Immune Tolerance Study With Aldurazyme® (Laronidase)

This study has been completed.
Sponsor:
Collaborator:
BioMarin/Genzyme LLC
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier:
NCT00741338
First received: August 13, 2008
Last updated: June 2, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Mucopolysaccharidosis I
Biological: Laronidase
Drug: Cyclosporine A (CsA)
Drug: Azathioprine (Aza)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Trial of Antigen-specific Immune Tolerance Induction in Mucopolysaccharidosis I (MPS I) Patients Initiating Enzyme Replacement Therapy With Aldurazyme® (Laronidase)

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Number of Participants Who Achieved Immune Tolerance Induction [ Time Frame: 24 weeks after start of full-dose laronidase therapy ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Percent Reduction of Urinary Glycosaminoglycan (uGAG) Level From Baseline to the End of Treatment/Early Withdrawal [ Time Frame: Baseline, end of treatment/early withdrawal (up to 24 weeks after start of full-dose laronidase therapy) ] [ Designated as safety issue: No ]
    Urinary Glycosaminoglycan (uGAG) Levels: concentration of glycosaminoglycan (GAG) relative to creatinine in urine. A greater decrease in uGAG level indicates a greater response.


Enrollment: 7
Study Start Date: September 2008
Study Completion Date: September 2012
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Aldurazyme®
Drug: Cyclosporine A (CsA)
Orally three times daily.
Other Name: Neoral®
Drug: Azathioprine (Aza)
Orally either every day for Cohort 1 or every other day for Cohort 2.
Other Name: 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 Name: Aldurazyme®
Drug: Cyclosporine A (CsA)
Orally three times daily.
Other Name: Neoral®
Drug: Azathioprine (Aza)
Orally either every day for Cohort 1 or every other day for Cohort 2.
Other Name: Imuran®

  Eligibility

Ages Eligible for Study:   up to 5 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00741338

Locations
Brazil
HCPA
Porto Alegre, Brazil
Russian Federation
Moscow Research Institute for Pediatrics and Children Surgery
Moscow, Russian Federation
Sponsors and Collaborators
Genzyme, a Sanofi Company
BioMarin/Genzyme LLC
Investigators
Study Director: Medical Monitor Genzyme Europe B.V.
  More Information

No publications provided

Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier: NCT00741338     History of Changes
Other Study ID Numbers: ALID02307, 2007-001163-30
Study First Received: August 13, 2008
Results First Received: June 2, 2014
Last Updated: June 2, 2014
Health Authority: Brazil: National Health Surveillance Agency
Russia: Ministry of Health of Russian Federation
United States: Food and Drug Administration

Keywords provided by Sanofi:
MPS I, Mucopolysaccharidosis, Hurler syndrome

Additional relevant MeSH terms:
Mucopolysaccharidosis I
Mucopolysaccharidoses
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases
Azathioprine
Cyclosporins
Cyclosporine
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Enzyme Inhibitors
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents

ClinicalTrials.gov processed this record on July 28, 2014