Iduronate-2-sulfatase Enzyme Replacement Therapy in Mucopolysaccharidosis II (MPS II)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Shire
ClinicalTrials.gov Identifier:
NCT00069641
First received: September 29, 2003
Last updated: April 27, 2015
Last verified: January 2014
  Purpose

The purpose of this study is to determine whether the administration of iduronate-2-sulfatase enzyme in a weekly or every other week therapy frequency is safe and efficacious in patients with MPS II.


Condition Intervention Phase
Mucopolysaccharidosis II
Biological: Iduronate-2-sulfatase enzyme replacement therapy
Biological: iduronate-2-sulfatase enzyme replacement therapy
Biological: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase II/III, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Weekly and Every Other Week Dosing Regimens of Iduronate-2-Sulfatase Enzyme Replacement Therapy in Patients With MPS II

Resource links provided by NLM:


Further study details as provided by Shire:

Primary Outcome Measures:
  • Ranked Adjusted 2-Component Composite Variable Score Based on Change From Baseline to Week 53 [ Time Frame: Baseline, Week 53 ] [ Designated as safety issue: No ]
    The 2-component composite variable consists of the sum of the ranked changes from baseline to Week 53 for percent predicted Forced Vital Capacity (FVC) and 6-Minute Walking Test (6MWT) total distance walked. For the 2 treatment groups being compared, ranking occurred within the comparison treatment groups combined (idursulfase weekly and placebo treatment groups). These comparison groups were pooled and ranked for each component separately. Within each component (% predicted FVC, 6MWT), the change from baseline was then ranked. The lowest change value was assigned a rank of 1, the next lowest a rank of 2, etc. The composite score for each participant was the sum of the 2 ranked scores corresponding to the 2 individual components (% predicted FVC and 6MWT) for each participant. Thus, the greater the composite score (greater the sum of the ranks of the changes from baseline, where the lowest change was ranked as 1), the greater the improvement.


Secondary Outcome Measures:
  • Change From Baseline in Mean Global Joint Range of Motion (JROM) Score at Week 53 [ Time Frame: Baseline, Week 53 ] [ Designated as safety issue: No ]
    Change was calculated at Week 53 from baseline. Global JROM (% of normal range of motion) is the average of 11 ratios multiplied by 100. Ratios are Left/Right means of passive range of motion in Shoulder (Flexion/Extension, Abduction, Internal/External Rotation), Elbow (Flexion/Extension), Wrist (Flexion/Extension), Index Finger (Flexion/Extension [Combined Metacarpophalangeal joint (MCP), Proximal interphalangeal joint (PIP), Distal interphalangeal joint (DIP) motion]), Hip (Flexion/Extension, Abduction, Internal/External Rotation), Knee (Flexion/Extension), and Ankle (Dorsiflexion) divided by the normal range (American Academy of Orthopedic Surgeons and American Medical Association).

  • Mean Combined Liver and Spleen Volume at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI).

  • Percent Change From Baseline in Mean Combined Liver and Spleen Volume at Week 53 [ Time Frame: Baseline, Week 53 ] [ Designated as safety issue: No ]
    Liver and Spleen volume was determined by Magnetic Resonance Imaging (MRI). Change was calculated at Week 53 from baseline.

  • Change From Baseline in Mean Normalized Urine Glycosaminoglycan (GAG) Levels at Week 53 [ Time Frame: Baseline, Week 53 ] [ Designated as safety issue: No ]
    Mean normalized urine GAG was analyzed using urine testing. Change was calculated at Week 53 from baseline. The urine GAG levels were normalized to urine creatinine and were reported as microgram GAG per milligram creatinine (mcg GAG/mg creatinine).

  • Mean Cardiac Left Ventricular Mass Index (LVMI) at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Cardiac LVMI was determined by echocardiography. LVMI is the left ventricular mass (LVM, in grams [g]) indexed to body surface area (BSA), in square meter [m^2]. LVMI (in gram per square meter [g/m^2]) = LVM divided by BSA.

  • Percent Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at Week 53 [ Time Frame: Baseline, Week 53 ] [ Designated as safety issue: No ]
    Cardiac LVMI was determined by echocardiography. Change was calculated at Week 53 from baseline. LVMI is the LVM, in grams indexed to BSA, in square meter [m^2]. LVMI in g/m^2 = LVM divided by BSA.


Enrollment: 96
Study Start Date: September 2003
Study Completion Date: March 2005
Primary Completion Date: March 2005 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Idursulfase weekly (0.5 mg/kg) Biological: Iduronate-2-sulfatase enzyme replacement therapy
Patients will receive weekly infusions of idursulfase at a dose of 0.5 mg/kg.
Other Name: Elaprase
Experimental: Idursulfase every other week (0.5 mg/kg) Biological: iduronate-2-sulfatase enzyme replacement therapy
Patients will receive every other week infusions of idursulfase at a dose of 0.5 mg/kg.
Other Name: Elaprase
Placebo Comparator: Placebo Biological: Placebo
Patients will receive weekly infusions of placebo.

