Phase 3b Study to Evaluate Skeletal Response to Eliglustat in Adult Patients Who Completed Phase 2 or Phase 3 Studies

Phase 3

Completed

Conditions: Gaucher Disease

Interventions: Drug: Eliglustat, GZ385660

Registration Number: NCT02536755

Lead Sponsor: Genzyme, a Sanofi Company

Brief Summary: Primary Objective:

Evaluate long term skeletal response to eliglustat in adult participants who successfully completed one of the Phase 2 or Phase 3 eliglustat studies.

Secondary Objective:

Evaluate the safety of eliglustat (by serious adverse event continuous monitoring), the quality of life (Short Form-36 Health Survey \[SF-36\]) and biomarkers of Gaucher disease type 1 (GD1) (chitotriosidase, plasma glucosylceramide \[GL-1\] and lyso glucosylceramide \[lyso-GL-1\]) in adult participants who successfully completed one of the Phase 2 or Phase 3 studies.

Detailed Description: Study duration for individual participants was to be of minimum 2 years and up to 4 years, or until commercial eliglustat was available to participants through reimbursement. If after 4 years since the beginning of the study eliglustat was not approved and available to participants in participating country, participants in this country might continue to receive study treatment until eliglustat was available to participants through the compassionate use (expanded access) program or was approved and available through reimbursement, whichever came first.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 31

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Eliglustat	Eliglustat, GZ385660	Participants who completed one of the Phase 2 (GZGD00304 \[NCT00358150\]) or Phase 3 studies (GZGD02507 \[NCT00891202\], GZGD02607 \[NCT00943111\], or GZGD03109 \[NCT01074944\]) were enrolled in this current (EFC13781) study. Participants who were cytochrome P450 (CYP) 2D6 intermediate metabolizer (IM), extensive metabolizer (EM) and ultra-rapid metabolizers (URM) received eliglustat 84 milligrams (mg) twice daily and participants who were CYP2D6 poor metabolizer (PM) received eliglustat 84 mg once daily, for duration of minimum 2 years (unless early discontinuation occurred) and up to 4 years, or until commercial eliglustat was available to participants through reimbursement or through the compassionate use (expanded access) program.

