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Immune Tolerance Study With Aldurazyme® (Laronidase)

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ClinicalTrials.gov Identifier: NCT00741338
Recruitment Status : Completed
First Posted : August 26, 2008
Results First Posted : July 2, 2014
Last Update Posted : July 2, 2014
Sponsor:
Collaborator:
BioMarin/Genzyme LLC
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )

Tracking Information
First Submitted Date  ICMJE August 13, 2008
First Posted Date  ICMJE August 26, 2008
Results First Submitted Date  ICMJE June 2, 2014
Results First Posted Date  ICMJE July 2, 2014
Last Update Posted Date July 2, 2014
Study Start Date  ICMJE September 2008
Actual Primary Completion Date September 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 2, 2014)
Number of Participants Who Achieved Immune Tolerance Induction [ Time Frame: 24 weeks after start of full-dose laronidase therapy ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 25, 2008)
Antibody titer to laronidase less than or equal to 1:3200 [ Time Frame: 24 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 2, 2014)
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) ]
Urinary Glycosaminoglycan (uGAG) Levels: concentration of glycosaminoglycan (GAG) relative to creatinine in urine. A greater decrease in uGAG level indicates a greater response.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 25, 2008)
Mean uGAG reduction [ Time Frame: 39 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Immune Tolerance Study With Aldurazyme® (Laronidase)
Official Title  ICMJE A Trial of Antigen-specific Immune Tolerance Induction in Mucopolysaccharidosis I (MPS I) Patients Initiating Enzyme Replacement Therapy With Aldurazyme® (Laronidase)
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Mucopolysaccharidosis I
Intervention  ICMJE
  • 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®
Study Arms  ICMJE
  • 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.
    Interventions:
    • Biological: Laronidase
    • Drug: Cyclosporine A (CsA)
    • Drug: Azathioprine (Aza)
  • 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.
    Interventions:
    • Biological: Laronidase
    • Drug: Cyclosporine A (CsA)
    • Drug: Azathioprine (Aza)
Publications * Giugliani R, Vieira TA, Carvalho CG, Muñoz-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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 2, 2014)
7
Original Estimated Enrollment  ICMJE
 (submitted: August 25, 2008)
18
Actual Study Completion Date  ICMJE September 2012
Actual Primary Completion Date September 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 5 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil,   Russian Federation
Removed Location Countries Ukraine
 
Administrative Information
NCT Number  ICMJE NCT00741338
Other Study ID Numbers  ICMJE ALID02307
2007-001163-30 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sanofi ( Genzyme, a Sanofi Company )
Study Sponsor  ICMJE Genzyme, a Sanofi Company
Collaborators  ICMJE BioMarin/Genzyme LLC
Investigators  ICMJE
Study Director: Medical Monitor Genzyme Europe B.V.
PRS Account Sanofi
Verification Date June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP