A Randomised, Placebo-controlled, Multi-dose Phase 2 Study to Determine the Efficacy, Safety and Tolerability of AMG 785 in the Treatment of Postmenopausal Women With Low Bone Mineral Density
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 419
- 主要终点
- Percent Change From Baseline at Month 12 in BMD at the Lumbar Spine
研究概览
简要总结
The primary objective was to determine the effect of treatment with romosozumab versus placebo at month 12 on the percent change from baseline in bone mineral density (BMD) at the lumbar spine in postmenopausal women with low bone density.
详细描述
This study included a 24-month treatment phase followed by rerandomization to a 12-month extension phase with denosumab or placebo, followed by a 12-month retreatment phase with romosozumab, followed by a 24-month follow-on phase with zoledronic acid or no intervention.
- 24-month Romosozumab Treatment Phase (months 1 to 24): Participants were randomized in a 1:1:1:1:1:1:1:1 ratio to receive 1 of 5 double-blind dosing regimens of romosozumab or placebo or open-label alendronate (ALN) or open-label teriparatide (TPTD) for the first 12 months of the study. At month 12, participants in the romosozumab and placebo groups continued their assigned treatment for an additional 12 months, participants in the TPTD group ended study participation, and participants in the ALN group transitioned to receive romosozumab 140 mg subcutaneously (SC) every month (QM) for an additional 12 months (months 12 to 24).
- 12-month Denosumab Extension Phase (months 24 to 36): At the end of the 24-month romosozumab treatment phase, eligible participants were randomized 1:1 within their original treatment group to receive either denosumab or placebo every 6 months (Q6M) for 12 months.
- 12-month Romosozumab Retreatment Phase (months 36 to 48): From months 36 to 48, participants initially randomized to romosozumab or placebo received romosozumab 210 mg SC QM. Participants who initially received ALN ended their participation at month 36 and were not retreated with romosozumab.
- 24-month Follow-on Phase (months 48 to 72): At month 48, participants received 1 dose of zoledronic acid 5 mg intravenously or no intervention for an additional 24 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 55 Years 至 85 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Ambulatory, postmenopausal women, aged ≥ 55 to ≤ 85
- •Low BMD measured by dual energy X-ray absorptiometry (DXA) and assessed by the central imaging vendor (equivalent to T-scores between -2.0 and -3.5)
排除标准
- •History of vertebral fracture, or fragility fracture of the wrist, humerus, hip or pelvis after age 50
- •Untreated hyper- or hypothyroidism
- •Current hyper- or hypoparathyroidism, hypo- or hypercalcemia
- •Elevated transaminases
- •Significantly impaired renal function
- •Positive for: human immunodeficiency virus (HIV), hepatitis-C or hepatitis-B surface antigen
- •Malignancy
- •History of solid organ or bone marrow transplants
- •Use of agents affecting bone metabolism
- •Contraindicated or intolerant of alendronate therapy
- •Contraindicated or intolerant of teriparatide therapy
- •Inclusion Criteria for the 12 month extension phase (Month 24 to 36):
- •Normocalcemia at or after the Month 21 visit but before the Month 24 study visit
- •Exclusion Criteria for the 12 month extension phase (Month 24 to 36)
- •Incidence of a clinical vertebral fracture or fragility fracture of the wrist, humerus, hip or pelvis during the initial 24 month treatment phase of the study
- •A BMD loss of ≥ 7.0% from baseline at any time up to the Month 18 visit of the initial 24-month treatment phase
- •Malignancy
- •History of osteonecrosis of the jaw
- •Use of proscribed medication during the initial 24 month treatment phase
- •Contraindicated or intolerant of denosumab therapy
- •Inclusion Criteria for the 12 month re-treatment phase (Month 36 to 48)
- •Albumin adjusted serum calcium of the most recent blood draw at or after the Month 30 visit but before the Month 36 study visit. Calcium repletion is permitted and central laboratory analysis of albumin adjusted serum calcium may be repeated before the Month 36 study visit
- •Participation in Group A or B during initial 24 month treatment phase
- •Subject has reached M36 of the study
- •Appropriate written informed consent must be obtained
- •Exclusion Criteria for the 12 month re-treatment phase (Month 36 to 48)
- •New malignancy
- •Use of proscribed medication during the 12 month extension phase
- •Inclusion Criteria for the 24 month follow-on phase (Month 48 to 72) General inclusion criteria for participation
- •Subject has reached month 48 of the study
- •Appropriate written informed consent must be obtained Inclusion criteria for assignment to the no intervention group
- •During the 24 month AMG 785 treatment phase, subject was assigned to any AMG 785 treatment group
- •During the 12 month denosumab extension phase, subject was assigned to the denosumab treatment group Exclusion for the 24 month follow-on phase (Month 48 to 72)
- •New malignancy
- •Use of proscribed meds during the 12 month re-treatment phase
- •Partial informed consent withdrawal and discontinuation of investigational product at any time up to month 48 visit
- •Incidence of a clinical vertebral fracture or fragility fracture of the wrist, humerus, hip or pelvis during the initial 24 month treatment phase of the study
- •BMD T-score of ≤ -2.5 at the lumbar spine, total hip, or femoral neck based on local read of the DXA scans at month 48
- •Intolerance to zoledronic acid
研究组 & 干预措施
Placebo
Participants received placebo matching to romosozumab once a month (QM) or once every 3 months (Q3M) administered subcutaneously (SC) for up to 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Placebo to Romosozumab (Drug)
Placebo
Participants received placebo matching to romosozumab once a month (QM) or once every 3 months (Q3M) administered subcutaneously (SC) for up to 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Denosumab (Drug)
Placebo
Participants received placebo matching to romosozumab once a month (QM) or once every 3 months (Q3M) administered subcutaneously (SC) for up to 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Placebo to Denosumab (Drug)
Placebo
Participants received placebo matching to romosozumab once a month (QM) or once every 3 months (Q3M) administered subcutaneously (SC) for up to 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Zoledronic acid (Drug)
Alendronate
Participants received open-label alendronate (ALN) 70 mg orally (PO) every week (QW) for 12 months. At month 12 participants transitioned to receive romosozumab 140 mg subcutaneously every month for an additional 12 months (months 12 to 24).
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. At month 36 participants ended study participation.
干预措施: Alendronate (Drug)
Alendronate
Participants received open-label alendronate (ALN) 70 mg orally (PO) every week (QW) for 12 months. At month 12 participants transitioned to receive romosozumab 140 mg subcutaneously every month for an additional 12 months (months 12 to 24).
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. At month 36 participants ended study participation.
干预措施: Romosozumab (Drug)
Alendronate
Participants received open-label alendronate (ALN) 70 mg orally (PO) every week (QW) for 12 months. At month 12 participants transitioned to receive romosozumab 140 mg subcutaneously every month for an additional 12 months (months 12 to 24).
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. At month 36 participants ended study participation.
干预措施: Denosumab (Drug)
Alendronate
Participants received open-label alendronate (ALN) 70 mg orally (PO) every week (QW) for 12 months. At month 12 participants transitioned to receive romosozumab 140 mg subcutaneously every month for an additional 12 months (months 12 to 24).
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. At month 36 participants ended study participation.
干预措施: Placebo to Denosumab (Drug)
Teriparatide
Participants received open-label teriparatide 20 μg subcutaneously every day (QD) for 12 months. At month 12 participants ended study participation.
