respiratory: New development of respiratory failure requiring the use of ventilatory assistance (invasive or non-invasive) after a minimum of 6 months of regular treatment with alglucosidase alfa. Ventilatory assistance must have been required for at least 4 weeks prior to study enrollment; OR
    3. Motor Skills:
  • For patients ≤ 2 years of age at study entry, failure to acquire at least 2 new gross motor milestones after a minimum of 6 months of regular treatment with alglucosidase alfa; OR
  • For patients > 2 years of age at study entry, worsening of proximal upper extremity muscle weakness as determined by the Investigator through loss of functional use of the upper extremities after a minimum of 6 months of regular treatment with alglucosidase alfa, OR
  • For patients > 8 years of age at study entry, worsening of proximal upper extremity muscle weakness as determined by the Investigator through longitudinal assessments of manual muscle testing after a minimum of 6 months of regular treatment with alglucosidase alfa, OR
  • For patients previously ambulatory, progression to use of an assistive device for ambulation due to worsening of proximal lower extremity muscle weakness after a minimum of 6 months of regular treatment with alglucosidase alfa.

Exclusion Criteria:

  • For patients < 18 years of age, negative Cross-Reactive Immunologic Material (CRIM) assay result (added in protocol amendment #2);
  • Any medical condition which, in the opinion of the Investigator, could interfere with treatment or evaluation of safety and/or efficacy of alglucosidase alfa;
  • The patient is not currently receiving alglucosidase alfa;
  • The patient has major congenital abnormality;
  • The patient has used any investigational product (other than alglucosidase alfa in those regions where the product is not commercially available) within 30 days prior to study enrollment;
  • The patient is pregnant or lactating.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

alglucosidase alfa 20 mg/kg every week

alglucosidase alfa 40 mg/kg every other week

Arm Description

Participants were treated with alglucosidase alfa 20 mg/kg every week for 52 weeks. This was the 'frequent dose' arm.

Participants were treated with alglucosidase alfa 40 mg/kg every other week for 52 weeks. This was the 'high dose' arm.

Outcomes

Primary Outcome Measures

Participants' Efficacy Response During the Treatment Period as Compared to Baseline for Participants With Respiratory Decline on Standard Treatment
Participants were enrolled based on clinical decline or sub-optimal clinical response in cardiac, respiratory and/or motor function parameters pre-study while on standard treatment. Each participant was evaluated at Week 52 for change from baseline in the criteria that declined; respiratory decline as measured by change in ventilator use is summarized in this outcome. Ventilator use might have improved (less use of ventilator support), had no change, or worsened (more use of ventilator support). Each participant served as his or her own control.
Participants' Efficacy Response During the Treatment Period as Compared to Baseline for Participants With Motor Function Decline on Standard Treatment
Participants were enrolled based on clinical decline or sub-optimal clinical response in cardiac, respiratory and/or motor function parameters pre-study while on standard treatment. Each participant was evaluated at Week 52 for change from baseline in the criteria that declined; motor function decline primarily based on Gross Motor Function Measure 66 and Pompe Pediatric Evaluation of Disability Inventory results is summarized. Participants could gain motor function (improve), had no change (declined stopped), or continued loss (worsened). Each participant served as his or her own control.
Summary of Participants Reporting Treatment-Emergent Adverse Events During the Treatment Period
Overall safety summary of participants experiencing Adverse Events (AEs), Serious Adverse Events (SAEs), treatment-related AEs, and Infusion Associated Reactions (IARs). Summary is based on Treatment-emergent AEs (TEAEs), defined as AEs that occurred following the initiation of study treatment.

