Gaucher Disease
Conditions
Brief summary
Gaucher disease is an inherited deficiency of the lysosomal enzyme glucocerebrosidase (GCB) that leads to progressive accumulation of glucocerebroside within macrophages and subsequent tissue and organ damage; typically of the liver, spleen, bone marrow, and brain. Type 1 Gaucher disease affects an estimated 30,000 persons worldwide and is the most common. Type 1 Gaucher disease does not involve the central nervous system. Patients with Type 2 Gaucher disease present with acute neurological deterioration, which leads to early death. Those with Type 3 disease typically display a more sub-acute neurological course, with later onset and slower progression. The primary objective of this study is to evaluate the long-term safety of every other week (EOW) dosing of velaglucerase alfa in Japanese patients with Gaucher disease who completed study HGT-GCB-087 and elected to continue treatment with velaglucerase alfa. Velaglucerase alfa has been developed and approved as an enzyme replacement therapy for Type 1 Gaucher disease.
Detailed description
Gaucher disease is an inherited deficiency of the lysosomal enzyme glucocerebrosidase (GCB) that leads to progressive accumulation of glucocerebroside within macrophages and subsequent tissue and organ damage; typically of the liver, spleen, bone marrow, and brain. Gaucher disease has been designated in the list of Specified Rare and Intractable Diseases by Specified Disease Treatment Research Program of Ministry of Health, Labor and Welfare (MHLW) as one of lysosomal storage diseases since 2001. Gaucher disease is also designated in the Medical Aid Program for Specified Categories of Chronic Pediatric Diseases. The prevalence of mutations and the phenotype of patients with Gaucher disease in Japan differs from that in non-Japanese populations. Some patients with type 1 Gaucher disease in Japan have more severe and progressive disease compared to non-Japanese patients and the disease is characterized by an earlier onset of symptoms. Velaglucerase alfa, a highly-purified form of the naturally occurring enzyme glucocerebrosidase, has been developed as an enzyme replacement therapy for Gaucher disease for the symptoms (anemia, thrombocytopenia, hepatomegaly, splenomegaly, and bone manifestation). The primary objective of this study is to evaluate the long-term safety of every other week (EOW) dosing of velaglucerase alfa in Japanese patients with Gaucher disease who completed study HGT-GCB-087 and elected to continue treatment with velaglucerase alfa.
Interventions
15-60 U/kg, EOW
Sponsors
Quintiles, Inc.
Shire
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The patient has completed treatment with EOW velaglucerase alfa through Week 51 of study HGT-GCB-087. * Female patients of child bearing potential must agree to use a medically acceptable method of contraception at all times during the study. * 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
* The patient has received treatment with any investigational drug, other than velaglucerase alfa, or investigational device within 30 days prior to study entry; such use during the study is not permitted. * 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, as determined by the Investigator that might affect study data or confound the study results. * The patient is unable to comply with the protocol as determined by the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Positive Anti-Velaglucerase Alfa Antibodies | From Week 65 until the end of study (Week 155) | Serum samples were collected for all participants for determination of anti-velaglucerase alfa antibodies every 12 weeks. |
| Number of Participants With Drug-related Adverse Events (AEs), Infusion-related AEs, and Serious AEs (SAEs) | From the day of first infusion (Week 53) up to 30 days after last infusion (approximately 107 weeks) | An AE was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered related to investigational product. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. An infusion-related AE was defined as an AE that started either during or within 12 hours after the start of the infusion and that was judged as possibly or probably related to investigational product. |
| Number of Participants Using Concomitant Medication | From the day of first infusion (Week 53) up to 30 days after last infusion (approximately 107 weeks) | — |
| Number of Participants With Abnormal and Clinically Significant Laboratory Test Results | From Week 65 until the end of study (Week 155) | Laboratory test results were considered abnormal and clinically significant at the discretion of the investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Bone Mineral Density (BMD) at Week 103: Z Score | Baseline, Week 103 | BMD was measured by dual energy x-ray absorptiometry (DXA) for lumbar spine and femurs. To ensure standardization and allow for comparisons of BMD, results were converted to standardized Z-scores (matched for age and gender). Z-scores express the BMD as the number of standard deviations (SDs) above or below the average BMD of a healthy participant of the same age and gender. Statistical analysis plan only required summarization if greater than (\>) 50 percent (%) of participants had evaluable data. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint. |
| Change From Baseline in Bone Mineral Density (BMD) at Week 103: T-Score | Baseline, Week 103 | BMD was measured by DXA for lumbar spine and femurs. To ensure standardization and allow for comparisons of BMD, results were converted to standardized T-scores; normal values were used from databases from Hologic based on standard criteria. T-scores are the number of SDs above or below the average for a young adult at peak BMD. Statistical analysis plan only required summarization if \>50% of participants had evaluable data. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint. |
| Change From Baseline in Bone Marrow Burden (BMB) Score at Week 103 | Baseline, Week 103 | BMB Score was measured using 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 score was calculated as the sum of scores for femur and lumbar spine regions which ranged from 0-16 points. A higher BMB score signified more severe bone marrow involvement. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint. |
| Change From Baseline in Growth Velocity at Week 101 : Height Z-Score | Baseline, Week 101 | The Z-score, or Standard Deviation Score, is a measure of number of SDs above or below the average BMD of a healthy participant of the same age and gender. World Health Organization 2007 growth reference data were used for Z-score calculation. Statistical analysis plan only required summarization if \>50% of participants had evaluable data. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint. |
| Change From Baseline in Hemoglobin Concentration at Week 101 | Baseline, Week 101 | Baseline was the modified baseline hemoglobin concentration, the average of the values from screening, baseline, and Week 1 Day 1 from Study HGT-GCB-087 (NCT01614574). |
| Change From Baseline in Plasma Chitotriosidase Levels at Week 101 | Baseline, Week 101 | Plasma chitotriosidase activity levels were measured using an enzymatic assay with 4-methylumbelliferyl-deoxychitobiose as a substrate. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint. |
| Number of Participants With Change From Baseline in Neurological Status at Week 103 | Baseline, Week 103 | Neurological status was considered normal or abnormal based on investigator's discretion. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint. |
| Change From Baseline in Chemokine [C-C Motif] Ligand 18 (CCL18) Levels at Week 101 | Baseline, Week 101 | Plasma CCL18 concentrations were measured using a time-resolved fluorescence assay. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint. |
| Change From Baseline in Skeletal Age at Week 103: Z-Score | Baseline, Week 103 | Skeletal age was measured via radiography (X-ray) of the left hand and wrist by the method of Greulich and Pyle. The Z-score, or Standard Deviation Score, is a measure of number of SDs above or below the average BMD of a healthy participant of the same age and gender. Statistical analysis plan only required summarization if \>50% of participants had evaluable data. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint. |
| Change From Baseline in Platelet Count at Week 101 | Baseline, Week 101 | Baseline was the modified baseline platelet count, the average of the values from screening, baseline, and Week 1 Day 1 from Study HGT-GCB-087 (NCT01614574). |
| Change From Baseline in Liver Volume Normalized to Body Weight at Week 103 | Baseline, Week 103 | Liver volume was measured using magnetic resonance imaging (MRI). Liver volume measurements were normalized to the percentage of body weight. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint. |
| Change From Baseline in Spleen Volume Normalized to Body Weight at Week 103 | Baseline, Week 103 | Spleen volume was measured using MRI. Spleen volume measurements were normalized to the percentage of body weight. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint. |
Countries
Japan
Participant flow
Recruitment details
Participants from study HGT-GCB-087 (NCT01614574) were enrolled in this study except one participant who was not enrolled due to personal reasons.
Participants by arm
| Arm | Count |
|---|---|
| Velaglucerase Alfa (VPRIV®) Velaglucerase alfa (VPRIV®) 15 to 60 U/kg, EOW, administered as an IV infusion over 60 minutes from Week 53 (2 weeks after the last infusion \[Week 51\] in Study HGT-GCB-087 \[NCT01614574\]) to Week 155. | 5 |
| Total | 5 |
Baseline characteristics
| Characteristic | Velaglucerase Alfa (VPRIV®) |
|---|---|
| Age, Continuous | 22.20 years STANDARD_DEVIATION 11.946 |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 2 / 5 |
Outcome results
Primary
Number of Participants Using Concomitant Medication
Time frame: From the day of first infusion (Week 53) up to 30 days after last infusion (approximately 107 weeks)
Population: Safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velaglucerase Alfa (VPRIV®) | Number of Participants Using Concomitant Medication | 5 participants |
Primary
Number of Participants With Abnormal and Clinically Significant Laboratory Test Results
Laboratory test results were considered abnormal and clinically significant at the discretion of the investigator.
