Immune Tolerance Study With Aldurazyme® (Laronidase)

A Trial of Antigen-specific Immune Tolerance Induction in Mucopolysaccharidosis I (MPS I) Patients Initiating Enzyme Replacement Therapy With Aldurazyme® (Laronidase)

The purpose of this study is to see if treatment with an antigen-specific immunosuppressive can decrease or stop an antibody response to laronidase (Aldurazyme®) during enzyme replacement therapy with laronidase in severe Mucopolysaccharidosis I (MPS I) participants.

Study Overview

• Status: Completed
• Conditions: Mucopolysaccharidosis I
• Intervention / Treatment: Biological: Laronidase; Drug: Cyclosporine A (CsA); Drug: Azathioprine (Aza)

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Brazil
  • Porto Alegre, Brazil
    • HCPA
• Russian Federation
  • Moscow, Russian Federation
    • Moscow Research Institute for Pediatrics and Children Surgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent is required from the parent(s) or legal guardian(s) prior to any protocol-related procedures being performed. (A separate informed consent will be requested from the parent(s) for their genotyping, which is independent of the inclusion)
• Participant's parent(s) or legal guardian(s) allow their child's participation and are willing and able to comply with trial procedures
• The participant must be up to and including 5 years of age at the time of enrollment
• Clinical diagnosis of the severe (Hurler) phenotype of MPS I
• Confirmed presence of 2 nonsense mutations in the alfa-L-iduronidase (IDUA) gene (that is, compound heterozygosity or homozygosity). For the purpose of enrollment, genotyping may be performed by a local laboratory. If no genotyping is performed by a local laboratory, a sample is collected for analysis by a central laboratory before enrollment
• Documented IDUA deficiency with fibroblast, plasma, serum, leukocyte or dried blood spot IDUA enzyme activity assay

Exclusion Criteria:

• The participant has a clinically significant organ disease including: cardiovascular, hepatic, pulmonary, neurologic, or renal disease, other serious intercurrent illness or extenuating circumstances that, in the opinion of the investigator, precludes participation in the trial or potentially decrease survival
• The participant has previously received treatment with laronidase
• The participant has known severe hypersensitivity to any excipients of the delivery solution for laronidase or to any of the other investigational drugs used in the study
• The participant has undergone a haematopoietic stem cell transplant (HSCT), regardless of outcome, or is currently under consideration for such a transplant. If a family later decides to obtain HSCT, the participant will be discontinued from the trial
• The participant has received an investigational product within the 30 days prior to enrollment
• The participant has prior treatment in any experimental protocol (for example, fibroblast injections) that might potentially induce antibodies to laronidase or might affect the interpretation of the participant's antibody response to laronidase
• The participant has received vaccination(s) within 1 month prior to enrollment, or is unwilling to postpone vaccinations during the Tolerance Induction Period in the trial
• The participant is homozygous for thiopurine methyltransferase (TPMT) deficiency, as determined by the genotype (the presence of 2 known null alleles for TPMT) or phenotype (near to complete absence of TPMT enzyme activity)
• The participant has a prior history of tuberculosis or a positive test for latent tuberculosis infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Tolerance Induction Period (TIP): Cyclosporine A (CsA) starting at 5 milligram per kilogram (mg/kg) orally three times daily until the target trough concentration of at least 350 nanogram per milliliter (ng/mL) (preferably 400 ng/mL) achieved along with azathioprine (Aza) 2.5 mg/kg/day orally. Once target CsA trough level achieved and maintained for at least 1 week, participants received laronidase 0.058 mg/kg (low-dose) once weekly intravenous (IV) infusion (starting from Day 1) up to Week 12. CsA and Aza were gradually discontinued. Immune Challenge Period (ICP): following TIP, laronidase dose increased to 0.12 mg/kg once weekly IV infusion for 1 week followed by 0.25 mg/kg once weekly IV infusion for 1 week and then 0.58 mg/kg (full-dose) once weekly IV infusion up to Week 39.	Biological: Laronidase; 0.058 mg/kg - 0.58 mg/kg IV infusion weekly.; Other Names: Aldurazyme®; Drug: Cyclosporine A (CsA); Orally three times daily.; Other Names: Neoral®; Drug: Azathioprine (Aza); Orally either every day for Cohort 1 or every other day for Cohort 2.; Other Names: Imuran®
Experimental: Cohort 2; TIP: CsA starting at 6.7 mg/kg orally three times daily until the target trough concentration of at least 350 ng/mL (preferably 400 ng/mL) achieved along with Aza 5 mg/kg orally every other day. Once target CsA trough level achieved and maintained for at least 1 week, participants received laronidase 0.058 mg/kg (low-dose) once weekly IV infusion (starting from Day 1) up to Week 18. CsA and Aza were gradually discontinued. ICP: following TIP, laronidase dose increased to 0.12 mg/kg once weekly IV infusion for 1 week followed by 0.25 mg/kg once weekly IV infusion for 1 week and then 0.58 mg/kg (full-dose) once weekly IV infusion up to Week 45.	Biological: Laronidase; 0.058 mg/kg - 0.58 mg/kg IV infusion weekly.; Other Names: Aldurazyme®; Drug: Cyclosporine A (CsA); Orally three times daily.; Other Names: Neoral®; Drug: Azathioprine (Aza); Orally either every day for Cohort 1 or every other day for Cohort 2.; Other Names: Imuran®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Achieved Immune Tolerance Induction	Immune tolerance induction success was defined as development of an anti-laronidase immunoglobulin G (IgG) antibody titer less than or equal to (<=) 1:3200 after 24 weeks of receiving full-dose (0.58 mg/kg) laronidase therapy.	24 weeks after start of full-dose laronidase therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Reduction of Urinary Glycosaminoglycan (uGAG) Level From Baseline to the End of Treatment/Early Withdrawal	Urinary Glycosaminoglycan (uGAG) Levels: concentration of glycosaminoglycan (GAG) relative to creatinine in urine. A greater decrease in uGAG level indicates a greater response.	Baseline, end of treatment/early withdrawal (up to 24 weeks after start of full-dose laronidase therapy)

Collaborators and Investigators

• Sponsor: Genzyme, a Sanofi Company
• Collaborators: BioMarin/Genzyme LLC
• Investigators: Study Director: Medical Monitor, Genzyme Europe B.V.

Publications and helpful links

General Publications

• Giugliani R, Vieira TA, Carvalho CG, Munoz-Rojas MV, Semyachkina AN, Voinova VY, Richards S, Cox GF, Xue Y. Immune tolerance induction for laronidase treatment in mucopolysaccharidosis I. Mol Genet Metab Rep. 2017 Jan 13;10:61-66. doi: 10.1016/j.ymgmr.2017.01.004. eCollection 2017 Mar.

Study record dates

Study Major Dates

• Study Start: September 1, 2008
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: August 13, 2008
• First Submitted That Met QC Criteria: August 25, 2008
• First Posted (Estimate): August 26, 2008

Study Record Updates

• Last Update Posted (Estimate): July 2, 2014
• Last Update Submitted That Met QC Criteria: June 2, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: MPS I, Mucopolysaccharidosis, Hurler syndrome
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mucopolysaccharidoses; Mucopolysaccharidosis I; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Azathioprine; Cyclosporine; Cyclosporins
• Other Study ID Numbers: ALID02307; 2007-001163-30 (EudraCT Number)