Glycogenesis 2 Acid Maltase Deficiency, Glycogen Storage Disease Type II (GSD-II), Pompe Disease
Conditions
Brief summary
An exploratory, open-labeled study of participants with Pompe disease, who had previously received Myozyme® (alglucosidase alfa) treatment, to evaluate the efficacy, safety and clinical benefit of 2 Immune Tolerance Induction (ITI) regimens in combination with Myozyme®. Eligible participants who were then receiving Myozyme® therapy were enrolled into the study, and were followed for a minimum of 18 months on-study (a 6-month ITI treatment module and a 12-month follow-up module on Myozyme® alone). Eligible participants were followed for a minimum of 18 months on treatment or, if a participant was \<6 months of age at the time of enrollment, until the participant was 2 years of age. Both cross-reacting immunologic material (CRIM)-negative and CRIM-positive participants were eligible for Regimen A depending if they met the required criteria. Regimen B, however, was limited to CRIM-negative participants.
Interventions
BIOLOGICALMyozyme® (alglucosidase alfa)
Myozyme®: IV infusion of 20 mg/kg qow; Cyclophosphamide: 250 mg/m\^2 IV q4w after Myozyme infusion for 6 months.
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Months to No maximum
Healthy volunteers
No
Inclusion criteria
* The participant (and/or participant's legal guardian if participant was \< 18 years) provided written informed consent prior to any study-related procedures that were performed. * The participants had a confirmed diagnosis of Pompe disease defined as a documented acid α-glucosidase (GAA) enzyme deficiency from any tissue source or 2 GAA gene mutations. * The participant (and/or legal guardian) had ability to comply with clinical protocol. * If the participant was CRIM-positive, he/she had received at least 6 consecutive months of Myozyme® infusions (20 mg/kg qow). * If the participant was CRIM-negative, he/she had received at least 1 Myozyme® infusion prior to enrollment. * Regimen A only: The participants exhibits clinical decline; The participant had persistent high anti-recombinant human acid α-glucosidase (anti-rhGAA) antibody titers and/or tested positive for antibodies that inhibit enzymatic activity and/or uptake of Myozyme®; * Regimen B only: The participant was CRIM-negative AND The participant did not exhibit clinical decline; OR all of the following: The participant was CRIM-negative AND The participant exhibited clinical decline AND The participant did not exhibit high anti-rhGAA antibody titers and had not tested positive for antibodies that inhibit enzymatic activity and/or uptake of Myozyme®.
Exclusion criteria
* The participant had a clinical condition unrelated to Pompe disease that would interfere with program assessments. * The participant was at risk of reactivation or was a carrier of Hepatitis B or Hepatitis C. * The participant was at risk of reactivation or had positive serology suggestive of active infection for cytomegalovirus, Herpes simplex, JC virus, Parvovirus or Epstein Barr virus. * The participant was at risk of reactivation of tuberculosis or had regular contact with individuals who were being actively treated for tuberculosis. * The participant had low serum albumin. * The participant had a major congenital abnormality. * The participant had used any investigational product (other than alglucosidase alfa) within 30 days prior to study enrollment. * The participant was pregnant or lactating. * The participant has had or was required to have any live vaccination within one month prior to enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From Baseline up to 18 months | An Adverse event (AE) was defined as any undesirable physical, psychological, or behavioral effect experienced by participant during his/her participation in an investigational study, in conjunction with the use of the drug or biologic, whether or not product-related. TEAEs were defined as AEs that occurred or worsened during the on-treatment period (time from the start of investigational medicinal product \[IMP\] administration up to 18 months). Serious AE (SAE) was any AE that resulted in any of the following outcomes: death, was life-threatening, required or prolonged inpatient hospitalization, persistent or significant disability/incapacity; congenital anomaly; or important medical events that may jeopardize the patient or participant and may require medical or surgical intervention to prevent one of the outcomes listed above; and/or new invasive ventilator use. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Recombinant Human Acid Alpha-glucosidase (rhGAA) Inhibitory Antibody at Month 18 | Month 18 | Participants with positive anti-rhGAA IgG antibody were planned to be 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. |
| Overall Survival (OS) | From randomization until death or study cut-off whichever comes earlier (up to 18 months) | OS was defined as the time interval from the date of first IMP administration to the date of death due to any cause. |
| Number of Participants With Ventilator Use | From Baseline up to 18 months | — |
| Number of Participants With Anti-Recombinant Human Acid Alpha-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibodies at Month 18 | Month 18 | — |
| Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) Score | From Baseline up to 18 months | 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; and walking, running and jumping. Each item is scored on a 4-point Likert scale (0=cannot do; 1=initiates \[\<10 percent (%) of the task\]; 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. |
| Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) Score | From Baseline up to 18 months | 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 are scored as observed or not observed. Items in observed range create a motor window. When scoring, subscale scores are calculated by giving child credit (1 point) for observed items within motor window in addition to being given credit (1 point) for all of the less mature items before motor window. AIMS total score is calculated by summing scores for 58 items and ranges from 0-58, with lower score indicating less mature motor development and higher score indicating more mature motor development. |
| Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Score | From Baseline up to 18 months | Pompe PEDI is a disease specific version of PEDI which assesses functional capabilities and performance in children with Pompe disease from 2 months through adolescence.It consists of all items of original PEDI (197 functional skill items in 3 domains: self-care; mobility; and social function) and additional items in functional skills, mobility, and self-care domains to reflect clinically relevant functional skills. Each domain consists of 2 subdomains: functional skill performance and caregiver assistance scale. Norm-based scoring was developed for these additional items, and scoring algorithms for PEDI have been adjusted to reflect additional normative data collected for Pompe PEDI. Total score range for each domain (mean of subdomains) and subdomains ranges from 0-100, higher score indicates higher capability. |
| Left Ventricular Mass (LVM) Z-Score and LVM Index | From Baseline up to 18 months | LVM Z-score and LVM index were assessed by echocardiograms (ECHOs). LVM Z-Score is an indicator of degree of standard deviations from the mean in a normal distribution. The normal range for LVM Z-Score is -2 to 2. Values \<-2 or \>2 indicate abnormal LVM Z-Score. Values less than 0 (negative values) indicate a smaller LVM than mean and values higher than 0 indicate a larger LVM than the mean. 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 square meter (g/m\^2) were considered as normal and LVM index values \>=65 g/m\^2 were considered as abnormal. |
Countries
Israel, United States
Participant flow
Recruitment details
The study was conducted in 2 countries. A total of 5 participants were screened between 14 December 2008 and 17 August 2010 (dates when first participant and last participant signed informed consent), of which one participant died before enrollment.
Pre-assignment details
A total of 4 participants were included and treated in this study. Participants were assigned to either Regimen A or Regimen B.
Participants by arm
| Arm | Count |
|---|---|
| Regimen A: Alglucosidase Alfa and Cyclophosphamide Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high rhGAA antibody titer (defined as at least 2 titers \>=25,600 obtained at least 1 month apart), regardless of their CRIM status, were assigned to Regimen A. In Regimen A, participants received alglucosidase alfa (Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was \<6 months of age at the time of enrollment). In addition, cyclophosphamide 250 mg/m\^2 IV infusion was administered q4w after Myozyme® infusion for 6 months. | 1 |
| Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate CRIM-negative participants were assigned to Regimen B if they either(1)exhibited clinical decline since starting alglucosidase alfa (Myozyme®)therapy and did not have inhibitory antibodies and/or a sustained rhGAA antibody titer(defined as at least 2 titers \>=25,600 obtained at least 1 month apart),or(2) did not exhibit clinical decline since starting alglucosidase alfa(Myozyme®) therapy, regardless of their anti-rhGAA or inhibitory antibody status. Regimen B participants with CRIM-negative status received alglucosidase alfa(Myozyme®) IV infusion of 20 mg/kg qow for a minimum of 18 months or,until participant reached the age of 2 years (if participant was \<6 months of age at time of enrollment). In addition,rituximab 375 mg/m\^2 IV was administered weekly beginning the day after Myozyme® infusion for 4 weeks(an optional 2nd cycle could be administered at the discretion of the investigator) and biweekly methotrexate 15 mg/m\^2 subcutaneous on the day after Myozyme® infusion for 6 months. | 3 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Regimen A: Alglucosidase Alfa and Cyclophosphamide | Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate | Total |
|---|---|---|---|
| Age, Customized Children (2-11 years) | 1 Participants | 1 Participants | 2 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 2 Participants | 2 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 1 / 3 |
| other Total, other adverse events | 1 / 1 | 3 / 3 |
| serious Total, serious adverse events | 1 / 1 | 3 / 3 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An Adverse event (AE) was defined as any undesirable physical, psychological, or behavioral effect experienced by participant during his/her participation in an investigational study, in conjunction with the use of the drug or biologic, whether or not product-related. TEAEs were defined as AEs that occurred or worsened during the on-treatment period (time from the start of investigational medicinal product \[IMP\] administration up to 18 months). Serious AE (SAE) was any AE that resulted in any of the following outcomes: death, was life-threatening, required or prolonged inpatient hospitalization, persistent or significant disability/incapacity; congenital anomaly; or important medical events that may jeopardize the patient or participant and may require medical or surgical intervention to prevent one of the outcomes listed above; and/or new invasive ventilator use.
Time frame: From Baseline up to 18 months
Population: Analysis was performed on safety set population that included participants who received at least 1 dose of alglucosidase alfa in the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Regimen A: Alglucosidase Alfa and Cyclophosphamide | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 1 Participants |
| Regimen A: Alglucosidase Alfa and Cyclophosphamide | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any Treatment-emergent SAE | 1 Participants |
| Regimen A: Alglucosidase Alfa and Cyclophosphamide | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE leading to withdrawal from study | 0 Participants |
| Regimen A: Alglucosidase Alfa and Cyclophosphamide | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE leading to death | 0 Participants |
| Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE leading to death | 1 Participants |
| Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 3 Participants |
| Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE leading to withdrawal from study | 1 Participants |
| Regimen B: Alglucosidase Alfa, Rituximab and Methotrexate | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any Treatment-emergent SAE | 3 Participants |
Other Pre-specified
Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Score
Pompe PEDI is a disease specific version of PEDI which assesses functional capabilities and performance in children with Pompe disease from 2 months through adolescence.It consists of all items of original PEDI (197 functional skill items in 3 domains: self-care; mobility; and social function) and additional items in functional skills, mobility, and self-care domains to reflect clinically relevant functional skills. Each domain consists of 2 subdomains: functional skill performance and caregiver assistance scale. Norm-based scoring was developed for these additional items, and scoring algorithms for PEDI have been adjusted to reflect additional normative data collected for Pompe PEDI. Total score range for each domain (mean of subdomains) and subdomains ranges from 0-100, higher score indicates higher capability.
Time frame: From Baseline up to 18 months
Population: Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.
Other Pre-specified
Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) Score
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; and walking, running and jumping. Each item is scored on a 4-point Likert scale (0=cannot do; 1=initiates \[\<10 percent (%) of the task\]; 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.
Time frame: From Baseline up to 18 months
Population: Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.
Other Pre-specified
Left Ventricular Mass (LVM) Z-Score and LVM Index
LVM Z-score and LVM index were assessed by echocardiograms (ECHOs). LVM Z-Score is an indicator of degree of standard deviations from the mean in a normal distribution. The normal range for LVM Z-Score is -2 to 2. Values \<-2 or \>2 indicate abnormal LVM Z-Score. Values less than 0 (negative values) indicate a smaller LVM than mean and values higher than 0 indicate a larger LVM than the mean. 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 square meter (g/m\^2) were considered as normal and LVM index values \>=65 g/m\^2 were considered as abnormal.
Time frame: From Baseline up to 18 months
Population: Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.
Other Pre-specified
Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) Score
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 are scored as observed or not observed. Items in observed range create a motor window. When scoring, subscale scores are calculated by giving child credit (1 point) for observed items within motor window in addition to being given credit (1 point) for all of the less mature items before motor window. AIMS total score is calculated by summing scores for 58 items and ranges from 0-58, with lower score indicating less mature motor development and higher score indicating more mature motor development.
Time frame: From Baseline up to 18 months
Population: Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.
Other Pre-specified
Number of Participants With Anti-Recombinant Human Acid Alpha-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibodies at Month 18
Time frame: Month 18
Population: Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.
Other Pre-specified
Number of Participants With Recombinant Human Acid Alpha-glucosidase (rhGAA) Inhibitory Antibody at Month 18
Participants with positive anti-rhGAA IgG antibody were planned to be 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: Month 18
Population: Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.
Other Pre-specified
Number of Participants With Ventilator Use
Time frame: From Baseline up to 18 months
Population: Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.
Other Pre-specified
Overall Survival (OS)
OS was defined as the time interval from the date of first IMP administration to the date of death due to any cause.
Time frame: From randomization until death or study cut-off whichever comes earlier (up to 18 months)
Population: Data were not summarized for this exploratory outcome measure due to low number of enrollment of participants.