Pompe Disease, Glycogen Storage Disease Type II
Conditions
Keywords
Glycogenesis 2, Acid, Maltase, Deficiency
Brief summary
The purpose of this study was to evaluate the efficacy, clinical benefits and safety of a prophylactic immunomodulatory regimen given prior to first treatment with alglucosidase alfa (Myozyme®) in patients with infantile-onset Pompe disease. The objectives were to assess the efficacy of a prophylactic immunomodulatory regimen given prior to first treatment with alglucosidase alfa, as assessed by anti-recombinant human acid alpha-glucosidase (anti-rhGAA) antibody titers, and antibodies that inhibit the activity and/or uptake of alglucosidase alfa; to evaluate the clinical benefit as measured by overall survival, ventilator-free survival, left ventricular mass index (LVMI), gross motor function and development, disability index and the incidence of adverse events (AEs), serious adverse events (SAEs), and clinical laboratory abnormalities.
Interventions
BIOLOGICALAlglucosidase Alfa
Administered as IV infusion.
DRUGMethotrexate
Administered subcutaneously.
DRUGRituximab
Administered as IV infusion.
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* The patient's legal guardian(s) must have provided written informed consent prior to any study-related procedures being performed * The patient must have had a clinical diagnosis of Pompe disease as defined by documented acid alpha-glucosidase (GAA) deficiency (deficient endogenous GAA activity) in skin fibroblasts, muscle, or blood, or 2 GAA mutations. Consent was also sought from the biological parent(s) for parental GAA mutational analysis, but was not a requirement for study eligibility * The patient must have not received Myozyme® or any rhGAA therapies prior to enrollment in the study * The patient must be CRIM negative via Western Blot analysis performed on skin fibroblasts or via 2 known CRIM negative mutations (in which case CRIM status was to be confirmed by Western Blot analysis after enrollment) * The patient's legal guardian(s) must have the ability to comply with the clinical protocol
Exclusion criteria
* The patient had any medical condition that, in the opinion of the Investigator, could be exacerbated/precipitated by or interfere with the study regimen or assessments; such conditions may include but were not limited to human immunodeficiency virus, cancer, Hepatitis B, Hepatitis C, Cytomegalovirus, Herpes Simplex, John Cunningham (JC) virus, Parvovirus, or Epstein Barr virus or tuberculosis * The patient had used any investigational product within 30 days prior to study enrollment * The patient had or was required to have any live vaccination within 1 month prior to enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Number of Patients With Anti-Recombinant Human Acid Alfa-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibody at End of Study | Baseline, End of Study (up to Week 79 or early termination) | Serum samples from patients were analyzed for the presence of anti-rhGAA IgG antibodies. End of study (EOS) refers to the last post baseline observation during study period (up to Week 79). |
| Number of Patients With Recombinant Human Acid Alfa-glucosidase (rhGAA) Inhibitory Antibody at End of Study | End of study (up to Week 79) | Patients with positive anti-rhGAA IgG antibody were assessed for the presence of inhibitory antibodies (inhibition of enzyme activity and inhibition of enzyme uptake). Enzyme-linked immunosorbent assay (ELISA) was used to measure inhibition of rhGAA enzymatic activity in vitro and a cell-based assay was used to measure the inhibition of the uptake of rhGAA in normal fibroblast cells by flow cytometry. |
| Number of Patients Who Survived at End of Study | Baseline up to End of study (Week 79) | — |
| Number of Patients With Normal/Abnormal Left Ventricular Mass (LVM) Z-Score and LVM Index at End of Study | End of study (up to Week 79 or early termination) | LVM Z-score and LVM index were assessed by ECHO. LVM Z-Score provides an indicator of degree of standard deviations from the mean in a normal distribution. Negative values indicate a smaller LVM than mean and values higher than 0 indicate a larger LVM than the mean. The normal range for LVM Z-Score is -2 to 2. Values \<-2 or \>2 indicate abnormal LVM Z-Score. LVM index is an index value derived by normalizing LVM by body surface area. LVM index provides evidence of cardiomyopathy. LVM index values \<65 gram per meter\^2 (g/m\^2) were considered as normal and LVM index values \>=65 g/m\^2 were considered as abnormal. End of study refers to the last post baseline observation during study period (up to Week 79). |
| Number of Patients With Ventilator Use at End of Study | End of study (up to Week 79 or early termination) | Number of patients who had ventilator support at end of study was reported. End of study refers to the last post baseline observation during study period (up to Week 79). |
| Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) at End of Study | End of study (up to Week 79 or early termination) | GMFM-88 is an 88-item measure to detect gross motor function. It consists of 5 categories: lying and rolling; sitting; crawling and kneeling; standing; walking, running and jumping. Each item is scored on a 4-point Likert scale (0 = cannot do; 1 = initiates \[\<10% of the task\]; 2 = partially completes \[10% to \<100% of the task\]; 3 = task completion). The score for each dimension is expressed as a percentage of the maximum score for that dimension. Total score is obtained by adding the percentage scores for each dimension and dividing the sum by the total number of dimensions. Total score ranges from 0% to 100%, where higher scores indicate better motor functions. A total score of \<7.5% demonstrates gross motor disability. End of study refers to the last post baseline observation during study period (up to Week 79). |
| Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) at End of Study | End of study (up to Week 79 or early termination) | AIMS is a 58-item reliable and valid measure of motor development for infants at risk for motor delay. It assesses infant movement in 4 positions (subscales): prone (reciprocal crawling); supine (moving hands to feet); sitting (sitting with arm support); and standing (pulls to stand). For each subscale, items were scored as observed or not observed. Item in the observed range create a motor window. When scoring, subscale scores are calculated by giving the child credit (1 point) for observed items within the motor window in addition to being given credit (1 point) for all of the less mature items before motor window. AIMS total score was calculated by summing the scores for 58 items and ranged from 0 to 58, with higher score indicating more mature motor development. Score was then compared with age-equivalent peers from normative sample and equivalence level age (in months) is reported. End of study refers to the last post baseline observation during study period (up to Week 79). |
| Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) at End of Study | End of study (up to Week 79 or early termination) | 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. It consists of all items of the original PEDI (197 functional skill items in 3 domains: self-care; mobility; and social function) and additional items in the functional skills, mobility, and self-care domains to reflect clinically relevant functional skills for children with Pompe disease. Each domain consisted of 2 subdomains: functional skill performance and caregiver assistance scale. Norm-based scoring was developed for these additional items, and scoring algorithms for the PEDI have been adjusted to reflect additional normative data collected for the Pompe PEDI. Total score range for each domain (mean of subdomains) and subdomain ranges from 0 to 100, where higher score indicates high capability. End of study refers to the last post baseline observation during study period (up to Week 79). |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 2 centers in the United States of America between October 01, 2009 and March 27, 2013.
Participants by arm
| Arm | Count |
|---|---|
| Alglucosidase Alfa Alglucosidase alfa (Myozyme®) 20 mg/kg IV infusion qow (or optionally 20 mg/kg IV infusion every week \[qw\]) beginning from Day 0 to a minimum of 18 months or if the patient was \<6 months of age at the time of enrollment, until the patient was 2 years of age, along with methotrexate 0.4 mg/kg subcutaneously for 3 consecutive days qow beginning from Day 0 to Week 6 (9 doses) and rituximab 375 mg/m\^2 (or 12.5 mg/kg for patients with body surface area less than or equal to 0.5 m\^2) IV infusion qw beginning from Day -1 to Week 4 (4 doses) as per local prescribing information. An additional 4-week cycle of rituximab (up to 4 additional doses) and 6-week cycle of methotrexate (up to 9 additional doses) may have been administered within the first 6 months of the study as per local prescribing information. | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
Baseline characteristics
| Characteristic | Alglucosidase Alfa |
|---|---|
| Age, Customized Greater Than (>) 6 Months | 2 participants |
| Age, Customized Less Than or Equal to (=<) 6 Months | 2 participants |
| Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Caregiver Assistance: Mobility Score (n=2) | 0 units on a scale |
| Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Caregiver Assistance: Self-Care Score (n=2) | 0 units on a scale |
| Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Caregiver Assistance: Social Function Score (n=2) | 0 units on a scale |
| Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Functional Skills: Mobility Score (n=4) | 4.5 units on a scale |
| Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Functional Skills: Self-Care Score (n=4) | 14.4 units on a scale |
| Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Functional Skills: Social Function Score (n=1) | 10.5 units on a scale |
| Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) | 5.10 percentage of maximum total score |
| Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) | 0 months |
| Number of Patients With Anti-Recombinant Human Acid Alfa-glucosidase (Anti-rhGAA) Immunoglobulin G Negative | 4 participants |
| Number of Patients With Anti-Recombinant Human Acid Alfa-glucosidase (Anti-rhGAA) Immunoglobulin G Positive | 0 participants |
| Number of Patients With Normal/Abnormal Left Ventricular Mass (LVM) Z-Score and LVM Index LVM index: Abnormal | 4 participants |
| Number of Patients With Normal/Abnormal Left Ventricular Mass (LVM) Z-Score and LVM Index LVM index: Normal | 0 participants |
| Number of Patients With Normal/Abnormal Left Ventricular Mass (LVM) Z-Score and LVM Index LVM Z-score: Abnormal | 4 participants |
| Number of Patients With Normal/Abnormal Left Ventricular Mass (LVM) Z-Score and LVM Index LVM Z-score: Normal | 0 participants |
| Number of Patients With Ventilator Use No | 1 participants |
| Number of Patients With Ventilator Use Yes | 3 participants |
| Race/Ethnicity, Customized Ethnicity: Hispanic | 2 participants |
| Race/Ethnicity, Customized Ethnicity: Non Hispanic | 2 participants |
| Race/Ethnicity, Customized Race: Black | 2 participants |
| Race/Ethnicity, Customized Race: White | 1 participants |
| Race/Ethnicity, Customized Race: White, Black | 1 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 3 / 4 |
Outcome results
Primary
Change From Baseline in Number of Patients With Anti-Recombinant Human Acid Alfa-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibody at End of Study
Serum samples from patients were analyzed for the presence of anti-rhGAA IgG antibodies. End of study (EOS) refers to the last post baseline observation during study period (up to Week 79).
