Safety and Clinical Outcomes in Hunter Syndrome Patients 5 Years of Age and Younger Receiving Idursulfase Therapy

• ClinicalTrials.gov Identifier: NCT00607386
• Recruitment Status: Completed
• First Posted: February 5, 2008
• Results First Posted: November 7, 2013
• Last Update Posted: October 28, 2015
• Sponsor: Shire
• Collaborators: Covance; PharmaNet; PRA Health Sciences
• Information provided by (Responsible Party): Shire

Study Description

Brief Summary:

The objective of this study is to determine the safety of once weekly dosing of idursulfase 0.5 mg/kg administered by intravenous (IV) infusion for male Hunter syndrome patients ≤ 5 years old.

Condition or disease	Intervention/treatment	Phase
Hunter Syndrome; Mucopolysaccharidosis II; MPS II	Biological: Idursulfase	Phase 4

Detailed Description:

This study will provide a basis for evaluating the safety of idursulfase administered to Hunter syndrome patients who are ≤ 5 years old. Additionally, this study will provide a basis for evaluating the idursulfase single- and repeated-dose pharmacokinetic profiles as well as the pharmacodynamic effect (as measured by urinary GAG excretion) in this pediatric population. Additional exploratory measures will include abdominal ultrasound measurements of liver and spleen volumes, assessments of growth with comparisons to normal population growth data, assessments of annualized growth velocity, assessments of routine developmental milestones using the Denver II, and assessments of clinical events, including the first occurrence of certain hearing-related events (e.g., hearing loss, otitis media), respiratory-related events (e.g., upper and lower respiratory infections), and specific surgical procedures (e.g., adenoidectomy, placement of PE tubes).

All patients in this open-label study will receive once-weekly infusions of idursulfase at a dose of 0.5 mg/kg.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 28 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-Center, Open-Label Study Evaluating Safety and Clinical Outcomes in Hunter Syndrome Patients 5 Years of Age and Younger Receiving Idursulfase Enzyme Replacement Therapy
• Study Start Date: December 2007
• Actual Primary Completion Date: July 2011
• Actual Study Completion Date: July 2011

Arms and Interventions

Arm	Intervention/treatment
Idursulfase; Open-label treatment with idursulfase	Biological: Idursulfase; Solution for intravenous infusion, 0.5 mg/kg weekly; Other Name: Elaprase

Outcome Measures

Primary Outcome Measures :

1. Safety Evaluation [ Time Frame: From the start of study treatment until 30 days after the last infusion of idursulfase, up to 53 weeks ]
   An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Number of participants with AEs occurred after start of study treatment until 30 days after the last infusion of idursulfase, were reported.

Secondary Outcome Measures :

1. Mean Change From Baseline to Week 53 in Normalized Urinary Glycosaminoglycan (GAG) Levels [ Time Frame: Baseline, Weeks 18, 36 and 53 ]
   Analysis of urinary GAG levels was performed at baseline, Week 18, Week 36, and Week 53 as an assessment of the pharmacodynamic effects of Elaprase (idursulfase).
2. Single- and Repeat-Dose Pharmacokinetics - Maximum Observed Serum Concentration (Cmax) [ Time Frame: Weeks 1 and 27 ]
3. Single- and Repeat-Dose Pharmacokinetics - Time of Maximum Observed Serum Concentration (Tmax) [ Time Frame: Weeks 1 and 27 ]
4. Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve From Time 0 to the Final Time Point With a Concentration of at Least Lower Limit of Quantitation (AUClast) [ Time Frame: Weeks 1 and 27 ]
5. Single- and Repeat-Dose Pharmacokinetics - Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) [ Time Frame: Weeks 1 and 27 ]
6. Single- and Repeat-Dose Pharmacokinetics - Elimination Half-Life (t1/2) [ Time Frame: Weeks 1 and 27 ]
   t1/2 refers to the elimination of the drug. It is the time taken for the blood plasma concentration to reach half the concentration in the terminal phase of elimination. It is expressed in minutes and derived from the terminal slope of the concentration versus time curve.
7. Single- and Repeat-Dose Pharmacokinetics - Mean Residence Time From Time 0 to Infinity (MRTinf) [ Time Frame: Weeks 1 and 27 ]
   MRTinf is an average duration of the drug in the body from time zero to infinity, and is expressed in minutes.
8. Single- and Repeat-Dose Pharmacokinetics - Clearance (CL) [ Time Frame: Weeks 1 and 27 ]
   Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
9. Single- and Repeat-Dose Pharmacokinetics - Volume of Distribution at Steady State (Vss) [ Time Frame: Weeks 1 and 27 ]
   Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steadystate.

