Romosozumab (AMG 785) in Postmenopausal Women With Low Bone Mineral Density

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Low Bone Mineral Density, Postmenopausal Osteoporosis

Intervention / Treatment
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* Drug: Placebo to Romosozumab
* Drug: Alendronate
* Drug: Teriparatide
* Drug: Romosozumab
* Drug: Denosumab
* Drug: Placebo to Denosumab
* Drug: Zoledronic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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Female

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>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. | Drug: Placebo to Romosozumab<br>* Administered by subcutaneous injection QM or Q3M.<br>Drug: Denosumab<br>* Denosumab 60 mg administered by subcutaneous injection Q6M<br>* Other names: Prolia®;Drug: Placebo to Denosumab<br>* Administered by subcutaneous injection Q6M<br>Drug: Zoledronic acid<br>* Zoledronic acid 5 mg administered intravenously<br>* Other names: Aclasta;|
| Active Comparator: Alendronate<br>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. | Drug: Alendronate<br>* Administered orally once a week<br>* Other names: Fosamax;Drug: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: EVENITY™;Drug: Denosumab<br>* Denosumab 60 mg administered by subcutaneous injection Q6M<br>* Other names: Prolia®;Drug: Placebo to Denosumab<br>* Administered by subcutaneous injection Q6M<br>|
| Active Comparator: Teriparatide<br>Participants received open-label teriparatide 20 μg subcutaneously every day (QD) for 12 months. At month 12 participants ended study participation. | Drug: Teriparatide<br>* Teriparatide 20 μg administered by subcutaneous injection once a day<br>* Other names: Forsteo;|
| Experimental: Romosozumab 70 mg QM<br>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. | Drug: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: EVENITY™;Drug: Denosumab<br>* Denosumab 60 mg administered by subcutaneous injection Q6M<br>* Other names: Prolia®;Drug: Placebo to Denosumab<br>* Administered by subcutaneous injection Q6M<br>Drug: Zoledronic acid<br>* Zoledronic acid 5 mg administered intravenously<br>* Other names: Aclasta;|
| Experimental: Romosozumab 140 mg Q3M<br>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. | Drug: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: EVENITY™;Drug: Denosumab<br>* Denosumab 60 mg administered by subcutaneous injection Q6M<br>* Other names: Prolia®;Drug: Placebo to Denosumab<br>* Administered by subcutaneous injection Q6M<br>Drug: Zoledronic acid<br>* Zoledronic acid 5 mg administered intravenously<br>* Other names: Aclasta;|
| Experimental: Romosozumab 140 mg QM<br>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. | Drug: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: EVENITY™;Drug: Denosumab<br>* Denosumab 60 mg administered by subcutaneous injection Q6M<br>* Other names: Prolia®;Drug: Placebo to Denosumab<br>* Administered by subcutaneous injection Q6M<br>Drug: Zoledronic acid<br>* Zoledronic acid 5 mg administered intravenously<br>* Other names: Aclasta;|
| Experimental: Romosozumab 210 mg Q3M<br>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. | Drug: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: EVENITY™;Drug: Denosumab<br>* Denosumab 60 mg administered by subcutaneous injection Q6M<br>* Other names: Prolia®;Drug: Placebo to Denosumab<br>* Administered by subcutaneous injection Q6M<br>Drug: Zoledronic acid<br>* Zoledronic acid 5 mg administered intravenously<br>* Other names: Aclasta;|
| Experimental: Romosozumab 210 mg QM<br>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. | Drug: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: EVENITY™;Drug: Denosumab<br>* Denosumab 60 mg administered by subcutaneous injection Q6M<br>* Other names: Prolia®;Drug: Placebo to Denosumab<br>* Administered by subcutaneous injection Q6M<br>Drug: Zoledronic acid<br>* Zoledronic acid 5 mg administered intravenously<br>* Other names: Aclasta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline at Month 12 in BMD at the Lumbar Spine | Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. | Baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline at Month 6 in BMD at the Lumbar Spine | Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. Percent change from baseline to month 6 was analyzed using a linear mixed effects model with the percent change from baseline to month 6 in DXA BMD as dependent variable, and baseline BMD value, machine type, geographic region, interaction of baseline BMD and machine type, visit, treatment (categorical) and interaction of treatment and visit as the independent variables. | Baseline to 6 months | 
