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Study of the Effect of Velaglucerase Alfa (VPRIV®) on Bone-related Pathology in Treatment-naïve Participants With Type 1 Gaucher Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02574286
Recruitment Status : Completed
First Posted : October 12, 2015
Results First Posted : February 1, 2022
Last Update Posted : February 1, 2022
Sponsor:
Information provided by (Responsible Party):
Takeda ( Shire )

Brief Summary:
The primary purpose of this study is to evaluate the effect of VPRIV therapy (60 units per kilogram [U/kg] every other week [EOW]) in treatment-naive participants with type 1 Gaucher disease on change from baseline in lumbar spine (LS) bone mineral density (BMD) Z-score as measured by dual energy x-ray absorptiometry (DXA) after 24 months of treatment.

Condition or disease Intervention/treatment Phase
Gaucher Disease Drug: Velaglucerase alfa Dietary Supplement: Vitamin D Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Multicenter, Single-arm, Phase 4 Study of the Effect of Treatment With Velaglucerase Alfa on Bone-related Pathology in Treatment-naïve Patients With Type 1 Gaucher Disease
Actual Study Start Date : June 29, 2016
Actual Primary Completion Date : November 12, 2020
Actual Study Completion Date : November 30, 2020


Arm Intervention/treatment
Experimental: Velaglucerase alfa 60 U/kg
Participants will receive 60-minute intravenous infusion of 60 units per kilogram (U/kg) velaglucerase alfa every other week (EOW) and an oral daily dose of 800 IU vitamin D for 24 months (101 weeks).
Drug: Velaglucerase alfa
Participants will receive 60-minute intravenous infusion of 60 U/kg velaglucerase alfa EOW.

Dietary Supplement: Vitamin D
Participants will receive 800 IU vitamin D orally daily.




Primary Outcome Measures :
  1. Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-Score up to End of Study (EOS) (Week 103) [ Time Frame: Baseline up to EOS (Week 103) ]
    Bone mineral density of the lumbar spine was measured by dual energy x-ray absorptiometry (DXA), and the results was converted to Z-scores appropriate for age, sex, and race. The Z-score indicated the number of standard deviations away from a reference population in the same age range, race and with the same sex. A Z-score of 0 was equal to the mean. Negative numbers indicated values lower than the mean and positive numbers indicated values higher than the mean. Baseline was defined as last data collected prior to the first administration of study drug. Change from baseline in lumbar spine BMD Z-Score up to EOS (Week 103) was reported.


Secondary Outcome Measures :
  1. Change From Baseline in Lumbar Spine (LS) BMD Z-score at Week 51 [ Time Frame: Baseline, Week 51 ]
    BMD of the LS was measured by DXA, and the results was converted to Z-scores appropriate for age, sex, and race. The Z-score indicated the number of standard deviations away from a reference population in the same age range, race and with the same sex. A Z-score of 0 was equal to the mean. Negative numbers indicated values lower than the mean and positive numbers indicated values higher than the mean. Baseline was defined as last data collected prior to the first administration of study drug. Change From baseline in LS BMD Z-score at Week 51 was reported. ITT Population was defined as all enrolled subjects who received at least one study drug infusion (full or partial). Here, "number of subjects analysed" signifies subjects who were evaluable for this endpoint.

  2. Change From Baseline in Lumbar Spine BMD at Week 51 and EOS (Week 103) [ Time Frame: Baseline, Week 51 and EOS (Week 103) ]
    Bone mineral density of the LS was measured by DXA, and the results was measured in gram per square centimeter (g/cm^2). Baseline was defined as last data collected prior to the first administration of study drug. Change From baseline in LS BMD at Week 51 and EOS (Week 103) was reported.

  3. Change From Baseline in Total Bone Marrow Burden (BMB) Score at Week 51 and EOS (Week 103) [ Time Frame: Baseline, Week 51 and EOS (Week 103) ]
    BMB score was a semi-quantitative magnetic resonance imaging (MRI) scoring system for assessing the extent of bone marrow involvement in Gaucher disease. BMB Score was measured using magnetic resonance imaging (MRI), range from 0 (no abnormalities) to 8 points (severe disease) for the lumbar spine and from 0 (no abnormalities) to 8 points (severe disease) for the femurs. The total BMB score was calculated as the sum of scores for femur and lumbar spine regions which ranged from 0 (no abnormalities) to 16 (severe disease) points. A higher BMB score signified more severe bone marrow involvement. Baseline was defined as last data collected prior to the first administration of study drug. Change from baseline in total BMB Score at Week 51 and EOS (Week 103) was reported.

  4. Change From Baseline in Hemoglobin Concentration at Week 13, 25, 37, 51, 65, 77, 89, and EOS (Week 103) [ Time Frame: Baseline, Week 13, 25, 37, 51, 65, 77, 89, and EOS (Week 103) ]
    Blood samples were collected for measurement of hemoglobin concentration. Baseline was defined as last data collected prior to the first administration of study drug. Change from baseline in hemoglobin concentration at Week 13, 25, 37, 51, 65, 77, 89, and EOS (Week 103) was reported.

