Study of Gene-Activated® Human Glucocerebrosidase (GA-GCB) ERT Compared With Imiglucerase in Type I Gaucher Disease

Overview

Gaucher disease is a rare lysosomal storage disorder caused by the deficiency of the enzyme glucocerebrosidase (GCB). Due to the deficiency of functional GCB, glucocerebroside accumulates within macrophages leading to cellular engorgement, organomegaly, and organ system dysfunction. The purpose of this non-inferiority study is to evaluate the efficacy and safety of GA-GCB (velaglucerase alfa) administered every other week in comparison to imiglucerase in treatment naive patients with type 1 Gaucher disease.

Full Title of Study: “A Multicenter, Randomized, Double-Blind, Parallel-Group Study of Gene-Activated® Human Glucocerebrosidase (GA-GCB) Enzyme Replacement Therapy Compared With Imiglucerase in Patients With Type I Gaucher Disease”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: May 2009

Detailed Description

Type 1 Gaucher disease, the most common form, accounts for more than 90% of all cases and does not involve the CNS. Typical manifestations of type 1 Gaucher disease include hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life. Gene-Activated® human glucocerebrosidase (GA-GCB; velaglucerase alfa) is produced in a continuous human cell line using proprietary gene-activation technology and has an identical amino acid sequence to the naturally occurring human enzyme. GA-GCB (velaglucerase alfa) contains terminal mannose residues that target the enzyme to the macrophages-the primary target cells in Gaucher disease. This study was designed to determine the efficacy and safety of GA-GCB (velaglucerase alfa) in comparison to imiglucerase in men, women, and children with Type 1 Gaucher disease.

Interventions

  • Biological: velaglucerase alfa
    • IV infusion, 60 U/kg every other week for 9 months
  • Biological: imiglucerase
    • IV infusion, 60 U/kg every other week for 9 months

Arms, Groups and Cohorts

  • Experimental: GA-GCB
    • VPRIV™ ,velaglucerase alfa
  • Active Comparator: imiglucerase

Clinical Trial Outcome Measures

Primary Measures

  • Mean Change From Baseline to Month 9 in Hemoglobin (Hgb) Concentration for Each Treatment Group.
    • Time Frame: Baseline to Month 9

Secondary Measures

  • Change From Baseline to Month 9 in Platelet Counts for Each Treatment Group.
    • Time Frame: Baseline to Month 9
    • Values shown are observed change from Baseline to Month 9.
  • Change From Baseline to Month 9 in Normalized Liver Volume (Percent (%) Body Weight) for Each Treatment Group.
    • Time Frame: Baseline to Month 9
    • Values shown are observed change from Baseline to Month 9. Measured by Magnetic resonance imaging (MRI). Liver volume has been normalized for percent (%) body weight for each treatment arm. Liver size relative to body weight = (Liver volume [cubic centimeter (cc)]/Body weight [kg]*1000.
  • Change From Baseline to Month 9 in Normalized Spleen Volume (Percent (%) Body Weight) for Each Treatment Group.
    • Time Frame: Baseline to Month 9
    • Values shown are observed change from Baseline to month 9. Measured by Magnetic resonance imaging (MRI). Spleen volume was normalized for percent (%) of body weight for each treatment arm. Spleen size relative to body weight=(Spleen volume [cc]/Body weight [kg])*100.
  • Change From Baseline to Month 9 in Plasma Chitotriosidase for Each Treatment Group.
    • Time Frame: Baseline to Month 9.
    • Values shown are observed change from Baseline to Month 9. Units of measure is defined as nanomole per milliliter per hour.
  • Change From Baseline to Month 9 in Plasma Chemokine (C-C Motif) Ligand 18 (CCL18) for Each Treatment Group.
    • Time Frame: Baseline to Month 9
    • Values shown are observed change from Baseline to Month 9.
  • Number of Participants Who Developed Antibody for Each Treatment Group.
    • Time Frame: Baseline to Month 9
    • Measure type is actual number of participants who developed antibodies to treatment; GA-GCB or imiglucerase. Antibody detection was based upon serum samples collected at various time points throughout the study. Serum samples were screened using an enzyme-linked immunosorbent assay (ELISA) and positive antibody confirmation was determined using a radioimmunoprecipitation assay (RIP); positive samples were also tested for enzyme neutralizing activity. Participant samples were compared to internal assay controls (positive/negative), positive samples were determined based upon individual assay criteria.
  • Time to Response- Comparison of GA-GCB and Imiglucerase on the Earliest Time to Respond as Assessed Via Hemoglobin Concentration
    • Time Frame: Response rate at Month 9 compared to Baseline
    • Time to response was defined as a ≥ 1 g/dL improvement in hemoglobin levels relative to Baseline. Units (%) correlates to the percentage of participants who had a change of ≥ 1 g/dL improvement in hemoglobin levels relative to Baseline during their participation in the study.

Participating in This Clinical Trial

Inclusion Criteria Includes:

  • The patient has a documented diagnosis and clinical manifestation of type 1 Gaucher disease – The patient is at least 2 years of age. – The patient has not received treatment for Gaucher disease (investigational products, miglustat, or imiglucerase) within 12 months prior to study entry, as documented in the patient's medical history. – Female patients of child-bearing potential must agree to use a medically acceptable method of contraception at all times during the study and must have negative results to a pregnancy test performed at the time of enrollment and as required throughout their participation in the study. Male patients must use a medically acceptable method of birth control throughout their participation in the study and must report their partner's pregnancy. – The patient, the patient's parent(s) or legal guardian(s) has provided written informed consent that has been approved by the Institutional Review Board/Independent Ethics Committee (IRB/IEC). – The patient must be sufficiently cooperative to participate in this clinical study as judged by the Investigator. Exclusion Criteria Includes: – The patient has type 2 or 3 Gaucher disease or is suspected of having type 3 Gaucher disease. – The patient has received treatment with any non-Gaucher disease-related investigational drug or device within the 30 days prior to study entry; such use during the study is not permitted. – The patient is known to be positive for human immunodeficiency virus (HIV). – The patient is known to be positive for hepatitis B and/or C. – The patient, patient's parent(s), or patient's legal guardian(s) is/are unable to understand the nature, scope, and possible consequences of the study. – The patient has a significant comorbidity(ies) that might affect study data or confound the study results (e.g., malignancies, primary biliary cirrhosis, autoimmune liver disease, etc.). – The patient is unable to comply with the protocol, e.g., has a clinically relevant medical condition making implementation of the protocol difficult, has an uncooperative attitude, is unable to return for safety evaluations, or is otherwise unlikely to complete the study, as determined by the Investigator.

Gender Eligibility: All

Minimum Age: 2 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Shire
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Kiran Bhirangi, M.D., Study Director, Shire Human Genetic Therapies, Inc.
    • Priya Kishnani, M.D., Principal Investigator, Duke Children’s Hospital & Health Center
    • Isaac Kisinovsky, M.D., Principal Investigator, Your Health S.A. (Hipolito Yrigoyen)
    • Derlis Gonzalez Rodriguez, M.D., Principal Investigator, Sociedad Espanola de Socorros Mutuos
    • Elena A. Lukina, M.D., Principal Investigator, National Research Center for Haematology
    • Atul Mehta, M.D., Principal Investigator, The Royal Free Hospital
    • Ari Zimran, M.D., Principal Investigator, Shaare Zedek Medical Center
    • Pilar Giraldo, M.D., Principal Investigator, Hospital Universitario Miguel Servet
    • Suresh Kumar, M.D., Principal Investigator, Malabar Institute of Medical Sciences Ltd.
    • Madhulika Kabra, M.D., Principal Investigator, All India Institute of Medical Sciences, New Delhi
    • Ashish Bavdekar, M.D., Principal Investigator, KEM Hospital Research Centre
    • Marie-Francoise Ben Dridi, M.D., Principal Investigator, La Rabta Hospital

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