干预措施: Teriparatide (Drug)
Romosozumab 70 mg QM
Participants received double-blind romosozumab 70 mg subcutaneously every month for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Romosozumab (Drug)
Romosozumab 70 mg QM
Participants received double-blind romosozumab 70 mg subcutaneously every month for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Denosumab (Drug)
Romosozumab 70 mg QM
Participants received double-blind romosozumab 70 mg subcutaneously every month for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Placebo to Denosumab (Drug)
Romosozumab 70 mg QM
Participants received double-blind romosozumab 70 mg subcutaneously every month for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Zoledronic acid (Drug)
Romosozumab 140 mg Q3M
Participants received double-blind romosozumab 140 mg subcutaneously once every 3 months for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Romosozumab (Drug)
Romosozumab 140 mg Q3M
Participants received double-blind romosozumab 140 mg subcutaneously once every 3 months for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Denosumab (Drug)
Romosozumab 140 mg Q3M
Participants received double-blind romosozumab 140 mg subcutaneously once every 3 months for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Placebo to Denosumab (Drug)
Romosozumab 140 mg Q3M
Participants received double-blind romosozumab 140 mg subcutaneously once every 3 months for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Zoledronic acid (Drug)
Romosozumab 140 mg QM
Participants received double-blind romosozumab 140 mg QM subcutaneously for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Romosozumab (Drug)
Romosozumab 140 mg QM
Participants received double-blind romosozumab 140 mg QM subcutaneously for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Denosumab (Drug)
Romosozumab 140 mg QM
Participants received double-blind romosozumab 140 mg QM subcutaneously for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Placebo to Denosumab (Drug)
Romosozumab 140 mg QM
Participants received double-blind romosozumab 140 mg QM subcutaneously for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Zoledronic acid (Drug)
Romosozumab 210 mg Q3M
Participants received double-blind romosozumab 210 mg Q3M subcutaneously for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Romosozumab (Drug)
Romosozumab 210 mg Q3M
Participants received double-blind romosozumab 210 mg Q3M subcutaneously for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Denosumab (Drug)
Romosozumab 210 mg Q3M
Participants received double-blind romosozumab 210 mg Q3M subcutaneously for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Placebo to Denosumab (Drug)
Romosozumab 210 mg Q3M
Participants received double-blind romosozumab 210 mg Q3M subcutaneously for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Zoledronic acid (Drug)
Romosozumab 210 mg QM
Participants received double-blind romosozumab 210 mg QM subcutaneously for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Romosozumab (Drug)
Romosozumab 210 mg QM
Participants received double-blind romosozumab 210 mg QM subcutaneously for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Denosumab (Drug)
Romosozumab 210 mg QM
Participants received double-blind romosozumab 210 mg QM subcutaneously for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Placebo to Denosumab (Drug)
Romosozumab 210 mg QM
Participants received double-blind romosozumab 210 mg QM subcutaneously for 24 months.
Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.
干预措施: Zoledronic acid (Drug)
结局指标
主要结局
Percent Change From Baseline at Month 12 in BMD at the Lumbar Spine
时间窗: Baseline to 12 months
Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader.
次要结局
- Percent Change From Baseline at Month 6 in BMD at the Lumbar Spine(Baseline to 6 months)
- Percent Change From Baseline at Month 12 in BMD of the Femoral Neck(Baseline to 12 months)
- Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP)(Baseline and months 1, 3, 6, 9, and 12)
- Percent Change From Baseline in Type 1 Collagen C-telopeptide (CTX)(Baseline and months 1, 3, 6, 9, and 12)
- Percent Change From Baseline at Month 6 in BMD of the Total Hip(Baseline to 6 months)
- Percent Change From Baseline at Month 12 in BMD of the Total Hip(Baseline to 12 months)
- Percent Change From Baseline at Month 6 in BMD of the Femoral Neck(Baseline to 6 months)
- Percent Change From Baseline in Bone-specific Alkaline Phosphatase (BSAP)(Baseline and months 1, 3, 6, 9, and 12)
- Percent Change From Baseline at Month 12 in BMD of the Distal Radius(Baseline to 12 months)
- Percent Change From Baseline in Osteocalcin(Baseline and months 1, 3, 6, 9, and 12)