Mucopolysaccharidosis I
Conditions
Keywords
MPS I, Mucopolysaccharidosis, Hurler syndrome
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.
Interventions
BIOLOGICALLaronidase
0.058 mg/kg - 0.58 mg/kg IV infusion weekly.
Orally three times daily.
Orally either every day for Cohort 1 or every other day for Cohort 2.
Sponsors
BioMarin/Genzyme LLC
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 5 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Immune Tolerance Induction | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Urinary Glycosaminoglycan (uGAG) Levels: concentration of glycosaminoglycan (GAG) relative to creatinine in urine. A greater decrease in uGAG level indicates a greater response. |
Countries
Brazil, Russia
Participant flow
Recruitment details
The study was conducted at 2 centers in Brazil and Russia between September 2008 and September 2013.
Pre-assignment details
A total of 7 participants were enrolled, 3 in Cohort 1 and 4 in Cohort 2. Of the 4 participants enrolled in Cohort 2, one participant was screen failure.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 3 |
| 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. | 4 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Total |
|---|---|---|---|
| Age, Continuous | 2.60 years | 3.77 years | 3.18 years |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 |
Outcome results
Primary
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.
Time frame: 24 weeks after start of full-dose laronidase therapy
Population: Safety population included all participants who received any study drug treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants Who Achieved Immune Tolerance Induction | 0 participants |
| Cohort 2 | Number of Participants Who Achieved Immune Tolerance Induction | 1 participants |
Secondary
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.
Time frame: Baseline, end of treatment/early withdrawal (up to 24 weeks after start of full-dose laronidase therapy)
Population: Safety population included all participants who received any study drug treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Percent Reduction of Urinary Glycosaminoglycan (uGAG) Level From Baseline to the End of Treatment/Early Withdrawal | -43.80 percent change in uGAG level |
| Cohort 2 | Percent Reduction of Urinary Glycosaminoglycan (uGAG) Level From Baseline to the End of Treatment/Early Withdrawal | -72.50 percent change in uGAG level |