Time frame: From Week 65 until the end of study (Week 155)
Population: Safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velaglucerase Alfa (VPRIV®) | Number of Participants With Abnormal and Clinically Significant Laboratory Test Results | 1 participants |
Primary
Number of Participants With Drug-related Adverse Events (AEs), Infusion-related AEs, and Serious AEs (SAEs)
An AE was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered related to investigational product. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. An infusion-related AE was defined as an AE that started either during or within 12 hours after the start of the infusion and that was judged as possibly or probably related to investigational product.
Time frame: From the day of first infusion (Week 53) up to 30 days after last infusion (approximately 107 weeks)
Population: Safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Velaglucerase Alfa (VPRIV®) | Number of Participants With Drug-related Adverse Events (AEs), Infusion-related AEs, and Serious AEs (SAEs) | Study drug-related AEs | 2 participants |
| Velaglucerase Alfa (VPRIV®) | Number of Participants With Drug-related Adverse Events (AEs), Infusion-related AEs, and Serious AEs (SAEs) | Infusion-related AEs | 0 participants |
| Velaglucerase Alfa (VPRIV®) | Number of Participants With Drug-related Adverse Events (AEs), Infusion-related AEs, and Serious AEs (SAEs) | Serious AEs | 2 participants |
Primary
Number of Participants With Positive Anti-Velaglucerase Alfa Antibodies
Serum samples were collected for all participants for determination of anti-velaglucerase alfa antibodies every 12 weeks.
Time frame: From Week 65 until the end of study (Week 155)
Population: Safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velaglucerase Alfa (VPRIV®) | Number of Participants With Positive Anti-Velaglucerase Alfa Antibodies | 0 participants |
Secondary
Change From Baseline in Bone Marrow Burden (BMB) Score at Week 103
BMB Score was measured using 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 score was calculated as the sum of scores for femur and lumbar spine regions which ranged from 0-16 points. A higher BMB score signified more severe bone marrow involvement. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint.
Time frame: Baseline, Week 103
Population: Safety population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Velaglucerase Alfa (VPRIV®) | Change From Baseline in Bone Marrow Burden (BMB) Score at Week 103 | Lumbar spine scores | -1.2 units on a scale | Standard Deviation 1.79 |
| Velaglucerase Alfa (VPRIV®) | Change From Baseline in Bone Marrow Burden (BMB) Score at Week 103 | Femur scores | 0.0 units on a scale | Standard Deviation 2.12 |
| Velaglucerase Alfa (VPRIV®) | Change From Baseline in Bone Marrow Burden (BMB) Score at Week 103 | Total scores | -1.2 units on a scale | Standard Deviation 2.95 |
Secondary
Change From Baseline in Bone Mineral Density (BMD) at Week 103: T-Score
BMD was measured by DXA for lumbar spine and femurs. To ensure standardization and allow for comparisons of BMD, results were converted to standardized T-scores; normal values were used from databases from Hologic based on standard criteria. T-scores are the number of SDs above or below the average for a young adult at peak BMD. Statistical analysis plan only required summarization if \>50% of participants had evaluable data. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint.
Time frame: Baseline, Week 103
Population: Data was not reported as there were \<50% of participants with evaluable data.
Secondary
Change From Baseline in Bone Mineral Density (BMD) at Week 103: Z Score
BMD was measured by dual energy x-ray absorptiometry (DXA) for lumbar spine and femurs. To ensure standardization and allow for comparisons of BMD, results were converted to standardized Z-scores (matched for age and gender). Z-scores express the BMD as the number of standard deviations (SDs) above or below the average BMD of a healthy participant of the same age and gender. Statistical analysis plan only required summarization if greater than (\>) 50 percent (%) of participants had evaluable data. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint.
Time frame: Baseline, Week 103
Population: Data was not reported as there were lesser than (\<) 50% of participants with evaluable data.
Secondary
Change From Baseline in Chemokine [C-C Motif] Ligand 18 (CCL18) Levels at Week 101
Plasma CCL18 concentrations were measured using a time-resolved fluorescence assay. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint.
Time frame: Baseline, Week 101
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Velaglucerase Alfa (VPRIV®) | Change From Baseline in Chemokine [C-C Motif] Ligand 18 (CCL18) Levels at Week 101 | -11.4 nanogram per milliliter (ng/mL) | Standard Deviation 50.97 |
Secondary
Change From Baseline in Growth Velocity at Week 101 : Height Z-Score
The Z-score, or Standard Deviation Score, is a measure of number of SDs above or below the average BMD of a healthy participant of the same age and gender. World Health Organization 2007 growth reference data were used for Z-score calculation. Statistical analysis plan only required summarization if \>50% of participants had evaluable data. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint.
Time frame: Baseline, Week 101
Population: Data was not reported as there was \<50% of participants had evaluable data.
Secondary
Change From Baseline in Hemoglobin Concentration at Week 101
Baseline was the modified baseline hemoglobin concentration, the average of the values from screening, baseline, and Week 1 Day 1 from Study HGT-GCB-087 (NCT01614574).
Time frame: Baseline, Week 101
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Velaglucerase Alfa (VPRIV®) | Change From Baseline in Hemoglobin Concentration at Week 101 | 0.22 gram per deciliter (g/dL) | Standard Deviation 0.817 |
Secondary
Change From Baseline in Liver Volume Normalized to Body Weight at Week 103
Liver volume was measured using magnetic resonance imaging (MRI). Liver volume measurements were normalized to the percentage of body weight. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint.
Time frame: Baseline, Week 103
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Velaglucerase Alfa (VPRIV®) | Change From Baseline in Liver Volume Normalized to Body Weight at Week 103 | 0.01 Percentage of body weight | Standard Deviation 0.207 |
Secondary
Change From Baseline in Plasma Chitotriosidase Levels at Week 101
Plasma chitotriosidase activity levels were measured using an enzymatic assay with 4-methylumbelliferyl-deoxychitobiose as a substrate. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint.
Time frame: Baseline, Week 101
Population: Safety population. Number of participants analyzed signifies participants who were not deficient at baseline in chitotriosidase activity or who did not have a 24 base pair duplication in either copy of the chitotriosidase gene.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Velaglucerase Alfa (VPRIV®) | Change From Baseline in Plasma Chitotriosidase Levels at Week 101 | -181.0 nanomole/milliliter/hour (nmol/mL/h) | Standard Deviation 268.7 |
Secondary
Change From Baseline in Platelet Count at Week 101
Baseline was the modified baseline platelet count, the average of the values from screening, baseline, and Week 1 Day 1 from Study HGT-GCB-087 (NCT01614574).
Time frame: Baseline, Week 101
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Velaglucerase Alfa (VPRIV®) | Change From Baseline in Platelet Count at Week 101 | 9.8 *10^9 platelets per liter | Standard Deviation 13.14 |
Secondary
Change From Baseline in Skeletal Age at Week 103: Z-Score
Skeletal age was measured via radiography (X-ray) of the left hand and wrist by the method of Greulich and Pyle. The Z-score, or Standard Deviation Score, is a measure of number of SDs above or below the average BMD of a healthy participant of the same age and gender. Statistical analysis plan only required summarization if \>50% of participants had evaluable data. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint.
Time frame: Baseline, Week 103
Population: Data was not reported as there was \<50% of participants had evaluable data.
Secondary
Change From Baseline in Spleen Volume Normalized to Body Weight at Week 103
Spleen volume was measured using MRI. Spleen volume measurements were normalized to the percentage of body weight. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint.
Time frame: Baseline, Week 103
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Velaglucerase Alfa (VPRIV®) | Change From Baseline in Spleen Volume Normalized to Body Weight at Week 103 | 0.04 Percentage of body weight | Standard Deviation 0.089 |
Secondary
Number of Participants With Change From Baseline in Neurological Status at Week 103
Neurological status was considered normal or abnormal based on investigator's discretion. Week 51 of Study HGT-GCB-087 (NCT01614574) was considered as baseline for this endpoint.
Time frame: Baseline, Week 103
Population: Safety population. Number of participants analyzed signifies participants evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Velaglucerase Alfa (VPRIV®) | Number of Participants With Change From Baseline in Neurological Status at Week 103 | 0 participants |