Time frame: Baseline, End of Study (up to Week 79 or early termination)
Population: FAS population included all enrolled patients who signed informed consent and received at least 1 dose of alglucosidase alfa.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alglucosidase Alfa | Change From Baseline in Number of Patients With Anti-Recombinant Human Acid Alfa-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibody at End of Study | Baseline - Negative; EOS - Positive | 2 participants |
| Alglucosidase Alfa | Change From Baseline in Number of Patients With Anti-Recombinant Human Acid Alfa-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibody at End of Study | Baseline - Negative; EOS - Negative | 2 participants |
Primary
Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) at End of Study
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. It consists of all items of the original PEDI (197 functional skill items in 3 domains: self-care; mobility; and social function) and additional items in the functional skills, mobility, and self-care domains to reflect clinically relevant functional skills for children with Pompe disease. Each domain consisted of 2 subdomains: functional skill performance and caregiver assistance scale. Norm-based scoring was developed for these additional items, and scoring algorithms for the PEDI have been adjusted to reflect additional normative data collected for the Pompe PEDI. Total score range for each domain (mean of subdomains) and subdomain ranges from 0 to 100, where higher score indicates high capability. End of study refers to the last post baseline observation during study period (up to Week 79).
Time frame: End of study (up to Week 79 or early termination)
Population: FAS population included all enrolled patients who signed informed consent and received at least 1 dose of alglucosidase alfa. Here, number of patient analyzed = number of patients with end of study Pompe PEDI assessment and n = number of patients with end of study assessment of specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alglucosidase Alfa | Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) at End of Study | Functional Skills: Mobility Score (n=3) | 25.1 units on a scale |
| Alglucosidase Alfa | Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) at End of Study | Functional Skills: Self-Care Score (n=3) | 39.3 units on a scale |
| Alglucosidase Alfa | Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) at End of Study | Functional Skills: Social Function Score (n=3) | 46.2 units on a scale |
| Alglucosidase Alfa | Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) at End of Study | Caregiver Assistance: Self-Care Score (n=2) | 28.7 units on a scale |
| Alglucosidase Alfa | Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) at End of Study | Caregiver Assistance: Social Function Score (n=3) | 48.5 units on a scale |
| Alglucosidase Alfa | Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) at End of Study | Caregiver Assistance: Mobility Score (n=3) | 20.3 units on a scale |
Primary
Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) at End of Study
GMFM-88 is an 88-item measure to detect gross motor function. It consists of 5 categories: lying and rolling; sitting; crawling and kneeling; standing; walking, running and jumping. Each item is scored on a 4-point Likert scale (0 = cannot do; 1 = initiates \[\<10% of the task\]; 2 = partially completes \[10% to \<100% of the task\]; 3 = task completion). The score for each dimension is expressed as a percentage of the maximum score for that dimension. Total score is obtained by adding the percentage scores for each dimension and dividing the sum by the total number of dimensions. Total score ranges from 0% to 100%, where higher scores indicate better motor functions. A total score of \<7.5% demonstrates gross motor disability. End of study refers to the last post baseline observation during study period (up to Week 79).
Time frame: End of study (up to Week 79 or early termination)
Population: FAS population included all enrolled patients who signed informed consent and received at least 1 dose of alglucosidase alfa. Here, numbers of patients analyzed = patients with end of study GMFM-88 assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alglucosidase Alfa | Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) at End of Study | 8.24 percentage of maximum total score |
Primary
Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) at End of Study
AIMS is a 58-item reliable and valid measure of motor development for infants at risk for motor delay. It assesses infant movement in 4 positions (subscales): prone (reciprocal crawling); supine (moving hands to feet); sitting (sitting with arm support); and standing (pulls to stand). For each subscale, items were scored as observed or not observed. Item in the observed range create a motor window. When scoring, subscale scores are calculated by giving the child credit (1 point) for observed items within the motor window in addition to being given credit (1 point) for all of the less mature items before motor window. AIMS total score was calculated by summing the scores for 58 items and ranged from 0 to 58, with higher score indicating more mature motor development. Score was then compared with age-equivalent peers from normative sample and equivalence level age (in months) is reported. End of study refers to the last post baseline observation during study period (up to Week 79).