Primary Outcome Measures

Name	Time	Method
Change From Current Study Baseline in Total Bone Marrow Burden (BMB) Scores at Weeks 52, 104, 156 and 208	Study Baseline, Weeks 52, 104, 156 and 208	Bone marrow burden (BMB) scores indicate the degree of bone marrow infiltration. BMB score was measured using MRI (magnetic resonance imaging (MRI), ranged 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. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Change From Eliglustat Baseline in Total Bone Marrow Burden (BMB) Scores at Weeks 52, 104, 156 and 208	Eliglustat Baseline, Weeks 52, 104, 156 and 208 of the current study	Bone marrow burden (BMB) scores indicate the degree of bone marrow infiltration was measured using MRI, ranged 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. For this outcome measure, baseline refers to the eliglustat baseline, which was defined as participant's status at the time of first dose of eliglustat in the previous Phase 2 or Phase 3 study.
Change From Eliglustat Baseline in Bone Biomarker Level: Macrophage Inflammatory Protein 1 Beta (MIP-1β) at Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234	Eliglustat Baseline, Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234 of the current study	MIP-1β considered a biomarker of active bone disease, was assayed from plasma. For this outcome measure, baseline refers to the eliglustat baseline, which was defined as participant's status at the time of first dose of eliglustat in the previous Phase 2 or Phase 3 study.
Number of Participants With Bone Pain Levels During the Past 4 Weeks at Study Baseline, Weeks 52, 104, 156 and 208	Study Baseline, Weeks 52, 104, 156 and 208	Bone pain was assessed as a part of Gaucher disease assessment in participants. Participants were categorized as none (no bone pain), very mild bone pain, mild bone pain, moderate bone pain, severe bone pain and extreme bone pain during the past 4 weeks at each specified visit. In this outcome measure, number of participants with different level of bone pain during the past 4 weeks at specified time points were reported. Baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Change From Eliglustat Baseline in Total Spine and Femur Bone Mineral Density (BMD) at Weeks 52, 104, 156 and 208	Eliglustat Baseline, Weeks 52, 104, 156 and 208 of the current study	BMD measurements of the spine and bilateral femur were acquired by DXA scan. Worst total femur at Baseline refers to the "worst" diseased left or right femur at baseline. For this outcome measure, baseline refers to the eliglustat baseline, which was defined as participant's status at the time of first dose of eliglustat in the previous Phase 2 or Phase 3 study.
Number of Participants With Mobility Status Assessments at Study Baseline, Weeks 52, 104, 156 and 208	Study Baseline, Weeks 52, 104, 156 and 208	Mobility, i.e., ability to walk was assessed as a part of Gaucher disease assessment in participants. In this outcome measure, number of participants with their different mobility status along with the use of mobility aids (unrestricted mobility, walks with difficulty, walks with orthopaedic aid, requires wheelchair, bedridden) at specified time points were reported. Baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Number of Participants With Bone Crisis at Study Baseline, Weeks 52, 104, 156 and 208	Study Baseline, Weeks 52, 104, 156 and 208	Bone crisis was assessed as a part of Gaucher disease assessment in participants. Acute, excruciating episodic bone pain is characteristic of Gaucher bone crisis, which typically causes periosteal elevation, elevated white blood cell count, fever, or debilitation lasting several days or longer and requires treatment with immobilization of the affected area, and opioid analgesics. Participants were categorized as 0= no bone crisis, 1= 1 bone crisis, 2= 2 bone crisis and \>=3 = more than 3 bone crisis during the assessment period. In this outcome measure, number of participants with different bone crises levels at specified time points were reported. Baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Change From Current Study Baseline in Total Spine and Femur Bone Mineral Density (BMD) at Weeks 52, 104, 156 and 208	Study Baseline, Weeks 52, 104, 156 and 208	Bone Mineral Density (BMD) measurements of the spine and bilateral femur were acquired by dual energy X-Ray absorptiometry (DXA) scan. Worst total femur at Baseline refers to the "worst" diseased left or right femur at Baseline. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Change From Current Study Baseline in Spine and Femur Total T-Scores for BMD at Weeks 52, 104, 156 and 208	Study Baseline, Weeks 52, 104, 156 and 208	BMD measurements of the spine and bilateral femur were acquired by DXA scan. The T-score bone density categories were: normal (score \>-1), osteopenia (score -2.5 to \<=-1), and osteoporosis (score \<= -2.5). Worst total femur at Baseline refers to the "worst" diseased left or right femur at baseline. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Change From Current Study Baseline in Spine and Femur Total Z-Scores for BMD at Weeks 52, 104, 156 and 208	Study Baseline, Weeks 52, 104, 156 and 208	BMD measurements of the spine and bilateral femur were acquired by DXA scan. The Z-score bone density categories were: normal (score \>-2) and below normal (score \<=-2). Worst total femur at Baseline refers to the "worst" diseased left or right femur at baseline. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Total Number of New or Worsening Osteonecrosis Events for Spine and Femur at Study Baseline, Week 52, 104, 156 and 208	Study Baseline, Weeks 52, 104, 156 and 208	Osteonecrosis was assessed by bone MRI and X-Ray for spine and by MRI for femur. Total number of new or worsening osteonecrosis events among all the participants with corresponding assessment at specified time points were reported in this outcome measure. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Observed Annual Incidence Rate for Spine Lytic Lesion at Week 104, and 208	For 104 Weeks (i.e., 2 year), and 208 Weeks (i.e., 4 years)	Observed annual incidence rate was estimated using the total number of events divided by the total years of follow-up in each specified year (for all participants). Lytic Lesions were assessed by bone X-Ray for spine.
Change From Current Study Baseline in Bone Biomarker Level: Macrophage Inflammatory Protein 1 Beta (MIP-1β) at Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234	Study Baseline, Weeks 26, 52, 78, 104, 130, 156, 182, 208 and 234	MIP-1β considered a biomarker of active bone disease, was assayed from plasma. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Change From Current Study Baseline in Bone Biomarker Level: Procollagen 1 N- Terminal Propeptide (P1NP) at Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234	Study Baseline, Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234	P1NP, a marker of bone formation was assayed from plasma. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Change From Eliglustat Baseline in Spine and Femur Total T-Scores for BMD at Weeks 52, 104, 156 and 208	Eliglustat Baseline, Weeks 52, 104, 156 and 208 of the current study	BMD measurements of the spine and bilateral femur were acquired by DXA scan. The T-score bone density categories were: normal (score \>-1), osteopenia (score -2.5 to \<=-1), and osteoporosis (score \<= -2.5). Worst total femur at Baseline refers to the "worst" diseased left or right femur at baseline. For this outcome measure, baseline refers to the eliglustat baseline, which was defined as participant's status at the time of first dose of eliglustat in the previous Phase 2 or Phase 3 study.