Secondary Outcome Measures

Baseline Values for Left Ventricular Mass (LVM) Z-Scores
Z-Scores indicate the number of standard deviations (SD) from the mean in a normal distribution. Negative values indicate a smaller than mean LVM and values higher than 0 indicate a larger LVM than the mean. The normal range is -2 to 2 and greater than 2 may indicate left ventricular hypertrophy. The Z-scores for all parameters are calculated with reference to the normative data from the Children's Hospital, Boston, MA (Colan, 1992, J Am Coll Cardiol) based on the reference population with matched body surface area (BSA). Z-scores for LVM were provided by the central cardiologist.
Change From Baseline in Left Ventricular Mass (LVM) Z-Score at Week 52
Z-Scores indicate the number of standard deviations (SD) from the mean in a normal distribution. A negative change from baseline indicates a decrease and positive change from baseline an increase in LVM Z-score. The normal range is -2 to 2 and greater than 2 may indicate left ventricular hypertrophy. The Z-scores for all parameters are calculated with reference to the normative data from the Children's Hospital, Boston, MA (Colan, 1992, J Am Coll Cardiol) based on the reference population with matched body surface area (BSA). Z-scores for LVM were provided by the central cardiologist.
Baseline Values for Left Ventricular Mass Index (LVMI)
Cardiac pathophysiology was assessed by a central cardiologist using left ventricular mass index (LVMI) measured by echocardiogram at Baseline. Left Ventricular Mass is adjusted to the participant's body surface area in the calculation of LVMI.
Change From Baseline in Left Ventricular Mass Index (LVMI) at Week 52
Cardiac pathophysiology was assessed by a central cardiologist using left ventricular mass index (LVMI) measured by echocardiogram at Baseline and after 12 months of treatment (Week 52). Left Ventricular Mass is adjusted to the participant's body surface area in the calculation of LVMI.
Change From Baseline in Ventilator Use at Last Assessment (Approximately Week 52)
The change from baseline in ventilator use at the last assessment is summarized as improved (less use of ventilator support), no change, worsened (increased use of ventilator support), and did not use ventilator support.
Change From Baseline in Body Strength Measured by the Manual Muscle Testing (MMT) Total Score at Week 52
Body strength is measured by the MMT score on a scale of 0-10 with higher scores representing greater body strength.
Baseline Values of Raw Scores for Gross Motor Function Measure 66 (GMFM-66) Results
The Gross Motor Function Measure 66 contains sixty-six questions with a total raw score range of 0 - 198. Raw scores are derived from the following dimensions: Lying and rolling = 12; Sitting = 45; Crawling and kneeling = 30; Standing = 39; Walking, running and jumping = 72. Higher scores indicate better gross motor functions.
Change From Baseline in Raw Scores for Gross Motor Function Measure 66 (GMFM-66) Results at Week 52
The Gross Motor Function Measure 66 contains sixty-six questions with a total raw score range of 0 - 198. Raw scores are derived from the following dimensions: Lying and rolling = 12; Sitting = 45; Crawling and kneeling = 30; Standing = 39; Walking, running and jumping = 72. Higher scores indicate better gross motor functions.
Baseline Values in Mobility as Measured by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI)
The Pompe PEDI is a disease specific version of the PEDI that was developed to assess functional capabilities and performance in children with Pompe disease from 2 months through adolescence. Baseline results for the mobility domain are reported. Scaled scores are used as an evaluative measure of change in performance over time with acquisition of new skills or new levels of independence. The range of scores is from 0-100 with scores near "0" reflecting low capability and scores near "100" reflecting high capability.
Change From Baseline in Mobility as Measured by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) at Week 52
The Pompe PEDI is a disease specific version of the PEDI that was developed to assess functional capabilities and performance in children with Pompe disease from 2 months through adolescence. Change from baseline results for the mobility domain are reported. Scaled scores are used as an evaluative measure of change in performance over time with acquisition of new skills or new levels of independence. The range of scores is from 0-100 with scores near "0" reflecting low capability and scores near "100" reflecting high capability.
Baseline Values for Normative Physical Component Summary of Medical Outcomes Study Short Form Health Survey (SF-36)
Health related quality of life is measured using the Physical Component Summary (PCS) score of the Medical Outcomes Study (MOS) Short Form Health Survey (SF-36) for participants ≥14 years of age. SF-36 normative-based scoring has a mean of 50 and a standard deviation of 10. Higher scores represent better quality of life.
Change From Baseline in Normative Physical Component Summary of Medical Outcomes Study Short Form Health Survey (SF-36) at Week 52
Health related quality of life is measured using the Physical Component Summary (PCS) score of the Medical Outcomes Study (MOS) Short Form Health Survey (SF-36) for participants ≥14 years of age. SF-36 normative-based scoring has a mean of 50 and a standard deviation of 10. Higher scores represent better quality of life.

Full Information

First Posted
June 6, 2007
Last Updated
February 4, 2014
Sponsor
Genzyme, a Sanofi Company
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1. Study Identification

Unique Protocol Identification Number
NCT00483379
Brief Title
High Dose or High Dose Frequency Study of Alglucosidase Alfa
Official Title
An Exploratory, Open-Label Study of the Safety and Efficacy of High Dose or High Dosing Frequency Alglucosidase Alfa Treatment in Patients With Pompe Disease Who Do Not Have an Optimal Response to the Standard Dose Regimen
Study Type
Interventional

2. Study Status

Record Verification Date
February 2014
Overall Recruitment Status
Completed
Study Start Date
May 2007 (undefined)
Primary Completion Date
December 2009 (Actual)
Study Completion Date
July 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Genzyme, a Sanofi Company

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Pompe disease (also known as glycogen storage disease Type II) is caused by a deficiency of a critical enzyme in the body called acid alpha-glucosidase (GAA). Normally, GAA is used by the body's cells to break down glycogen (a stored form of sugar) within specialized structures called lysosomes. In patients with Pompe disease, an excessive amount of glycogen accumulates and is stored in various tissues, especially heart and skeletal muscle, which prevents their normal function. The objective of this exploratory study is to evaluate the safety and efficacy of alternative dosing regimens of alglucosidase alfa in patients with Pompe disease who have not demonstrated an optimal response to the standard dosing regimen of 20 mg/kg every other week after a minimum of 6 months treatment immediately prior to study entry.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pompe Disease, Glycogen Storage Disease Type II (GSD-II), Glycogenesis 2 Acid Maltase Deficiency

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
13 (Actual)