  5. Change From Baseline in Platelet Count at Week 13, 25, 37, 51, 65, 77, 89, and EOS (Week 103) [ Time Frame: Baseline, Week 13, 25, 37, 51, 65, 77, 89, and EOS (Week 103) ]
    Blood samples were collected for measurement of platelet count. Baseline was defined as last data collected prior to the first administration of study drug. Change from baseline over time in platelet count at Week 13, 25, 37, 51, 65, 77, 89, and EOS (Week 103) was reported.

  6. Change From Baseline in Normalized Liver Volume at Week 51 and EOS (Week 103) [ Time Frame: Baseline, Week 51 and EOS (Week 103) ]
    Normalized liver volume was measured by abdominal MRI. Baseline was defined as last data collected prior to the first administration of study drug. Liver volume has been normalized for percent (%) body weight. Liver size relative to body weight = (Liver volume [cubic centimeter (cc)]/Body weight [kg])*100. Change from baseline in normalized liver volume at Week 51 and EOS (Week 103) was reported.

  7. Change From Baseline in Normalized Spleen Volume at Week 51 and EOS (Week 103) [ Time Frame: Baseline, Week 51 and EOS (Week 103) ]
    Normalized spleen volume was measured by MRI. Spleen volume was normalized for % of body weight. Spleen size relative to body weight= (Spleen volume [cc]/Body weight [kg])*100. Baseline was defined as last data collected prior to the first administration of study drug. Change from baseline in normalized spleen volume at Week 51 and EOS (Week 103) was reported.

  8. Change From Baseline in Severity of Bone Pain at Week 51 and EOS (Week 103) [ Time Frame: Baseline, Week 51 and EOS (Week 103) ]
    Bone pain was measured by questions taken from the Brief Pain Inventory-short form (BPI-SF). Pain severity was evaluated based on the average of 4 questions from BPI-SF (Questions 3 through 6) assessing worst pain, least pain, average pain, and pain right now, each rated on a scale from 0 (no pain) to 10 (pain as bad as you can imagine) with mild pain- score (1 to 4), moderate pain- score (5 to 6), and severe pain score (7 to 10). Overall severity score was calculated as average of 4 questions ranging from 0 (no pain) to 10 (pain as bad as you can imagine). A negative change from baseline score indicates improvement. Baseline was defined as last data collected prior to the first administration of study drug. Change from baseline in severity of bone pain at Week 51 and EOS (Week 103) was reported.

  9. Change From Baseline in Bone Pain Interference Score at Week 51 and EOS (Week 103) [ Time Frame: Baseline, Week 51 and EOS (Week 103) ]
    Bone pain interference was measured by questions taken from the BPI-SF. Pain interference was evaluated based upon average of 7 questions from BPI-SF (9A through 9G) regarding the extent to which pain interfered with daily activities, including general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life in the last 24 hours, each rated on a scale from 0 (does not interfere) to 10 (completely interferes). Overall pain interference score was calculated as average of 7 questions ranging from 0 (does not interfere) to 10 (completely interferes). A negative change from baseline score indicates improvement. Baseline was defined as last data collected prior to the first administration of study drug. Change from baseline in bone pain interference score at Week 51 and EOS (Week 103) was reported.

  10. Change From Baseline in Overall Fatigue Measured by Brief Fatigue Inventory (BFI) at Week 51 and EOS (Week 103) [ Time Frame: Baseline, Week 51 and EOS (Week 103) ]
    Overall fatigue was measured by the BFI. BFI was a 9-item questionnaire developed to assess subjective fatigue. Each question asked the respondent to rate the level of their experienced fatigue over the past 24 hours on an 11-point (0-10) scale. First 3 questions measure fatigue severity at current, usual, and worst levels, respectively, with 0 indicating "no fatigue" and 10 indicating fatigue "as bad as you can imagine". Next 6 questions assessed the level fatigue interference with daily activities included general activity, mood, walking ability, normal work (both inside and outside the home), relations with other people, and enjoyment of life. A score of 0="no interference" while a score of 10="complete interference. Overall fatigue score was calculated as average score of all 9 items on the BFI ranging from 0="no fatigue" to 10="as bad as you can imagine".

  11. Number of Participants With Shift in World Health Organization (WHO) BMD Classifications Based on LS T-Scores at Week 51 and EOS (Week 103) [ Time Frame: Baseline, Week 51 and EOS (Week 103) ]
    WHO BMD Classifications (Normal Bone Density, Osteopenia, Osteoporosis), bone mineral density was classified based on LS BMD T-scores. BMD T-score was a comparison of an individual's BMD compared to "normal". Also, BMD T-score is the standard deviation of the difference between measured BMD and that of the healthy young adult "normal". The T-score scale was as follows: -1 and above=normal, -1 to -2.5=osteopenia (below normal and may lead to osteoporosis), and -2.5 and below=osteoporosis. Number of participants with shift in WHO BMD classifications based on LS T-Scores at Week 51 and EOS (Week 103) were reported.

  12. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From start of study drug infusion up to follow-up (107 weeks) ]
    An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any AE that occurred on or after the time of the first infusion of study drug until 30 days after the last infusion of study drug. Number of participants with TEAEs were reported.

  13. Number of Participants Who Developed Positive Anti-velaglucerase Alfa Antibody Status [ Time Frame: Baseline up to EOS (Week 103) ]
    Anti-velaglucerase alfa antibody included anti-velaglucerase antibodies (ADA) and neutralizing anti-velaglucerase antibodies (NAb). The Anti-velaglucerase antibody status was summarized as categorical variable by positive and negative. Number of participants who developed positive anti-velaglucerase alfa antibody were reported.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The participant has a documented diagnosis of type 1 Gaucher disease, as documented by deficient GCB activity in leukocytes (whole blood only) or cultured skin fibroblasts. Diagnosis by only dry blood spot test is insufficient. Diagnosis may be based on results obtained prior to screening if documented in the participant's medical history.
  • Participants must have a LS BMD Z-score less than (<) -1 or BMD T-score of < -1 as measured by DXA during the screening phase.
  • Participant is treatment-naive, that is (ie,) has not received ERT or SRT in the 12 months prior to enrollment.
  • The participant is greater than or equal to (>=) 18 and less than or equal to (<=) 70 years of age.
  • Female participants of childbearing potential must agree to use a medically acceptable method of contraception at all times during the study.
  • The participant, or participant's legally authorized representative(s), if applicable, understands the nature, scope, and possible consequences of the study and has provided written informed consent that has been approved by the Institutional Review Board/Independent Ethics Committee (IRB/IEC).
  • The participant must be sufficiently cooperative to participate in this clinical study as judged by the investigator.

Exclusion criteria

  • Neurological symptoms indicating that the participant may have type 3 Gaucher disease.
  • A significant comorbidity, which, as determined by the investigator, might affect study data or confound the study results (eg, malignancies, primary biliary cirrhosis, autoimmune liver disease, etc).
  • Any osteoporosis-specific treatment (eg, bisphosphonates) or treatment with erythropoietin (or erythropoietin-like substances) during the past year.
  • Structural, joint-associated bone damage of such extent and severity that the investigator deems it could impact participation in the study and assessment of relevant study endpoints (example, pain).
  • The participant is pregnant or lactating.
  • The participant has had a splenectomy. (This criterion is not meant to exclude participants who have accessory spleens.)
  • The participant is enrolled in another clinical study that involves clinical investigations or use of any investigational product (drug or device) within 30 days prior to study enrollment or at any time during the study.
  • Severe vitamin D deficiency to the level that would be expected to result in osteomalacia (vitamin D < 10 nanograms per milliliter [ng/mL] [25 nanomoles per liter {nmol/L}]). If there is mild vitamin D insufficiency at screening (vitamin D greater than [>] 10 and < 30 ng/mL) treat with 4000 IU vitamin D per day for 1 month and rescreen.
  • The participant has previously interrupted ERT for safety reasons.
  • The participant has had hypersensitivity to the active substance or to any of the excipients.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02574286


Locations
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United States, California
Cedars Sinai Medical Center
Beverly Hills, California, United States, 90211
Kaiser Permanente
Los Angeles, California, United States, 90027
United States, Georgia
Emory Genetics
Atlanta, Georgia, United States, 30322
United States, Illinois
Ann and Robert H Lurie Childrens Hospital of Chicago
Chicago, Illinois, United States, 60611
United States, New York
NYU School of Medicine
New York, New York, United States, 10016
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Virginia
Lysosomal and Rare Disorders Research and Treatment Center
Fairfax, Virginia, United States, 22030
Israel
Rambam Health Care Campus
Haifa, Israel, 3109601
Shaare Zedek Medical Center
Jerusalem, Israel, 91031
Rabin Medical Center
Petah Tikva, Israel, 49100
Spain
Hospital Universitario Ramon y Cajal
Madrid, Spain, 28034
Hospital Quironsalud Zaragoza
Zaragoza, Spain, 50006
United Kingdom
Addenbrooke's Hospital
Cambridge, United Kingdom, CB20QQ
Royal Free Hospital
London, United Kingdom, NW3 2QG
Sponsors and Collaborators
Shire
Investigators
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Study Director: Study Director Shire
  Study Documents (Full-Text)

Documents provided by Takeda ( Shire ):
Study Protocol  [PDF] November 2, 2020
Statistical Analysis Plan  [PDF] August 30, 2021

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Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT02574286    
Other Study ID Numbers: SHP-GCB-402
2015-001578-17 ( EudraCT Number )
First Posted: October 12, 2015    Key Record Dates
Results First Posted: February 1, 2022
Last Update Posted: February 1, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://vivli.org/ourmember/takeda/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Gaucher Disease
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Vitamin D
Vitamins
Micronutrients
Physiological Effects of Drugs
Bone Density Conservation Agents