| Percent Change From Baseline at Month 6 in BMD of the Total Hip | Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. Percent change from baseline to month 6 was analyzed using a linear mixed effects model with the percent change from baseline to month 6 in DXA BMD as dependent variable, and baseline BMD value, machine type, geographic region, interaction of baseline BMD and machine type, visit, treatment (categorical) and interaction of treatment and visit as the independent variables. | Baseline to 6 months | 
| Percent Change From Baseline at Month 6 in BMD of the Femoral Neck | Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. Percent change from baseline to month 6 was analyzed using a linear mixed effects model with the percent change from baseline to month 6 in DXA BMD as dependent variable, and baseline BMD value, machine type, geographic region, interaction of baseline BMD and machine type, visit, treatment (categorical) and interaction of treatment and visit as the independent variables. | Baseline to 6 months | 
| Percent Change From Baseline at Month 12 in BMD of the Total Hip | Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. Percent change from baseline to 12 months in BMD was analyzed using a linear mixed effects model with the percent change from baseline to month 12 in DXA BMD as dependent variable, and baseline BMD value, machine type, geographic region, interaction of baseline BMD and machine type, visit, treatment (categorical) and interaction of treatment and visit as the independent variables. | Baseline to 12 months | 
| Percent Change From Baseline at Month 12 in BMD of the Femoral Neck | Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. Percent change from baseline to 12 months in BMD was analyzed using a linear mixed effects model with the percent change from baseline to month 12 in DXA BMD as dependent variable, and baseline BMD value, machine type, geographic region, interaction of baseline BMD and machine type, visit, treatment (categorical) and interaction of treatment and visit as the independent variables. | Baseline to 12 months | 
| Percent Change From Baseline at Month 12 in BMD of the Distal Radius | Bone mineral density was measured using dual energy x-ray absorptiometry (DXA). Images were analyzed by a central imaging reader. Percent change from baseline in distal radius BMD was analyzed using an analysis of covariance (ANCOVA) model with the percent change from baseline to Month 12 in DXA BMD as dependent variable, baseline BMD value, machine type, interaction of baseline BMD and machine type, treatment (categorical) and geographic region as the independent class variables. | Baseline to 12 months | 
| Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) | Percent change from baseline in the bone turnover marker (BTM) P1NP was analyzed using a linear mixed effects model with the natural logarithm of the ratio of BTM (follow-up versus baseline) as the dependent variables, and visit, treatment (categorical), interaction of treatment and visit and the natural logarithm of the baseline BTM as the independent variables; outcomes were then transformed back to percent change from baseline. | Baseline and months 1, 3, 6, 9, and 12 | 
| Percent Change From Baseline in Type 1 Collagen C-telopeptide (CTX) | Percent change from baseline in the bone turnover marker (BTM) CTX was analyzed using a linear mixed effects model with the natural logarithm of the ratio of BTM (follow-up versus baseline) as the dependent variables, and visit, treatment (categorical), interaction of treatment and visit and the natural logarithm of the baseline BTM as the independent variables; outcomes were then transformed back to percent change from baseline. | Baseline and months 1, 3, 6, 9, and 12 | 
| Percent Change From Baseline in Osteocalcin | Percent change from baseline in the bone turnover marker (BTM) osteocalcin was analyzed using a linear mixed effects model with the natural logarithm of the ratio of BTM (follow-up versus baseline) as the dependent variables, and visit, treatment (categorical), interaction of treatment and visit and the natural logarithm of the baseline BTM as the independent variables; outcomes were then transformed back to percent change from baseline. | Baseline and months 1, 3, 6, 9, and 12 | 
| Percent Change From Baseline in Bone-specific Alkaline Phosphatase (BSAP) | Percent change from baseline in the bone turnover marker (BTM) BSAP was analyzed using a linear mixed effects model with the natural logarithm of the ratio of BTM (follow-up versus baseline) as the dependent variables, and visit, treatment (categorical), interaction of treatment and visit and the natural logarithm of the baseline BTM as the independent variables; outcomes were then transformed back to percent change from baseline. | Baseline and months 1, 3, 6, 9, and 12 |