Clinical Trial Results:
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
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Summary
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EudraCT number |
2015-001578-17 |
Trial protocol |
GB DE ES IT |
Global end of trial date |
30 Nov 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Dec 2021
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First version publication date |
15 Dec 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
SHP-GCB-402
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02574286 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Shire
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Sponsor organisation address |
300 Shire Way, Lexington, United States, MA 02421
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Public contact |
Study Director, Shire, ClinicalTransparenc@takeda.com
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Scientific contact |
Study Director, Shire, ClinicalTransparenc@takeda.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 Nov 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Nov 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective of the study is to evaluate the effect of velaglucerase alfa (VPRIV) therapy (60 units per kilogram [U/kg] every other week [EOW]) in treatment-naïve subjects 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.
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Protection of trial subjects |
The study was conducted in accordance with current applicable industry regulations, International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 (1996) and any updates, European Union (EU) Directive 2001/20/EC and its updates, the ethical principles in the Declaration of Helsinki, and local ethical and legal requirements.
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Background therapy |
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Evidence for comparator |
- | ||
Actual start date of recruitment |
07 Jun 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 4
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Country: Number of subjects enrolled |
Israel: 12
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Country: Number of subjects enrolled |
Spain: 2
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Country: Number of subjects enrolled |
United Kingdom: 3
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Worldwide total number of subjects |
21
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EEA total number of subjects |
2
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
19
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From 65 to 84 years |
2
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted in the United States, Israel, Spain and United Kingdom from 07 June 2016 (first subjects first visit) to 30 November 2020 (last subjects last visit) | ||||||||||||
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Pre-assignment
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Screening details |
A total of 21 subjects were enrolled and received treatment in this study. | ||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Velaglucerase alfa 60 U/kg | ||||||||||||
Arm description |
Subjects received 60-minute intravenous (IV) infusion of 60 U/kg velaglucerase alfa EOW for 24 months (up to 101 weeks). | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Velaglucerase alfa
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received 60-minute IV infusion of 60 U/kg velaglucerase alfa EOW for 24 months.
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Baseline characteristics reporting groups
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Reporting group title |
Velaglucerase alfa 60 U/kg
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Reporting group description |
Subjects received 60-minute intravenous (IV) infusion of 60 U/kg velaglucerase alfa EOW for 24 months (up to 101 weeks). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Velaglucerase alfa 60 U/kg
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Reporting group description |
Subjects received 60-minute intravenous (IV) infusion of 60 U/kg velaglucerase alfa EOW for 24 months (up to 101 weeks). | ||
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End point title |
Change From Baseline in Lumbar Spine (LS) Bone Mineral Density (BMD) Z-Score up to End of Study (EOS) (Week 103) [1] | ||||||||
End point description |
BMD of the LS was measured by dual energy x-ray absorptiometry (DXA), and the result 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. Intent-to-Treat (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.
