Immune Tolerance Study With Aldurazyme® (Laronidase)

NCT00741338 | Completed Phase 1 Results DMC

• 2 other identifiers: ALID023072007-001163-30
• Study Type: interventional
• Target: 7
• Locations: 2 countries
• Sites: 2

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.

Conditions

Mucopolysaccharidosis I

Keywords

MPS I, Mucopolysaccharidosis, Hurler syndrome

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Percent Reduction of Urinary Glycosaminoglycan (uGAG) Level From Baseline to the End of Treatment/Early Withdrawal

  Baseline, end of treatment/early withdrawal (up to 24 weeks after start of full-dose laronidase therapy)

Study Arms (2)

Cohort 1

EXPERIMENTAL

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; Drug: Cyclosporine A (CsA); Drug: Azathioprine (Aza)

Cohort 2

EXPERIMENTAL

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; Drug: Cyclosporine A (CsA); Drug: Azathioprine (Aza)

Interventions

Laronidase BIOLOGICAL

0.058 mg/kg - 0.58 mg/kg IV infusion weekly.

Also known as: Aldurazyme®

Cohort 1; Cohort 2

Cyclosporine A (CsA) DRUG

Orally three times daily.

Also known as: Neoral®

Cohort 1; Cohort 2

Azathioprine (Aza) DRUG

Orally either every day for Cohort 1 or every other day for Cohort 2.

Also known as: Imuran®

Cohort 1; Cohort 2

Eligibility Criteria

• Age: Up to 5 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead
• BioMarin/Genzyme LLC: collaborator

Study Sites (2)

HCPA

Porto Alegre, Brazil

Location

Moscow Research Institute for Pediatrics and Children Surgery

Moscow, Russia

Location

Related Publications (1)

• 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.

  PMID: 28119821 DERIVED

MeSH Terms

Conditions

Mucopolysaccharidosis I; Mucopolysaccharidoses

Interventions

Iduronidase; Cyclosporine; Azathioprine

Condition Hierarchy (Ancestors)

Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Glycoside Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Thionucleosides; Sulfur Compounds; Organic Chemicals; Mercaptopurine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Limitations and Caveats

Study was discontinued on September 10,2013 due to changing standards of care for this population, practical infeasibility of routinely monitoring plasma CsA in clinical setting, inconclusive results of interim analysis and not due to safety concern.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi

Contact-us@sanofi.com

Study Officials

• Medical Monitor

  Genzyme Europe B.V.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 13, 2008
• First Posted: August 26, 2008
• Study Start: September 1, 2008
• Primary Completion: September 1, 2012
• Study Completion: September 1, 2012
• Last Updated: July 2, 2014
• Results First Posted: July 2, 2014

Record last verified: 2014-06

Locations

BR (1); RU (1)