8. Arms, Groups, and Interventions

Arm Title
alglucosidase alfa 20 mg/kg every week
Arm Type
Experimental
Arm Description
Participants were treated with alglucosidase alfa 20 mg/kg every week for 52 weeks. This was the 'frequent dose' arm.
Arm Title
alglucosidase alfa 40 mg/kg every other week
Arm Type
Experimental
Arm Description
Participants were treated with alglucosidase alfa 40 mg/kg every other week for 52 weeks. This was the 'high dose' arm.
Intervention Type
Biological
Intervention Name(s)
alglucosidase alfa
Other Intervention Name(s)
Recombinant human acid glucosidase, Myozyme
Intervention Description
intravenous infusion
Primary Outcome Measure Information:
Title
Participants' Efficacy Response During the Treatment Period as Compared to Baseline for Participants With Respiratory Decline on Standard Treatment
Description
Participants were enrolled based on clinical decline or sub-optimal clinical response in cardiac, respiratory and/or motor function parameters pre-study while on standard treatment. Each participant was evaluated at Week 52 for change from baseline in the criteria that declined; respiratory decline as measured by change in ventilator use is summarized in this outcome. Ventilator use might have improved (less use of ventilator support), had no change, or worsened (more use of ventilator support). Each participant served as his or her own control.
Time Frame
Baseline, Week 52
Title
Participants' Efficacy Response During the Treatment Period as Compared to Baseline for Participants With Motor Function Decline on Standard Treatment
Description
Participants were enrolled based on clinical decline or sub-optimal clinical response in cardiac, respiratory and/or motor function parameters pre-study while on standard treatment. Each participant was evaluated at Week 52 for change from baseline in the criteria that declined; motor function decline primarily based on Gross Motor Function Measure 66 and Pompe Pediatric Evaluation of Disability Inventory results is summarized. Participants could gain motor function (improve), had no change (declined stopped), or continued loss (worsened). Each participant served as his or her own control.
Time Frame
Baseline, Week 52
Title
Summary of Participants Reporting Treatment-Emergent Adverse Events During the Treatment Period
Description
Overall safety summary of participants experiencing Adverse Events (AEs), Serious Adverse Events (SAEs), treatment-related AEs, and Infusion Associated Reactions (IARs). Summary is based on Treatment-emergent AEs (TEAEs), defined as AEs that occurred following the initiation of study treatment.
Time Frame
Day 1 up to Week 52
Secondary Outcome Measure Information:
Title
Baseline Values for Left Ventricular Mass (LVM) Z-Scores
Description
Z-Scores indicate the number of standard deviations (SD) from the mean in a normal distribution. Negative values indicate a smaller than mean LVM and values higher than 0 indicate a larger LVM than the mean. The normal range is -2 to 2 and greater than 2 may indicate left ventricular hypertrophy. The Z-scores for all parameters are calculated with reference to the normative data from the Children's Hospital, Boston, MA (Colan, 1992, J Am Coll Cardiol) based on the reference population with matched body surface area (BSA). Z-scores for LVM were provided by the central cardiologist.
Time Frame
Day 0
Title
Change From Baseline in Left Ventricular Mass (LVM) Z-Score at Week 52
Description
Z-Scores indicate the number of standard deviations (SD) from the mean in a normal distribution. A negative change from baseline indicates a decrease and positive change from baseline an increase in LVM Z-score. The normal range is -2 to 2 and greater than 2 may indicate left ventricular hypertrophy. The Z-scores for all parameters are calculated with reference to the normative data from the Children's Hospital, Boston, MA (Colan, 1992, J Am Coll Cardiol) based on the reference population with matched body surface area (BSA). Z-scores for LVM were provided by the central cardiologist.
Time Frame
Baseline, Week 52
Title
Baseline Values for Left Ventricular Mass Index (LVMI)
Description
Cardiac pathophysiology was assessed by a central cardiologist using left ventricular mass index (LVMI) measured by echocardiogram at Baseline. Left Ventricular Mass is adjusted to the participant's body surface area in the calculation of LVMI.
Time Frame
Day 0
Title
Change From Baseline in Left Ventricular Mass Index (LVMI) at Week 52
Description
Cardiac pathophysiology was assessed by a central cardiologist using left ventricular mass index (LVMI) measured by echocardiogram at Baseline and after 12 months of treatment (Week 52). Left Ventricular Mass is adjusted to the participant's body surface area in the calculation of LVMI.
Time Frame
Baseline, Week 52
Title
Change From Baseline in Ventilator Use at Last Assessment (Approximately Week 52)
Description
The change from baseline in ventilator use at the last assessment is summarized as improved (less use of ventilator support), no change, worsened (increased use of ventilator support), and did not use ventilator support.
Time Frame
Baseline, approximately Week 52
Title
Change From Baseline in Body Strength Measured by the Manual Muscle Testing (MMT) Total Score at Week 52
Description
Body strength is measured by the MMT score on a scale of 0-10 with higher scores representing greater body strength.
Time Frame
Baseline, Week 52
Title
Baseline Values of Raw Scores for Gross Motor Function Measure 66 (GMFM-66) Results
Description
The Gross Motor Function Measure 66 contains sixty-six questions with a total raw score range of 0 - 198. Raw scores are derived from the following dimensions: Lying and rolling = 12; Sitting = 45; Crawling and kneeling = 30; Standing = 39; Walking, running and jumping = 72. Higher scores indicate better gross motor functions.
Time Frame
Day 0
Title
Change From Baseline in Raw Scores for Gross Motor Function Measure 66 (GMFM-66) Results at Week 52
Description
The Gross Motor Function Measure 66 contains sixty-six questions with a total raw score range of 0 - 198. Raw scores are derived from the following dimensions: Lying and rolling = 12; Sitting = 45; Crawling and kneeling = 30; Standing = 39; Walking, running and jumping = 72. Higher scores indicate better gross motor functions.