Time frame: End of study (up to Week 79 or early termination)
Population: FAS population included all enrolled patients who signed informed consent and received at least 1 dose of alglucosidase alfa. Here, numbers of patients analyzed = patients with end of study AIMS assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alglucosidase Alfa | Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) at End of Study | 1.09 months |
Primary
Number of Patients Who Survived at End of Study
Time frame: Baseline up to End of study (Week 79)
Population: FAS population included all enrolled patients who signed informed consent and received at least 1 dose of alglucosidase alfa.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alglucosidase Alfa | Number of Patients Who Survived at End of Study | 2 participants |
Primary
Number of Patients With Normal/Abnormal Left Ventricular Mass (LVM) Z-Score and LVM Index at End of Study
LVM Z-score and LVM index were assessed by ECHO. LVM Z-Score provides an indicator of degree of standard deviations from the mean in a normal distribution. Negative values indicate a smaller LVM than mean and values higher than 0 indicate a larger LVM than the mean. The normal range for LVM Z-Score is -2 to 2. Values \<-2 or \>2 indicate abnormal LVM Z-Score. LVM index is an index value derived by normalizing LVM by body surface area. LVM index provides evidence of cardiomyopathy. LVM index values \<65 gram per meter\^2 (g/m\^2) were considered as normal and LVM index values \>=65 g/m\^2 were considered as abnormal. End of study refers to the last post baseline observation during study period (up to Week 79).
Time frame: End of study (up to Week 79 or early termination)
Population: FAS population included all enrolled patients who signed informed consent and received at least 1 dose of alglucosidase alfa.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alglucosidase Alfa | Number of Patients With Normal/Abnormal Left Ventricular Mass (LVM) Z-Score and LVM Index at End of Study | LVM Z-score: Normal | 3 participants |
| Alglucosidase Alfa | Number of Patients With Normal/Abnormal Left Ventricular Mass (LVM) Z-Score and LVM Index at End of Study | LVM Z-score: Abnormal | 1 participants |
| Alglucosidase Alfa | Number of Patients With Normal/Abnormal Left Ventricular Mass (LVM) Z-Score and LVM Index at End of Study | LVM index: Normal | 2 participants |
| Alglucosidase Alfa | Number of Patients With Normal/Abnormal Left Ventricular Mass (LVM) Z-Score and LVM Index at End of Study | LVM index: Abnormal | 2 participants |
Primary
Number of Patients With Recombinant Human Acid Alfa-glucosidase (rhGAA) Inhibitory Antibody at End of Study
Patients with positive anti-rhGAA IgG antibody were assessed for the presence of inhibitory antibodies (inhibition of enzyme activity and inhibition of enzyme uptake). Enzyme-linked immunosorbent assay (ELISA) was used to measure inhibition of rhGAA enzymatic activity in vitro and a cell-based assay was used to measure the inhibition of the uptake of rhGAA in normal fibroblast cells by flow cytometry.
Time frame: End of study (up to Week 79)
Population: FAS population included all enrolled patients who signed informed consent and received at least 1 dose of alglucosidase alfa. Here, number of patients analyzed = patients with positive anti-rhGAA IgG antibody.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alglucosidase Alfa | Number of Patients With Recombinant Human Acid Alfa-glucosidase (rhGAA) Inhibitory Antibody at End of Study | Inhibition of Enzyme Activity | 0 participants |
| Alglucosidase Alfa | Number of Patients With Recombinant Human Acid Alfa-glucosidase (rhGAA) Inhibitory Antibody at End of Study | Inhibition of Enzyme Uptake | 0 participants |
Primary
Number of Patients With Ventilator Use at End of Study
Number of patients who had ventilator support at end of study was reported. End of study refers to the last post baseline observation during study period (up to Week 79).
Time frame: End of study (up to Week 79 or early termination)
Population: FAS population included all enrolled patients who signed informed consent and received at least 1 dose of alglucosidase alfa.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alglucosidase Alfa | Number of Patients With Ventilator Use at End of Study | No | 1 participants |
| Alglucosidase Alfa | Number of Patients With Ventilator Use at End of Study | Yes | 3 participants |