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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Gaucher Disease

Intervention / Treatment
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* Drug: Velaglucerase alfa
* Dietary Supplement: Vitamin D


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Velaglucerase alfa 60 U/kg<br>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<br>* Participants will receive 60-minute intravenous infusion of 60 U/kg velaglucerase alfa EOW.<br>Dietary Supplement: Vitamin D<br>* Participants will receive 800 IU vitamin D orally daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-Score up to End of Study (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. | Baseline up to EOS (Week 103) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Lumbar Spine (LS) BMD Z-score at 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. | Baseline, Week 51 | 
| Change From Baseline in Lumbar Spine BMD at 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. | Baseline, Week 51 and EOS (Week 103) | 
| Change From Baseline in Total Bone Marrow Burden (BMB) Score at 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. | Baseline, Week 51 and EOS (Week 103) | 
| Change From Baseline in Hemoglobin Concentration at 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. | Baseline, Week 13, 25, 37, 51, 65, 77, 89, and EOS (Week 103) | 
| Change From Baseline in Platelet Count at 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. | Baseline, Week 13, 25, 37, 51, 65, 77, 89, and EOS (Week 103) | 
| Change From Baseline in Normalized Liver Volume at 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. | Baseline, Week 51 and EOS (Week 103) | 
| Change From Baseline in Normalized Spleen Volume at 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. | Baseline, Week 51 and EOS (Week 103) | 
| Change From Baseline in Severity of Bone Pain at 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. | Baseline, Week 51 and EOS (Week 103) | 
| Change From Baseline in Bone Pain Interference Score at 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. | Baseline, Week 51 and EOS (Week 103) | 
| Change From Baseline in Overall Fatigue Measured by Brief Fatigue Inventory (BFI) at 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. | Baseline, Week 51 and EOS (Week 103) | 
| Number of Participants With Shift in World Health Organization (WHO) BMD Classifications Based on LS T-Scores at 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. | Baseline, Week 51 and EOS (Week 103) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 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. | From start of study drug infusion up to follow-up (107 weeks) | 
| Number of Participants Who Developed Positive Anti-velaglucerase Alfa Antibody Status | 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. | Baseline up to EOS (Week 103) |