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Immune Tolerance Study With Aldurazyme® (Laronidase)

Primary Purpose

Mucopolysaccharidosis I

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Laronidase
Cyclosporine A (CsA)
Azathioprine (Aza)
Sponsored by
Genzyme, a Sanofi Company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mucopolysaccharidosis I focused on measuring MPS I, Mucopolysaccharidosis, Hurler syndrome

Eligibility Criteria

undefined - 5 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • HCPA
  • Moscow Research Institute for Pediatrics and Children Surgery

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Cohort 1

Cohort 2

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

First Posted
August 13, 2008
Last Updated
June 2, 2014
Sponsor
Genzyme, a Sanofi Company
Collaborators
BioMarin/Genzyme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT00741338
Brief Title
Immune Tolerance Study With Aldurazyme® (Laronidase)
Official Title
A Trial of Antigen-specific Immune Tolerance Induction in Mucopolysaccharidosis I (MPS I) Patients Initiating Enzyme Replacement Therapy With Aldurazyme® (Laronidase)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2014
Overall Recruitment Status
Completed
Study Start Date
September 2008 (undefined)
Primary Completion Date
September 2012 (Actual)
Study Completion Date
September 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Genzyme, a Sanofi Company
Collaborators
BioMarin/Genzyme LLC

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mucopolysaccharidosis I
Keywords
MPS I, Mucopolysaccharidosis, Hurler syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Laronidase
Other Intervention Name(s)
Aldurazyme®
Intervention Description
0.058 mg/kg - 0.58 mg/kg IV infusion weekly.
Intervention Type
Drug
Intervention Name(s)
Cyclosporine A (CsA)
Other Intervention Name(s)
Neoral®
Intervention Description
Orally three times daily.
Intervention Type
Drug
Intervention Name(s)
Azathioprine (Aza)
Other Intervention Name(s)
Imuran®
Intervention Description
Orally either every day for Cohort 1 or every other day for Cohort 2.
Primary Outcome Measure Information:
Title
Number of Participants Who Achieved Immune Tolerance Induction
Description
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.
Time Frame
24 weeks after start of full-dose laronidase therapy
Secondary Outcome Measure Information:
Title
Percent Reduction of Urinary Glycosaminoglycan (uGAG) Level From Baseline to the End of Treatment/Early Withdrawal
Description
Urinary Glycosaminoglycan (uGAG) Levels: concentration of glycosaminoglycan (GAG) relative to creatinine in urine. A greater decrease in uGAG level indicates a greater response.
Time Frame
Baseline, end of treatment/early withdrawal (up to 24 weeks after start of full-dose laronidase therapy)

10. Eligibility

Sex
All
Maximum Age & Unit of Time
5 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Genzyme Europe B.V.
Official's Role
Study Director
Facility Information:
Facility Name
HCPA
City
Porto Alegre
Country
Brazil
Facility Name
Moscow Research Institute for Pediatrics and Children Surgery
City
Moscow
Country
Russian Federation

12. IPD Sharing Statement

Citations:
PubMed Identifier
28119821
Citation
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.
Results Reference
derived

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Immune Tolerance Study With Aldurazyme® (Laronidase)

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