Time Frame
Baseline, Week 52
Title
Baseline Values in Mobility as Measured by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI)
Description
The Pompe PEDI is a disease specific version of the PEDI that was developed to assess functional capabilities and performance in children with Pompe disease from 2 months through adolescence. Baseline results for the mobility domain are reported. Scaled scores are used as an evaluative measure of change in performance over time with acquisition of new skills or new levels of independence. The range of scores is from 0-100 with scores near "0" reflecting low capability and scores near "100" reflecting high capability.
Time Frame
Day 0
Title
Change From Baseline in Mobility as Measured by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) at Week 52
Description
The Pompe PEDI is a disease specific version of the PEDI that was developed to assess functional capabilities and performance in children with Pompe disease from 2 months through adolescence. Change from baseline results for the mobility domain are reported. Scaled scores are used as an evaluative measure of change in performance over time with acquisition of new skills or new levels of independence. The range of scores is from 0-100 with scores near "0" reflecting low capability and scores near "100" reflecting high capability.
Time Frame
Baseline, Week 52
Title
Baseline Values for Normative Physical Component Summary of Medical Outcomes Study Short Form Health Survey (SF-36)
Description
Health related quality of life is measured using the Physical Component Summary (PCS) score of the Medical Outcomes Study (MOS) Short Form Health Survey (SF-36) for participants ≥14 years of age. SF-36 normative-based scoring has a mean of 50 and a standard deviation of 10. Higher scores represent better quality of life.
Time Frame
Day 0
Title
Change From Baseline in Normative Physical Component Summary of Medical Outcomes Study Short Form Health Survey (SF-36) at Week 52
Description
Health related quality of life is measured using the Physical Component Summary (PCS) score of the Medical Outcomes Study (MOS) Short Form Health Survey (SF-36) for participants ≥14 years of age. SF-36 normative-based scoring has a mean of 50 and a standard deviation of 10. Higher scores represent better quality of life.
Time Frame
Baseline, Week 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The patient or patient's legal guardian must provide signed, informed consent prior to performing any study-related procedures; The patient must have a clinical diagnosis of Pompe disease as defined by documented GAA deficiency in skin fibroblasts or blood; The patient must have been compliant with the standard dosing regimen of alglucosidase alfa (20 mg/kg every other week) for a minimum of 6 months immediately prior to study entry The patient must have clinical decline or sub-optimal improvement in at least one of the following parameters as compared to their condition prior to the beginning alglucosidase alfa treatment: Cardiac: Left Ventricular Mass (LVM) Z-score ≥6 or LVM index ≥150 g/m2 after a minimum of 6 months of regular treatment with alglucosidase alfa; OR Respiratory: New development of respiratory failure requiring the use of ventilatory assistance (invasive or non-invasive) after a minimum of 6 months of regular treatment with alglucosidase alfa. Ventilatory assistance must have been required for at least 4 weeks prior to study enrollment; OR Motor Skills: For patients ≤ 2 years of age at study entry, failure to acquire at least 2 new gross motor milestones after a minimum of 6 months of regular treatment with alglucosidase alfa; OR For patients > 2 years of age at study entry, worsening of proximal upper extremity muscle weakness as determined by the Investigator through loss of functional use of the upper extremities after a minimum of 6 months of regular treatment with alglucosidase alfa, OR For patients > 8 years of age at study entry, worsening of proximal upper extremity muscle weakness as determined by the Investigator through longitudinal assessments of manual muscle testing after a minimum of 6 months of regular treatment with alglucosidase alfa, OR For patients previously ambulatory, progression to use of an assistive device for ambulation due to worsening of proximal lower extremity muscle weakness after a minimum of 6 months of regular treatment with alglucosidase alfa. Exclusion Criteria: For patients < 18 years of age, negative Cross-Reactive Immunologic Material (CRIM) assay result (added in protocol amendment #2); Any medical condition which, in the opinion of the Investigator, could interfere with treatment or evaluation of safety and/or efficacy of alglucosidase alfa; The patient is not currently receiving alglucosidase alfa; The patient has major congenital abnormality; The patient has used any investigational product (other than alglucosidase alfa in those regions where the product is not commercially available) within 30 days prior to study enrollment; The patient is pregnant or lactating.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Genzyme, a Sanofi Company
Official's Role
Study Director
Facility Information:
City
Birmingham
State/Province
Alabama
Country
United States
City
Stanford
State/Province
California
Country
United States
City
Washington D.C.
State/Province
District of Columbia
Country
United States
City
Chicago
State/Province
Illinois
Country
United States
City
Kansas City
State/Province
Kansas
Country
United States
City
Boston
State/Province
Massachusetts
Country
United States
City
Grand Rapids
State/Province
Michigan
Country
United States
City
Glenn Falls
State/Province
New York
Country
United States
City
Durham
State/Province
North Carolina
Country
United States
City
Parkville Victoria
Country
Australia
City
Calgary
State/Province
Alberta
Country
Canada

12. IPD Sharing Statement

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High Dose or High Dose Frequency Study of Alglucosidase Alfa

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