NCT02536755 - Phase 3b Study to Evaluate Skeletal Response to Eliglustat in Adult Patients Who Completed Phase 2 or Phase 3 Studies | Crick | Crick

NCT02536755 - Phase 3b Study to Evaluate Skeletal Response to Eliglustat in Adult Patients Who Completed Phase 2 or Phase 3 Studies | Crick | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion criteria : * The participant must have successfully completed the Phase 2 (GZGD00304) or a Phase 3 study (GZGD02507, GZGD02607 or GZGD03109). Successful completion was defined as participants enrolled in one of the above mentioned studies who received eliglustat through the end of the study and completed the end-of-study visit without having discontinued or been withdrawn prematurely. * The participant was willing and able to provide signed informed consent prior to any protocol-required procedures being performed. * Female participants of childbearing potential must have had a documented negative pregnancy test prior to enrollment and while they were receiving eliglustat treatment. * Female participants of childbearing potential must have been willing to practice true abstinence in line with their preferred and usual lifestyle, or used a medically accepted form of contraception (either a barrier method, such as condom or diaphragm + spermicide, or a non-barrier method such as oral, injected, or implanted hormonal methods, or an intra-uterine device or system) while receiving eliglustat. Exclusion criteria: * The participant was unwilling to comply with the requirements of the protocol. * The participant had received an investigational product (other than eliglustat) within 30 days prior to enrollment. * The participant had received miglustat within the 6 months prior to enrollment. * The participant had documented prior esophageal varices or liver infarction or current liver enzymes (alanine transaminase, aspartate aminotransferase) or total bilirubin greater than (\>)2 times the upper limit of normal, unless the participant had a diagnosis of Gilbert Syndrome. * The participant had any clinically significant disease, other than Gaucher disease, including cardiovascular, renal, hepatic, gastrointestinal, pulmonary, neurologic, endocrine, metabolic (eg, hypokalemia, hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illnesses that might preclude participation in the study. * The participant was known to have any of the following: cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, or current treatment with Class IA or Class III antiarrhythmic medicinal products. * The participant had tested positive for the human immunodeficiency virus antibody, hepatitis C antibody, or hepatitis B surface antigen. * The participant had a history of cancer within 6 months of enrolment, with the exception of basal cell carcinoma. * Participant was a CYP2D6 IM, EM or URM and was taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor. * Participant was a CYP2D6 PM having taken a strong CYP3A inhibitor within 2 weeks prior to enrolment. * If a female participant of childbearing potential had a positive pregnancy test (blood β-human chorionic gonadotropin \[β-HCG\]) or was breastfeeding prior to first dosing of eliglustat in this study, the participant could not enroll in the study at that time, but might have been rescreened after the end of the pregnancy, and/or when she was no longer breast feeding, provided rescreening took place before the end of the enrollment period. * Women of childbearing potential who were unwilling or unable to be tested for pregnancy. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Outcomes

Primary Outcomes

Number of Participants With Mobility Status Assessments at 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.

Time frame: Study Baseline, Weeks 52, 104, 156 and 208

Number of Participants With Bone Pain Levels During the Past 4 Weeks at 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.

Time frame: Study Baseline, Weeks 52, 104, 156 and 208

Number of Participants With Bone Crisis at 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.

Time frame: Study Baseline, Weeks 52, 104, 156 and 208

Change From Current Study Baseline in Total Bone Marrow Burden (BMB) Scores at 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.

Time frame: Study Baseline, Weeks 52, 104, 156 and 208

Change From Eliglustat Baseline in Total Bone Marrow Burden (BMB) Scores at Weeks 52, 104, 156 and 208

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.

Time frame: Eliglustat Baseline, Weeks 52, 104, 156 and 208 of the current study

Change From Current Study Baseline in Total Spine and Femur Bone Mineral Density (BMD) at 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.

Time frame: Study Baseline, Weeks 52, 104, 156 and 208

Change From Eliglustat Baseline in Total Spine and Femur Bone Mineral Density (BMD) at Weeks 52, 104, 156 and 208

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.

Time frame: Eliglustat Baseline, Weeks 52, 104, 156 and 208 of the current study

Change From Current Study Baseline in Spine and Femur Total T-Scores for BMD at 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.

Time frame: Study Baseline, Weeks 52, 104, 156 and 208

Change From Eliglustat Baseline in Spine and Femur Total T-Scores for BMD at 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 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.

Time frame: Eliglustat Baseline, Weeks 52, 104, 156 and 208 of the current study

Change From Current Study Baseline in Spine and Femur Total Z-Scores for BMD at 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.

Time frame: Study Baseline, Weeks 52, 104, 156 and 208

Change From Eliglustat Baseline in Spine and Femur Total Z-Scores for BMD at 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 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.

Time frame: Eliglustat Baseline, Weeks 52, 104, 156 and 208 of the current study

Total Number of New or Worsening Osteonecrosis Events for Spine and Femur at Study Baseline, Week 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.

Time frame: Study Baseline, Weeks 52, 104, 156 and 208

Total Number of New or Worsening Fracture Events for Spine and Femur at Study Baseline, Week 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.

Time frame: Study Baseline, Weeks 52, 104, 156 and 208

Total Number of New or Worsening Infarcts Events for Spine and Femur at Study Baseline, Week 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.

Time frame: Study Baseline, Weeks 52, 104, 156 and 208

Total Number of New or Worsening Lytic Lesions Events for Spine at Study Baseline, Week 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.

Time frame: Study Baseline, Weeks 104, and 208

Observed Annual Incidence Rate for Spine and Femur Osteonecrosis at Week 52, 104, 156 and 208

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.

Time frame: 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 for Spine and Femur Fracture at Week 52, 104, 156 and 208

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.

Time frame: 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 for Spine and Femur Infarcts at Week 52, 104, 156 and 208

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.

Time frame: 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 for Spine Lytic Lesion at Week 104, and 208

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.

Time frame: For 104 Weeks (i.e., 2 year), and 208 Weeks (i.e., 4 years)

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

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.

Time frame: Study Baseline, Weeks 26, 52, 78, 104, 130, 156, 182, 208 and 234

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

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.

Time frame: Eliglustat Baseline, Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234 of the current study

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

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.

Time frame: Study Baseline, Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234

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

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.

Time frame: Eliglustat Baseline, Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234 of the current 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

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.

Time frame: Study Baseline, Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234

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

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.

Time frame: Eliglustat Baseline, Weeks 26, 52, 78, 104, 130, 156,182, 208 and 234 of the current study

Secondary Outcomes

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

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.

Time frame: Study Baseline, Week 26, 52, 78, 104, 130, 156, 182, 208 and 234

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

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).

Time frame: Eliglustat Baseline, Week 26, 52, 78, 104, 130, 156, 182, 208 and 234 of the current study

Change From Current Study Baseline in GD1 Biomarker Levels: Glucosylceramide (GL-1) at 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.

Time frame: Study Baseline, Week 26, 52, 78, 104, 130, 156, 182, 208 and 234

Change From Eliglustat Baseline in GD1 Biomarker Levels: Glucosylceramide (GL-1) at 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 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).