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End point type |
Primary
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End point timeframe |
Baseline up to EOS (Week 103)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Lumbar Spine (LS) BMD Z-score at Week 51 | ||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 51
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Lumbar Spine BMD at Week 51 and EOS (Week 103) | ||||||||||||
End point description |
BMD of the LS was measured by dual energy x-ray absorptiometry (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. 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 51 and EOS (Week 103)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Bone Marrow Burden (BMB) Score at Week 51 and EOS (Week 103) | ||||||||||||
End point description |
BMB score was a semi-quantitative magnetic resonance imaging (MRI) scoring system for assessing the extent of bone marrow involvement in Gaucher disease. BMB scores was calculated from MRI of the LS and femurs with a range from 0 (no abnormalities) to 8 points (severe disease). A positive BMB score indicated more severe bone marrow involvement and negative BMB score indicated less severe bone marrow involvement. Baseline was defined as last data collected prior to the first administration of study drug. 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 and “number analysed” signifies subjects who were evaluable at specific time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 51 and EOS (Week 103)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Hemoglobin Concentration at Week 13, 25, 37, 51, 65, 77, 89, and EOS (Week 103) | ||||||||||||||||||||||||
End point description |
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. 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 and “number analysed” signifies subjects who were evaluable at specific time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 13, 25, 37, 51, 65, 77, 89, and EOS (Week 103)
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change From Baseline in Platelet Count at Week 13, 25, 37, 51, 65, 77, 89, and EOS (Week 103) | ||||||||||||||||||||||||
End point description |
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. 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 and “number analysed” signifies subjects who were evaluable at specific time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 13, 25, 37, 51, 65, 77, 89, and EOS (Week 103)
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change From Baseline in Normalized Liver Volume at Week 51 and EOS (Week 103) | ||||||||||||
End point description |
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. 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 and “number analysed” signifies subjects who were evaluable at specific time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 51 and EOS (Week 103)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Normalized Spleen Volume at Week 51 and EOS (Week 103) | ||||||||||||
End point description |
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. 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 and “number analysed” signifies subjects who were evaluable at specific time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 51 and EOS (Week 103)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Severity of Bone Pain at Week 51 and EOS (Week 103) | ||||||||||||
End point description |
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 to 6) assessing worst pain, least pain, average pain, 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 (0 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. 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 and “99999” signifies standard deviation was not estimated due to single subject.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 51 and EOS (Week 103)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Bone Pain Interference Score at Weeks 51 and EOS (Week 103) | ||||||||||||
End point description |
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. ITT analysis population set. Here, "number of subjects analysed" signifies subjects who were evaluable for this endpoint and “99999” signifies standard deviation was not estimated due to single subject.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 51 and EOS (Week 103)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Overall Fatigue Measured by Brief Fatigue Inventory (BFI) at Week 51 and EOS (Week 103) | ||||||||||||
End point description |
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-fatigue severity at current, usual, and worst levels, with 0-"no fatigue" and 10-“fatigue”. Next 6 questions-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 ranged from 0="no interference" and 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”. Negative numbers=values lower than mean; positive numbers=values higher than mean. ITT Population. "Number of subjects analysed" signifies subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 51 and EOS (Week 103)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Subjects With Shift in World Health Organization (WHO) BMD Classifications Based on LS T-Scores at Week 51 and EOS (Week 103) | ||||||||||||||||||||||||||||||||||||||||||
End point description |
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 subjects with shift in WHO BMD classifications based on LS T-Scores at Week 51 and EOS (Week 103) were 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 and “number analysed” signifies subjects who were evaluable at specific time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 51 and EOS (Week 103)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) | ||||||
End point description |
An adverse event (AE) was any untoward medical occurrence in a clinical investigation subject 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 subjects with TEAEs were reported. Safety population was defined as all enrolled subjects who received at least one study drug infusion (full or partial).
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End point type |
Secondary
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End point timeframe |
From start of study drug infusion up to follow-up (107 weeks)
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects Who Developed Positive Antivelaglucerase Alfa Antibody Status | ||||||
End point description |
Anti-velaglucerase alfa antibody included antivelaglucerase antibodies (ADA) and neutralizing antivelaglucerase antibodies (NAb). The Anti-velaglucerase antibody status was summarized as categorical variable by positive and negative. Number of subjects who developed positive anti-velaglucerase alfa antibody were reported. Safety population was defined as all enrolled subjects who received at least one study drug infusion (full or partial).
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End point type |
Secondary
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End point timeframe |
Baseline up to EOS (Week 103)
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| No statistical analyses for this end point | |||||||
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Adverse events information
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Timeframe for reporting adverse events |
From start of study drug infusion up to follow-up (107 weeks)
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Velaglucerase alfa 60 U/kg
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Reporting group description |
Subjects received 60-minute intravenous (IV) infusion of 60 units per kilogram (U/kg) velaglucerase alfa every other Week (EOW) for 24 months (up to 101 weeks). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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14 Sep 2015 |
Protocol Amendment 1:
-Added details about emergency contact information.
