A Study Evaluating the Safety and Pharmacokinetics of Aldurazyme® (Laronidase) in MPS I Patients Less Than 5 Years Old

A Phase II Open-Label Clinical Trial of Recombinant Human Alpha-L-iduronidase (Aldurazyme®) to Evaluate the Safety and Pharmacokinetics in Mucopolysaccharidosis I (MPS I) Patients Less Than 5 Years Old

The main objectives of this study are to evaluate the safety and pharmacokinetics (PK) of enzyme replacement therapy with recombinant human alpha-L-iduronidase [Aldurazyme® (laronidase)] in mucopolysaccharidosis I (MPS I) patients less than 5 years old. Efficacy measurements will also be evaluated in this study.

Study Overview

• Status: Completed
• Conditions: Mucopolysaccharidosis I; Scheie Syndrome; Hurler Syndrome; Hurler-Scheie Syndrome
• Intervention / Treatment: Biological: Aldurazyme (Recombinant Human Alpha-L-Iduronidase); Biological: Aldurazyme (Recombinant Human Alpha-L-Iduronidase)

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Lyon, France
    • Hôpital E. Herriot
• Germany
  • Mainz
    • Kinderklinik, Mainz, Germany
      • Johannes Gutenberg Universität
• Netherlands
  • Rotterdam, Netherlands
    • Sophia Children's Hospital
• United Kingdom
  • Manchester, United Kingdom
    • Willink Biochemical Genetics Unit Royal Hospital for Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.)
• Be less than 5 years of age at the time of enrollment.
• Have confirmed iduronidase deficiency with a fibroblast or leukocyte alpha-L-iduronidase enzyme activity level of less than 10.0 % of the lower limit of the normal range, or below the detection range of the measuring laboratory.
• Have a clinical diagnosis of MPS I based on genotyping.
• Documentation in his/her medical record that the parent(s) or legal guardian(s) have had counseling or a consultation regarding HSCT in order to assure that the parent(s) or legal guardian(s) are fully informed regarding the risks and benefits of this alternative treatment for patients eligible for the trial and with the severe manifestations of MPS I with neurodegeneration.

Exclusion Criteria:

• The patient is under consideration for or has undergone hematopoietic stem cell transplantation (HSCT).
• The patient has acute hydrocephalus at the time of enrollment.
• The patient has a clinically significant organic disease (with the exception of symptoms relating to MPS I) including: cardiovascular, hepatic, pulmonary, neurologic, or renal disease, other serious intercurrent illness, or extenuating circumstances that, in the opinion of the Investigator, would preclude participation in the trial or potentially decrease survival.
• The patient has received any investigational product within 30 days prior to trial enrollment.
• The patient has known severe hypersensitivity to Aldurazyme® (laronidase) or components of the delivery solution.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aldurazyme (rhIDU) 100 U/kg ONLY every week; Patients received Aldurazyme (recombinant human alpha-L-iduronidase (rhIDU)) once per week at a dose of 100 Units/kg (approximately 0.58 mg/kg) for up to 52 weeks - labeled dose.	Biological: Aldurazyme (Recombinant Human Alpha-L-Iduronidase); 100 U/kg every week; Biological: Aldurazyme (Recombinant Human Alpha-L-Iduronidase); 200 U/kg every week (Week 26 onwards)
Experimental: Aldurazyme (rhIDU) 100-200 U/kg every week; After receiving 100 Units/kg dose of Aldurazyme (rhIDU) for the first 25 weeks, patients enrolling after January 1, 2004 were eligible to receive an increased dose of 200 Units/kg from Week 26 onwards if the patient's urinary glycosaminoglycan (uGAG) levels were >200µg/mg creatinine at Week 22.	Biological: Aldurazyme (Recombinant Human Alpha-L-Iduronidase); 100 U/kg every week; Biological: Aldurazyme (Recombinant Human Alpha-L-Iduronidase); 200 U/kg every week (Week 26 onwards)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Evaluation	Overall Safety Summary of Adverse Events (AEs) during Treatment Safety assessment was based on the incidence of AE reports.	52 weeks
Pharmacokinetics - Area Under the (Plasma Concentration-time) Curve (AUC∞)	AUC∞ is a measure of the total exposure to a drug.	52 weeks
Pharmacokinetics - Elimination Half Life (t1/2)	Half-life is the time it takes for the concentration of drug in plasma to decline by 50%.	52 weeks
Pharmacokinetics - Total Plasma Clearance (CL)	CL is volume of the body fluid cleared of the drug per unit of time.	52 weeks
Pharmacokinetics - Volume of Distribution (Vz)	Vz is the volume that relates the amount of drug in the body after absorption is complete to the concentration of drug in the plasma.	52 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline to Week 52 in Urinary Glycosaminoglycan (uGAG) Level	Percentage change in the concentration of GAG relative to creatinine (ug GAG/mg creatinine) in urine from Baseline to Week 52; A greater decrease in percent change indicates a greater response.	Baseline to 52 weeks
Percent Change From Baseline to Week 52 in Liver Size (Hepatomegaly)	Percent change in extent of Liver Edge Below Right Costal Margin (BRCM) measured in centimeters from Baseline to Week 52; A greater decrease in percent change indicates a greater response.	Baseline to 52 weeks
Change From Baseline to Week 52 in Apnea/Hypopnea Index (AHI)	Number of absent (apnea) and shallow (hypopnea) breaths per hour of sleep. A greater decrease in events per hour indicates a greater response.	Baseline to 52 weeks
Expert Global Assessment of Sleep Study Results at Week 52 Compared With Baseline	Independent experts provided a global assessment for each sleep study visit as well as the degree of clinically meaningful change over the course of the study. Assessment was based on AHI, severity and frequency of oxygen desaturations and sleep quality.	Baseline to 52 weeks
Change From Baseline to Week 52 in Left Ventricular Mass (LVM) Z-Score	Change in LVM Z-scores as measured by echocardiography from Baseline to Week 52. Z-score=number of standard deviations from mean. Z-scores greater than +2 and less than -2 are abnormal. A greater decrease in abnormally high z-score indicates a greater response.	Baseline to 52 weeks
Change From Baseline to Week 52 in Height	Change in Z-scores for standing height/lying-length-for-age from Baseline to Week 52. Z-score=number of standard deviations from mean. Z-scores greater than +2 and less than -2 are abnormal. A greater decrease in abnormally high z-score indicates a greater response.	Baseline to 52 weeks
Investigator's Clinical Assessment at Week 52 Compared With Baseline	The Investigator's impression of the patient's overall clinical status at Week 52 compared with Baseline.	Baseline to 52 weeks

Collaborators and Investigators

• Sponsor: Genzyme, a Sanofi Company
• Collaborators: BioMarin/Genzyme LLC

Study record dates

Study Major Dates

• Study Start: October 1, 2002
• Primary Completion (Actual): May 1, 2005
• Study Completion (Actual): May 1, 2005

Study Registration Dates

• First Submitted: September 2, 2005
• First Submitted That Met QC Criteria: September 2, 2005
• First Posted (Estimate): September 7, 2005

Study Record Updates

• Last Update Posted (Estimate): April 3, 2015
• Last Update Submitted That Met QC Criteria: March 17, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Disease; Genetic Diseases, Inborn; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Syndrome; Mucopolysaccharidoses; Mucopolysaccharidosis I
• Other Study ID Numbers: ALID-014-02