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Immune Tolerance Induction Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00701701
Recruitment Status : Terminated (Study was conducted to fulfill a post marketing commitment (PMC 6). FDA acknowledged fulfillment of PMC.)
First Posted : June 19, 2008
Results First Posted : October 12, 2020
Last Update Posted : April 7, 2022
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )

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.

Condition or disease Intervention/treatment Phase
Pompe Disease Glycogen Storage Disease Type II (GSD-II) Glycogenesis 2 Acid Maltase Deficiency Biological: Myozyme® (alglucosidase alfa) Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 14, 2008
Actual Primary Completion Date : February 18, 2020
Actual Study Completion Date : February 18, 2020


Arm Intervention/treatment
Experimental: 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 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.
Biological: Myozyme® (alglucosidase alfa)
Myozyme®: IV infusion of 20 mg/kg qow; Cyclophosphamide: 250 mg/m^2 IV q4w after Myozyme infusion for 6 months.
Other Name: Myozyme®

Experimental: 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.
Biological: Myozyme® (alglucosidase alfa)
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.
Other Name: Myozyme®




Primary Outcome Measures :
  1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: 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 Outcome Measures:
  1. Number of Participants With Anti-Recombinant Human Acid Alpha-glucosidase (Anti-rhGAA) Immunoglobulin G (IgG) Antibodies at Month 18 [ Time Frame: Month 18 ]
  2. Number of Participants With Recombinant Human Acid Alpha-glucosidase (rhGAA) Inhibitory Antibody at Month 18 [ Time Frame: 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.

  3. Overall Survival (OS) [ Time Frame: 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.

  4. Number of Participants With Ventilator Use [ Time Frame: From Baseline up to 18 months ]
  5. Left Ventricular Mass (LVM) Z-Score and LVM Index [ Time Frame: 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.

  6. Gross Motor Disability Assessed by Gross Motor Function Measure-88 (GMFM-88) Score [ Time Frame: 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.

  7. Motor Development Status Assessed by Alberta Infantile Motor Scale (AIMS) Score [ Time Frame: 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.

  8. Disability Index Assessed by the Pompe Pediatric Evaluation of Disability Inventory (Pompe PEDI) Score [ Time Frame: 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.



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Ages Eligible for Study:   1 Month and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00701701


Locations
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United States, Kentucky
Louisville, Kentucky, United States
United States, North Carolina
Durham, North Carolina, United States
United States, Utah
Salt Lake City, Utah, United States
United States, Virginia
Norfolk, Virginia, United States
Israel
Haifa, Israel
Sponsors and Collaborators
Genzyme, a Sanofi Company
Investigators
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Study Director: Medical Monitor Genzyme, a Sanofi Company
  Study Documents (Full-Text)

Documents provided by Sanofi ( Genzyme, a Sanofi Company ):
Study Protocol  [PDF] October 1, 2009
Statistical Analysis Plan  [PDF] January 23, 2012

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Responsible Party: Genzyme, a Sanofi Company
ClinicalTrials.gov Identifier: NCT00701701    
Other Study ID Numbers: MSC12817
AGLU03707 ( Other Identifier: Genzyme Corporation )
2015-000583-34 ( EudraCT Number )
First Posted: June 19, 2008    Key Record Dates
Results First Posted: October 12, 2020
Last Update Posted: April 7, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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
Additional relevant MeSH terms:
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Glycogen Storage Disease Type II
Glycogen Storage Disease
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Carbohydrate Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases