Back to resultsImmune Tolerance Induction Study
Primary Purpose
Pompe Disease, Glycogen Storage Disease Type II (GSD-II), Glycogenesis 2 Acid Maltase Deficiency
Status
Terminated
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
Myozyme® (alglucosidase alfa)
Myozyme® (alglucosidase alfa)
Sponsored by
About this trial
This is an interventional treatment trial for Pompe Disease
Eligibility Criteria
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.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Regimen A: Alglucosidase alfa and Cyclophosphamide
Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
Arm Description
Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high recombinant human acid alpha-glucosidase (rhGAA) antibody titer (defined as at least 2 titers greater than or equal to [>=] 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®) Intravenous (IV) infusion of 20 milligram per kilogram (mg/kg) every other week (qow) for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was less than [<6] months of age at the time of enrollment). In addition, cyclophosphamide 250 milligram per square meter (mg/m^2) IV infusion was administered every 4 weeks (q4w) after Myozyme® infusion for 6 months.
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Full Information
NCT ID
NCT00701701
First Posted
June 17, 2008
Last Updated
March 24, 2022
Sponsor
Genzyme, a Sanofi Company
1. Study Identification
Unique Protocol Identification Number
NCT00701701
Brief Title
Immune Tolerance Induction Study
Official Title
An Exploratory Study of the Safety and Efficacy of Immune Tolerance Induction (ITI) in Patients With Pompe Disease Who Have Previously Received Myozyme
Study Type
Interventional
2. Study Status
Record Verification Date
March 2022
Overall Recruitment Status
Terminated
Why Stopped
Study was conducted to fulfill a post marketing commitment (PMC 6). FDA acknowledged fulfillment of PMC.
Study Start Date
December 14, 2008 (Actual)
Primary Completion Date
February 18, 2020 (Actual)
Study Completion Date
February 18, 2020 (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
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.
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
Non-Randomized
Enrollment
4 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Regimen A: Alglucosidase alfa and Cyclophosphamide
Arm Type
Experimental
Arm Description
Participants exhibiting clinical decline since starting alglucosidase alfa (Myozyme®) therapy and having inhibitory antibodies and/or a sustained high recombinant human acid alpha-glucosidase (rhGAA) antibody titer (defined as at least 2 titers greater than or equal to [>=] 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®) Intravenous (IV) infusion of 20 milligram per kilogram (mg/kg) every other week (qow) for a minimum of 18 months or, until the participant reached the age of 2 years (if the participant was less than [<6] months of age at the time of enrollment). In addition, cyclophosphamide 250 milligram per square meter (mg/m^2) IV infusion was administered every 4 weeks (q4w) after Myozyme® infusion for 6 months.
Arm Title
Regimen B: Alglucosidase alfa, Rituximab and Methotrexate
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Myozyme® (alglucosidase alfa)
Other Intervention Name(s)
Myozyme®
Intervention Description
Myozyme®: IV infusion of 20 mg/kg qow; Cyclophosphamide: 250 mg/m^2 IV q4w after Myozyme infusion for 6 months.
Intervention Type
Biological
Intervention Name(s)
Myozyme® (alglucosidase alfa)
Other Intervention Name(s)
Myozyme®
Intervention Description
Myozyme®: IV infusion of 20 mg/kg qow; Rituximab: 375 mg/m^2 IV weekly beginning the day after Myozyme infusion for 4 weeks (an optional additional 2nd cycle could be administered at the discretion of the investigator); Methotrexate: 15 mg/m^2 subcutaneous qow on the day after Myozyme infusion for 6 months.
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description
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
Other Pre-specified Outcome Measures:
Title
Number of Participants With Anti-Recombinant Human Acid Alpha-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibodies at Month 18
Time Frame
Month 18
Title
Number of Participants With Recombinant Human Acid Alpha-glucosidase (rhGAA) Inhibitory Antibody at Month 18
Description
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
Title
Overall Survival (OS)
Description
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)
Title
Number of Participants With Ventilator Use
Time Frame
From Baseline up to 18 months
Title
Left Ventricular Mass (LVM) Z-Score and LVM Index
Description
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
Title
Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) Score
Description
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
Title
Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) Score
Description
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
Title
Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Score
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Month
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
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
Louisville
State/Province
Kentucky
Country
United States
City
Durham
State/Province
North Carolina
Country
United States
City
Salt Lake City
State/Province
Utah
Country
United States
City
Norfolk
State/Province
Virginia
Country
United States
City
Haifa
Country
Israel
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org
Learn more about this trial
Immune Tolerance Induction Study
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