Detailed Description:

MPS II is a rare, X-linked, lysosomal storage disorder caused by a deficiency in the enzyme iduronate-2-sulfatase. Because of this deficiency, glycosaminoglycans (GAG) accumulate in multiple tissues and organs, resulting in progressive cellular and organ system dysfunction. The purpose of this study is to determine if one year of therapy with iduronate-2-sulfatase enzyme replacement therapy, at a dose of 0.5mg/kg, weekly or every other week, is safe, and results in clinically meaningful improvement in multiple organ function, compared with a placebo group. Upon completion of the study, patients will be eligible to enroll in an open-label maintenance study.

  Eligibility

Ages Eligible for Study:   5 Years to 25 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

To be eligible to participate in this study, patients must meet the following inclusion criteria prior to enrollment:

  1. The diagnosis of MPS II will be determined by the investigator based upon both clinical and biochemical criteria.
  2. All patients must have at least one of the following Clinical Criteria considered by the investigator to be MPS II-related:

    • Hepatosplenomegaly
    • Radiographic evidence of dysostosis multiplex
    • Valvular heart disease
    • Evidence of obstructive pulmonary disease
  3. In addition, patients must have the following Biochemical Criteria:

    • Documented deficiency in iduronate-2-sulfastase enzyme activity of less than or equal to 10% of the lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory).
    • A normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory).
  4. Must be male, 5 to 25 years of age.
  5. Forced vital capacity of <80% of predicted obtained at the baseline evaluation of this study.
  6. Must be able to adequately perform the testing required in this study, including reproducible pulmonary function testing by spirometry, as judged by the investigator.
  7. Patient, patient's parent(s), or legally authorized guardian must have voluntarily signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient.

Exclusion Criteria:

Patients meeting any of the following criteria are not eligible for participation in this study:

  1. Patient has received treatment with another investigational therapy within the past 60 days.
  2. Patient, patient's parent(s), or patient's legal guardian is unable to understand the nature, scope, and possible consequences of the study.
  3. Patient is unable to comply with the protocol (e.g., due to a medical condition such as cervical cord compression or uncooperative attitude) or is unlikely to complete the study, as determined by the investigator.
  4. Patient has a tracheostomy.
  5. Patient has received a bone marrow or cord blood transplant.
  6. Patient with known hypersensitivity to any of the components of iduronate-2-sulfatase.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00069641

Locations
United States, California
Children's Hospital Oakland
Oakland, California, United States, 94609
United States, Missouri
St. Louis Children's Hospital, Washington University
St. Louis, Missouri, United States, 63110
United States, North Carolina
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27599
United States, Texas
Texas Children's Hospital, Baylor College of Medicine
Houston, Texas, United States, 77030
Brazil
Hospital de Clinicas de Porto Alegre
Porto Alegre, Brazil
Germany
Children's Hospital, Johannes-Gutenburg Universitaet Mainz
Mainz, Germany
United Kingdom
Addenbrooke's Hospital
Cambridge, England, United Kingdom, CB2 2QQ
Great Ormond Street Hospital for Sick Children
London, England, United Kingdom, WC1N3JH
Royal Manchester Children's Hospital
Manchester, England, United Kingdom, M27 4HA
Sponsors and Collaborators
Shire
Investigators
Principal Investigator: Joseph Muenzer, MD, PhD University of North Carolina, Chapel Hill
Principal Investigator: Rick A. Martin, MD St. Louis Children's Hospital, Washington University
Principal Investigator: Paul Harmatz, MD Children's Hospital & Research Center Oakland
Principal Investigator: Christine Eng, MD Texas Children's Hospital, Baylor College of Medicine
Principal Investigator: Michael Beck, MD, PhD Children's Hospital, Johannes-Gutenburg Universitaet Mainz
Principal Investigator: Roberto Giugliani, MD, PhD Hospital de Clinicas de Porto Alegre
Principal Investigator: Ashok Vellodi, MD Great Ormond Street Hospital for Sick Children
Principal Investigator: Edmund Wraith, MD Royal Manchester Children's Hospital
Principal Investigator: Uma Ramaswami, MD Cambridge University Hospitals NHS Foundation Trust
  More Information

No publications provided by Shire

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT00069641     History of Changes
Other Study ID Numbers: TKT024
Study First Received: September 29, 2003
Results First Received: January 16, 2014
Last Updated: April 27, 2015
Health Authority: United States: Food and Drug Administration
Brazil: National Health Surveillance Agency
Germany: Federal Institute for Drugs and Medical Devices
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Shire:
Mucopolysaccharidosis II
MPS II
Hunter Syndrome
iduronate-2-sulfatase
I2S
Iduronate-2-sulfatase deficiency

Additional relevant MeSH terms:
Mucopolysaccharidosis II
Mucopolysaccharidoses
Carbohydrate Metabolism, Inborn Errors
Connective Tissue Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Heredodegenerative Disorders, Nervous System
Intellectual Disability
Lysosomal Storage Diseases
Mental Retardation, X-Linked
Metabolic Diseases
Metabolism, Inborn Errors
Mucinoses
Nervous System Diseases
Neurobehavioral Manifestations
Neurologic Manifestations

ClinicalTrials.gov processed this record on July 01, 2015