Immune Tolerance Induction Study

Genzyme

Status and phase: Terminated; Phase 4

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

Treatments: Biological: Myozyme® (alglucosidase alfa)

Study type: Interventional

Funder types: Industry

Identifiers

NCT00701701

AGLU03707 (Other Identifier)

MSC12817

2015-000583-34 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 4 patients

Sex: All

Ages: 1+ month old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

4 participants in 2 patient groups

Regimen A: Alglucosidase alfa and Cyclophosphamide

Experimental group

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.

Treatment:

Biological: Myozyme® (alglucosidase alfa)

Biological: Myozyme® (alglucosidase alfa)

Regimen B: Alglucosidase alfa, Rituximab and Methotrexate

Experimental group

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.

Treatment:

Biological: Myozyme® (alglucosidase alfa)

Biological: Myozyme® (alglucosidase alfa)