-Updated the details in exploratory objectives endpoints.
-Added new section about home infusion of VPRIV.
-Updated safety language to bring it into alignment with Shire standard language. |
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02 Jun 2016 |
Protocol Amendment 2:
-Added information that all subjects will receive “600 IU 25 hydroxyvitamin D (oral) daily” as concomitant medication.
-Changed the evaluation of primary endpoint from 12 months to 24 months.
-Changed the evaluation of secondary endpoint from 24 months to 12 months.
-Timepoints for measurements of hemoglobin cocentration and platelet count were changed to baseline and weeks 13, 25, 37, 51, 65, 77, 89, and 103 (end of study).
-Clarified biomarkers for analysis.
-Revised age range to ≥18 and ≤65 years of age.
-Updated emergency contact information.
-Added specific guidance for contraception. |
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06 Jul 2016 |
Protocol Amendment 3:
-The minimum age for inclusion had been changed to 18 years; therefore, informed consent by parents was eliminated.
-Added “HBsAg, HCV, HIV, and 25 hydroxyvitamin D blood test” as a safety laboratory tests to be performed at screening.
-Changed the assessment of primary efficacy endpoint at the baseline visit to occur at the screening visit instead. |
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04 May 2017 |
Protocol Amendment 4:
-The dose of Vitamin D was revised from 600 IU to 800 IU.
-The subject age range for the enrollment in the study was increased from ≥18 and ≤65 to ≥18 and ≤70 years.
-The definition of IRR was updated to match the definition in summary of product characteristics.
-The assessments of BMB and LS BMD Z score were eliminated at Week 25 and Week 77 to ease subject burden as data from these visits will not be used in the determination of any endpoints.
-Added criterion of BMD T-score to facilitate enrollment after consideration of this measure as an appropriate alternative to BMD Z-score.
-Deleted “Change in the quadriceps cross sectional area and measures of relevance to determine lean muscle mass are additional exploratory endpoints.” as the proper imaging modality for its measurement was not being performed and MRI was no longer considered to be an adequate measure.
-The window of study procedures was changed to ±7 days to allow for subject rescheduling and to facilitate protocol execution.-- |
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26 Jul 2018 |
Protocol Amendment 5:
-The number of subjects planned for enrollment was reduced from approximately 40 subjects to at least 19 subjects.
-The number of expected evaluable subjects was decreased from 34 subjects to 13 subjects.
-The key secondary objectives were re-classified as secondary objectives.
-The BMB scoring was changed to follow the DeMayo et al. method instead of the Maas et al. method.
-The power provided by the sample size for the detection of change in the primary endpoint was changed from 99% to 90%.
-The early subject discontinuation rate previously estimated at 15% was revised to 30%.
-Viral testing was removed from the list of screening visit assessments. |
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02 Oct 2020 |
Protocol Amendment 6:
- Two new objectives and endpoints were added.
Objective:
* BMD as measured by the change from baseline in g/cm2 after 12 months of treatment.
* BMD as measured by the change from baseline in g/cm2 after 24 months of treatment.
Endpoints:
* Change from baseline to 12 months (Week 51) in BMD reported as g/cm2. Assessments will be performed at the screening visit and Weeks 51.
* Change from baseline to 24 months (Week 103 [end of study]) in BMD reported as g/cm2. Assessments will be performed at the screening visit and Week 103 (end of study)
- The Brief Pain Inventory – Short Form was updated to “Questions taken from the BPI-SF©”
- Added the optional transfer of study visit weeks 77 and/or 89 to home therapy and the addition of dose continuation infusions due to the COVID-19 pandemic.
- Added that infusion of VPRIV may be delivered intravenously with an in-line sterilizing filter that has a rated pore size of 0.22 micrometer (mcm). |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
