Extension of Study TKT024 Evaluating Long-Term Safety and Clinical Outcomes in MPS II Patients Receiving Idursulfase

An Open-Label Extension of Study TKT024 Evaluating Long-Term Safety and Clinical Outcomes in MPS II Patients Receiving Iduronate-2-Sulfatase Enzyme Replacement Therapy

Study TKT024EXT was a long-term, single-arm, open-label extension of Study TKT024, a one year Phase 2/Phase 3 registration study. The primary objective of this extension study was to collect long-term safety and clinical outcome data in Mucopolysaccharidosis II (MPS II), also known as Hunter Syndrome, from the Phase 2/Phase 3 Study TKT024. All patients enrolling into this study received weekly active treatment with idursulfase, the primary dosing regimen investigated in Study TKT024.

Hunter Syndrome is an X-linked recessive lysosomal storage disease caused by a deficiency of iduronate-2-sulfatase, an enzyme required to catabolize glycosaminoglycans (GAGS) in cells. As a result, GAGs accumulate in the lysosomes leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction. Hunter Syndrome is a rare disease with an estimated incidence of 1 in 162,000 live births.

Study Overview

• Status: Completed
• Conditions: Hunter Syndrome; Mucopolysaccharidosis II (MPS II)
• Intervention / Treatment: Biological: Idursulfase

Detailed Description

Study TKT024EXT was conducted in 2 phases. The first phase ("Phase I") was 2 years (104 weeks) in duration and consisted of weekly infusions of IV idursulfase (0.5 mg/kg), and the collection of patients' safety and clinical outcomes. Week 105 defined the beginning of the second phase of the study. The second phase ("Phase II") consisted of weekly infusions of IV idursulfase (0.5 mg/kg) and the monitoring of patients for safety (via collection of adverse events, concomitant medications, and vital signs). Study completion was defined as the time a patient either transitioned to commercially available idursulfase or discontinued this study.

Idursulfase was administered to patients as a continuous IV infusion at a dose of 0.5 mg of protein per kg of body weight (0.5 mg/kg). Final evaluations from Study TKT024, the one-year predecessor Phase 2/Phase 3 registration study, served as the baseline assessments for the TKT024EXT study. Forced vital capacity (FVC) and the 6-minute walk test (6MWT) continued to be the primary clinical outcomes of TKT024EXT study. Efficacy outcomes were evaluated over the course of 2 years and were determined at 4-month intervals during the first year (ie, Weeks 18, 36, and 53) and at 6-month intervals in the second year (ie, Weeks 79 and 105). Safety outcomes were assessed throughout the duration of the study. The safety and clinical testing performed in the TKT024EXT study were identical to those performed in the double-blind phase of Study TKT024.

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Brazil
  • AL
    • Maceio, AL, Brazil, 57010-382
      • Fundacao Universidade de Ciencias da Saude de Alagoas Governador Lamenha Filho / UNCISAL
  • BA
    • Barreiras, BA, Brazil, 47800-000
      • Clinica Casa de Saude Sao Joao
    • Salvador, BA, Brazil, 40110-060
      • c-HUPES/UFBA
  • MS
    • Campo Grande, MS, Brazil, 79008-900
      • Hospital Universitario da Faculdade de Medicina da Universidade Federal de Mato Grosso do Sul
  • RJ
    • Rio de Janeiro, RJ, Brazil, 21941-590
      • Instituto de Puericultura e Pediatria Martagao Gesteira / Hospital Pediatrico
  • RS
    • Porto Alegre, RS, Brazil, 90035-003
      • Hospital de Clinicas de Porto Alegre, Servico de Genetica Medica
  • SP
    • Sao Paulo, SP, Brazil, 04023-062
      • UNIFESP Instituto de Oncologia Pediatrica
    • Sao Paulo, SP, Brazil, 05403-000
      • Instituto da Crianca / Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1XB
      • The Hospital for Sick Children Research Institute
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • University of Montreal / Hopital Ste-Justine
• France
  • Lyon, France, 69003
    • Hopital Edouard Herriot
  • Strasbourg Cedex, France, 67098
    • Hopital de Hautepierre
  • Toulouse Cedex, France, 31076
    • Hospital Ducuing
• Germany
  • Aachen, Germany, D-52074
    • Universitatsklinikum Aachen Kinderklinik
  • Dusseldorf, Germany, 40225
    • Universitatsklinik Dusseldorf Kinderklinik
  • Giessen, Germany, 35385
    • Justus-Liebig Universität
  • Gottingen, Germany, D-37075
    • Universitätsklinikum Göttingen
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg Eppendorf
  • Mainz, Germany, 55101
    • Children's University Hospital Mainz AG
• Italy
  • Milan, Italy, 20052
    • Universita Milano Bicocca / Ospedale S. Gerardo
  • Napoli, Italy, 80131
    • Università degli Studi di Napoli Federico II
  • Padova, Italy, 35121
    • Universita di Padova
  • Savigliano, Italy, 12038
    • Ospedale S. S. Annunziata
• Romania
  • Cluj
    • Cluj Napoca, Cluj, Romania, 400370
      • Spitalul Clinic de Copii
• Spain
  • Badalona, Spain, 08916
    • University Hospital Germans Trias i Pujol
  • Jaen
    • Linares, Jaen, Spain, 23700
      • Servicio de Pediatria
• Sweden
  • Gothenberg, Sweden, 41685
    • Drottning Silvias barnsjukhus
  • Stockholm, Sweden, 14186
    • Karolinska University Hospital
• United Kingdom
  • Bath, United Kingdom, BA1 3QE
    • Bath and NE Somerset Primary Care Trust
  • Cambridge, United Kingdom, CB2 2QQ
    • Addenbrooke's Hospital
  • Derby, United Kingdom, DE22 3NE
    • Derbyshire Children's Hospital
  • Glasgow, United Kingdom, G3 8SJ
    • Royal Hospital for Sick Children
  • London, United Kingdom, WC1N3JH
    • Great Ormond Street Hospital for Sick Children
  • Manchester, United Kingdom, M27 4HA
    • Royal Manchester Children's Hospital
  • Newcastle, United Kingdom, NE1 4LP
    • Royal Victoria Infirmary
  • Surrey
    • Guildford, Surrey, United Kingdom, GU2 5XX
      • Royal Surrey County Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital
  • California
    • Oakland, California, United States, 94609
      • Pediatric Clinical Research Center, Children's Hospital Oakland
  • Colorado
    • Denver, Colorado, United States, 80218
      • The Children's Hospital
  • Georgia
    • Rome, Georgia, United States, 30165
      • Harbin Clinic
  • Illinois
    • Normal, Illinois, United States, 61761
      • Mid-Illinois Hematology and Oncology Associates
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • Saint Louis University Cardinal Glennon Children's Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Comprehensive Cancer Centers of Nevada
  • New York
    • Syracuse, New York, United States, 13210
      • Upstate Medical University, State University of New York (SUNY)
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • University of Utah Hospital
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Franciscan Skemp Healthcare