Eligibility Criteria

• Ages Eligible for Study: up to 5 Years (Child)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• The patient has a diagnosis of Hunter syndrome based upon biochemical criteria either documented in their medical history or established at Screening:

  1. A deficiency in iduronate-2-sulfatase (I2S) enzyme activity of ≤ 10 % of the lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory)

     AND

  2. A normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory).
• The patient is 5 years of age and under.
• The patient is male.
• The patient's parent(s), or patient's legal guardian must have voluntarily signed an Institutional Review Board approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient's parent(s), or the patient's legal guardian.

Exclusion Criteria:

• The patient has received treatment with another investigational therapy within 30 days prior to enrollment.
• The patient has clinically relevant medical condition(s) making implementation of the protocol difficult.
• The patient has previously received idursulfase.
• The patient has known hypersensitivity to any of the components of idursulfase.
• The patient has had a tracheostomy.

Contacts and Locations

Locations

Brazil

Hospital de Clinicas de Porto Alegre, Servico de Genetica Medica

Porto Alegre, RS, Brazil, 90035-903

Poland

Instytut Pomnik Centrum Zdrowia Dziecka, Klinika Chorob Metaboliczynch, Endokrynologii i Diabetologii

Warsaw, Poland, 04-730

Taiwan

National Taiwan University Hospital, Dept. of Pediatrics and Medical Genetics

Taipei, Taiwan, 10016

Sponsors and Collaborators

Shire

Covance

PharmaNet

PRA Health Sciences

Investigators

• Study Director: Arian Pano, MD, MPH; Shire Human Genetic Therapies, Inc.
• Principal Investigator: Roberto Giugliani, MD, PhD; Hospital de Clinicas de Porto Alegre
• Principal Investigator: Wuh-Liang Hwu, MD, PhD; National Taiwan University Hospital
• Principal Investigator: Anna Tylki-Szymanska, MD, PhD; Children's Memorial Health Institute, Poland

More Information

Publications of Results:

Pano A, Barbier AJ, Bielefeld B, Whiteman DA, Amato DA. Immunogenicity of idursulfase and clinical outcomes in very young patients (16 months to 7.5 years) with mucopolysaccharidosis II (Hunter syndrome). Orphanet J Rare Dis. 2015 Apr 24;10:50. doi: 10.1186/s13023-015-0265-2.

Other Publications:

Muenzer J, Gucsavas-Calikoglu M, McCandless SE, Schuetz TJ, Kimura A. A phase I/II clinical trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter syndrome). Mol Genet Metab. 2007 Mar;90(3):329-37. Epub 2006 Dec 20.

Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, Vellodi A, Martin R, Ramaswami U, Gucsavas-Calikoglu M, Vijayaraghavan S, Wendt S, Puga AC, Ulbrich B, Shinawi M, Cleary M, Piper D, Conway AM, Kimura A. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006 Aug;8(8):465-73. Erratum in: Genet Med. 2006 Sep;8(9):599. Wendt, Suzanne [corrected to Wendt, Susanne]; Puga, Antonio [corrected to Puga, Ana Cristina]; Conway, Ann Marie [corrected to Conway, Anne Marie].

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT00607386
• Other Study ID Numbers: HGT-ELA-038; 2007-006044-22 ( EudraCT Number )
• First Posted: February 5, 2008
• Results First Posted: November 7, 2013
• Last Update Posted: October 28, 2015
• Last Verified: February 2014

Keywords provided by Shire:

Hunter syndrome; hunters syndrome; hunter's syndrome; hunter disease; hunters disease; hunter's disease; MPS II; MPSII; MPS2; MPS 2; mucopolysaccharides; lysosomal storage disease; lysosomal storage disorder; chronic ear infection; enlarged adenoids; mps symptoms; mps diagnosis; mps ii therapy; MPS II treatment; ert treatment; elaprase; idursulfase; iduronate sulfatase; iduronate 2 sulfatase; enzyme replacement therapy; hunter syndrome treatment; hunter's syndrome treatment; hunter syndrome therapy; hunter's disease treatment; mps society

Additional relevant MeSH terms:

Mucopolysaccharidosis II; Mucopolysaccharidoses; Syndrome; Disease; Pathologic Processes; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Metabolic Diseases; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System