Immune Tolerance Induction Study

Study Overview
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Brief Summary
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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.

Official Title
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An Exploratory Study of the Safety and Efficacy of Immune Tolerance Induction (ITI) in Patients With Pompe Disease Who Have Previously Received Myozyme

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

Intervention / Treatment
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* Biological: Myozyme® (alglucosidase alfa)
* Biological: Myozyme® (alglucosidase alfa)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Month

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen A: Alglucosidase alfa and Cyclophosphamide<br>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)<br>* Myozyme®: IV infusion of 20 mg/kg qow; Cyclophosphamide: 250 mg/m^2 IV q4w after Myozyme infusion for 6 months.<br>* Other names: Myozyme®;|
| Experimental: Regimen B: Alglucosidase alfa, Rituximab and Methotrexate<br>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)<br>* 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.<br>* Other names: Myozyme®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From Baseline up to 18 months |