Total Number of New or Worsening Fracture Events for Spine and Femur at Study Baseline, Week 52, 104, 156 and 208	Study Baseline, Weeks 52, 104, 156 and 208	Fracture was assessed by bone MRI and X-Ray for spine and by MRI for femur. Total number of new or worsening fracture events among all the participants with corresponding assessment at specified time points were reported in this outcome measure. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Total Number of New or Worsening Infarcts Events for Spine and Femur at Study Baseline, Week 52, 104, 156 and 208	Study Baseline, Weeks 52, 104, 156 and 208	Infarcts were assessed by bone MRI and X-Ray for spine and by MRI for femur. Total number of new or worsening infarcts events among all the participants with corresponding assessment at specified time points were reported in this outcome measure. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Observed Annual Incidence Rate for Spine and Femur Osteonecrosis at Week 52, 104, 156 and 208	For 52 Weeks (i.e., 1 year),104 Weeks (i.e., 2 year), 156 Weeks (i.e., 3 year) and 208 Weeks (i.e., 4 years)	Observed annual incidence rate was estimated using the total number of events divided by the total years of follow-up in each specified year (for all participants). Osteonecrosis was assessed by bone MRI and X-Ray for spine and by MRI for femur.
Observed Annual Incidence Rate for Spine and Femur Fracture at Week 52, 104, 156 and 208	For 52 Weeks (i.e., 1 year),104 Weeks (i.e., 2 year), 156 Weeks (i.e., 3 year) and 208 Weeks (i.e., 4 years)	Observed annual incidence rate was estimated using the total number of events divided by the total years of follow-up in each specified year (for all participants). Fracture was assessed by bone MRI and X-Ray for spine and by MRI for femur.
Change From Eliglustat Baseline in Bone Biomarker Level: Procollagen 1 N- Terminal Propeptide (P1NP) at Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234	Eliglustat Baseline, Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234 of the current study	P1NP, a marker of bone formation was assayed from plasma. For this outcome measure, baseline refers to the eliglustat baseline, which was defined as participant's status at the time of first dose of eliglustat in the previous Phase 2 or Phase 3 study.
Change From Eliglustat Baseline in Spine and Femur Total Z-Scores for BMD at Weeks 52, 104, 156 and 208	Eliglustat Baseline, Weeks 52, 104, 156 and 208 of the current study	BMD measurements of the spine and bilateral femur were acquired by DXA scan. The Z-score bone density categories are: normal (score \>-2) and below normal (score \<=-2). Worst total femur at Baseline refers to the "worst" diseased left or right femur at baseline. For this outcome measure, baseline refers to the eliglustat baseline, which was defined as participant's status at the time of first dose of eliglustat in the previous Phase 2 or Phase 3 study.
Total Number of New or Worsening Lytic Lesions Events for Spine at Study Baseline, Week 104, and 208	Study Baseline, Weeks 104, and 208	Lytic Lesions were assessed by bone X-Ray for spine. Total number of new or worsening lytic lesions events among all the participants with corresponding assessment at specified time points were reported in this outcome measure. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Observed Annual Incidence Rate for Spine and Femur Infarcts at Week 52, 104, 156 and 208	For 52 Weeks (i.e., 1 year),104 Weeks (i.e., 2 year), 156 Weeks (i.e., 3 year) and 208 Weeks (i.e., 4 years)	Observed annual incidence rate was estimated using the total number of events divided by the total years of follow-up in each specified year (for all participants). Infarcts were assessed by bone MRI and X-Ray for spine and by MRI for femur.
Change From Eliglustat Baseline in Bone Biomarker Level: Type 1 Collagen C-Telopeptides (CTx) at Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234	Eliglustat Baseline, Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234 of the current study	CTx, a marker of bone resorption was assayed from plasma. For this outcome measure, baseline refers to the eliglustat baseline, which was defined as participant's status at the time of first dose of eliglustat in the previous Phase 2 or Phase 3 study.
Change From Current Study Baseline in Bone Biomarker Level: Type 1 Collagen C-Telopeptides (CTx) at Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234	Study Baseline, Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234	CTx, a marker of bone resorption was assayed from plasma. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.

Secondary Outcome Measures

Name	Time	Method
Change From Eliglustat Baseline in SF-36 Scores at Weeks 26, 52, 78, 104, 130, 156, 182, 208 and 234	Eliglustat Baseline, Weeks 26, 52, 78, 104, 130, 156, 182, 208 and 234 of the current study	SF-36 is a standardized survey evaluating 8 aspects of functional health and well-being. PCS with 4 sub-scales: physical function, role limitations due to physical problems, pain, and general health perception; and MCS with 4 sub-scales: vitality, social function, role limitations due to emotional problems, and mental health. Summations of item scores of same sub-scale give the sub-scale scores, which are transformed into range from 0 to 100; 0= worst, and 100=best outcome. Both PCS and MCS range from 0 to 100, higher scores indicating better physical and mental health. For this outcome measure, baseline refers to the eliglustat baseline, which was defined as participant's status at the time of first dose of eliglustat in the previous Phase 2 or Phase 3 study.
Change From Eliglustat Baseline in Gaucher Disease Type 1 (GD1) Biomarker Levels: Chitotriosidase at Week 26, 52, 78, 104, 130, 156, 182, 208 and 234	Eliglustat Baseline, Week 26, 52, 78, 104, 130, 156, 182, 208 and 234 of the current study	Chitotriosidase biomarker was assayed from plasma. Chitotriosidase biomarker levels for participants who were CYP2D6 non-URM was reported in this outcome measure. For this outcome measure, baseline refers to the eliglustat baseline, which was defined as participant's status at the time of first dose of eliglustat in the previous Phase 2 or Phase 3 study. Data for this outcome measure was planned to be collected and analyzed in reference to eliglustat baseline separately for Phase 2, ENGAGE and EDGE studies (GD treatment naïve participants) and from ENCORE study (participants switched from ERT).
Change From Current Study Baseline in GD1 Biomarker Levels: Glucosylceramide (GL-1) at Week 26, 52, 78, 104, 130, 156, 182, 208 and 234	Study Baseline, Week 26, 52, 78, 104, 130, 156, 182, 208 and 234	Glucosylceramide (GL-1) biomarker was assayed from plasma. GL-1 biomarker levels for participants who were CYP2D6 non-URM was reported in this outcome measure. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Change From Current Study Baseline in GD1 Biomarker Levels: Lyso Glucosylceramide (Lyso-GL-1) at Week 26, 52, 78, 104, 130, 156, 182, 208 and 234	Study Baseline, Week 26, 52, 78, 104, 130, 156, 182, 208 and 234	Lyso-GL-1 biomarker was assayed from plasma. Lyso-GL-1 biomarker levels for participants who were CYP2D6 non-URM was reported in this outcome measure. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Change From Current Study Baseline in Gaucher Disease Type 1 (GD1) Biomarker Levels: Chitotriosidase at Week 26, 52, 78, 104, 130, 156, 182, 208 and 234	Study Baseline, Week 26, 52, 78, 104, 130, 156, 182, 208 and 234	Chitotriosidase biomarker was assayed from plasma. Chitotriosidase biomarker levels for participants who were CYP2D6 non-Ultra Rapid Metabolizers (non-URM) was reported in this outcome measure. For this outcome measure, baseline refers to the study baseline, which was defined as status at study entry.
Change From Eliglustat Baseline in GD1 Biomarker Levels: Glucosylceramide (GL-1) at Week 26, 52, 78, 104, 130, 156, 182, 208 and 234	Eliglustat Baseline, Week 26, 52, 78, 104, 130, 156, 182, 208 and 234 of the current study	Glucosylceramide (GL-1) biomarker was assayed from plasma. GL-1 biomarker levels for participants who were CYP2D6 non-URM was reported in this outcome measure. For this outcome measure, baseline refers to the eliglustat baseline, which was defined as participant's status at the time of first dose of eliglustat in the previous Phase 2 or Phase 3 study. Data for this outcome measure was planned to be collected and analyzed in reference to eliglustat baseline separately for participants from Phase 2, ENGAGE and EDGE studies (GD treatment naïve participants) and from ENCORE study (participants switched from ERT).
Change From Eliglustat Baseline in GD1 Biomarker Levels: Lyso Glucosylceramide (Lyso-GL-1) at Week 26, 52, 78, 104, 130, 156, 182, 208 and 234	Eliglustat Baseline, Week 26, 52, 78, 104, 130, 156, 182, 208 and 234 of the current study	Lyso-GL-1 biomarker was assayed from plasma. Lyso-GL-1 biomarker levels for participants who were CYP2D6 non-URM was reported in this outcome measure. For this outcome measure, baseline refers to the eliglustat baseline, which was defined as participant's status at the time of first dose of eliglustat in the previous Phase 2 or Phase 3 study. Data for this outcome measure was planned to be collected and analyzed in reference to eliglustat baseline separately for participants from Phase 2, ENGAGE and EDGE studies (GD treatment naïve participants) and from ENCORE study (participants switched from ERT).
Change From Current Study Baseline in Short Form-36 Health Survey (SF-36) Scores at Weeks 26, 52, 78, 104, 130, 156, 182, 208 and 234	Study Baseline, Weeks 26, 52, 78, 104, 130, 156, 182, 208 and 234	The 36-Item Short-Form Health Survey (SF-36) is standardized survey evaluating 8 aspects of functional health and well-being. Physical Component Summary (PCS) with 4 sub-scales: physical function, role limitations due to physical problems, bodily pain, and general health perception; and Mental Component Summary (MCS) with 4 sub-scales: vitality, social function, role limitations due to emotional problems, and mental health. Summations of item scores of the same sub-scale give the sub-scale scores, which are transformed into a range from 0 to 100; 0= worst and 100=best outcome. Both PCS and MCS range from 0 to 100 with higher scores indicating better physical and mental health. For this outcome measure, baseline refers to the current study baseline, which was defined as status at this study (EFC13781) entry.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)	From the first administration of the IMP to the last administration of the IMP + 5 days (up to 4 years, or until commercial eliglustat was available to participants through reimbursement or through the compassionate use [expanded access] program)	An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had to have a causal relationship with the treatment. A serious adverse event (SAE) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the treatment-emergent period (time from the first administration of the investigational medicinal product (IMP) to the last administration of the IMP + 5 days).

Trial Locations

Locations (4): Investigational Site Number 124002
🇨🇦
Montreal, Canada
Investigational Site Number 788001
🇹🇳
Tunis, Tunisia
Investigational Site Number 643002
🇷🇺
St-Petersburg, Russian Federation
Investigational Site Number 643001
🇷🇺
Moscow, Russian Federation