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Patient must have completed the double-blind phase of Study TKT024, defined as completing the Week 53 final evaluations.
• Patient, patient's parent(s), or legally authorized representative 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:

• Patient has received treatment with an investigational therapy other than iduronate-2-sulfatase in Study TKT024 within the past 60 days.
• 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.
• Patient has experienced an adverse reaction to study drug in Study TKT024, which contraindicates further treatment with idursulfase.
• Patient with known hypersensitivity to any of the components of idursulfase.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Idursulfase	Biological: Idursulfase; Solution for intravenous infusion, 0.5 mg/kg once-weekly; Other Names: Elaprase®; iduronate-2-sulfatase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Percent Predicted Forced Vital Capacity (FVC) at Week 105	Determined by spirometry. The change is calculated as Week 105 minus baseline.	Baseline and at Week 105
Change From Baseline in Mean Distance Walked in the 6-minute Walk Test (6MWT) at Week 105	Determined on a walking course. The change was calculated as Week 105 minus baseline.	Baseline and at Week 105

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Passive Joint Range of Motion (JROM) at Week 105	Change was calculated as Week 105 minus baseline. Global JROM (% 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).	Baseline and at Week 105
Change From Baseline in Mean Combined Liver and Spleen Volume at Week 105	Determined by Magnetic Resonance Imaging (MRI). The change was calculated as Week 105 minus baseline.	Baseline and at Week 105
Change From Baseline in Mean Normalized Urine Glycosaminoglycans (GAG) Levels at Week 105	Determined by urine testing. The change was calculated as Week 105 minus baseline.	Baseline and at Week 105
Change From Baseline in Mean Cardiac Left Ventricular Mass Index (LVMI) at Week 105	Determined by echocardiogram. LVMI indexed to body surface area (g/m^2). The change was calculated as Week 105 minus baseline.	Baseline and at Week 105

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General 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. doi: 10.1016/j.ymgme.2006.09.001. 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. doi: 10.1097/01.gim.0000232477.37660.fb. 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].
• Muenzer J, Beck M, Eng CM, Giugliani R, Harmatz P, Martin R, Ramaswami U, Vellodi A, Wraith JE, Cleary M, Gucsavas-Calikoglu M, Puga AC, Shinawi M, Ulbrich B, Vijayaraghavan S, Wendt S, Conway AM, Rossi A, Whiteman DA, Kimura A. Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome. Genet Med. 2011 Feb;13(2):95-101. doi: 10.1097/GIM.0b013e3181fea459. Erratum In: Genet Med. 2013 Oct;15(10):849.
• Beusterien KM, Yeung JE, Pang F, Brazier J. Development of the multi-attribute Adolescent Health Utility Measure (AHUM). Health Qual Life Outcomes. 2012 Aug 28;10:102. doi: 10.1186/1477-7525-10-102.

Study record dates

Study Major Dates

• Study Start (Actual): September 13, 2004
• Primary Completion (Actual): January 31, 2008
• Study Completion (Actual): January 31, 2008

Study Registration Dates

• First Submitted: February 28, 2008
• First Submitted That Met QC Criteria: March 6, 2008
• First Posted (Estimate): March 7, 2008

Study Record Updates

• Last Update Posted (Actual): June 10, 2021
• Last Update Submitted That Met QC Criteria: May 26, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: enzyme replacement therapy; MPS II; Hunter syndrome; lysosomal storage disorder; lysosomal storage disease; MPS 2; mps symptoms; enlarged adenoids; elaprase; hunter's syndrome; MPS2; hunters disease; hunter's disease treatment; hunter syndrome therapy; iduronate sulfatase; mps society; MPSII; hunter syndrome treatment; hunter's disease; iduronate 2 sulfatase; mucopolysaccharides; mps diagnosis; chronic ear infection; hunters syndrome; ert treatment; hunter disease; idursulfase; hunter's syndrome treatment; mps ii therapy; MPS II treatment
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Syndrome; Mucopolysaccharidosis II; Mucopolysaccharidoses
• Other Study ID Numbers: TKT024EXT; 2004-002743-27 (EudraCT Number)