Study to Determine the Efficacy and Safety of Romosozumab in the Treatment of Postmenopausal Women With Osteoporosis

Study Overview
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Brief Summary
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The purpose of this study is to determine if treatment is effective in preventing fractures in women with postmenopausal osteoporosis.

Detailed Description
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In this trial, women were randomly assigned in a 1:1 ratio to receive monthly subcutaneous romosozumab or weekly oral alendronate for 12 months. Randomization was stratified according to age (<75 vs. ≥75 years). After completion of the double-blind treatment period, all the participants were to receive open-label weekly oral alendronate until the end of the trial, with blinding to the initial treatment assignment maintained. The primary analysis was performed when clinical fracture events had been confirmed in at least 330 participants and all the participants had completed the month 24 visit. The study was to continue in an event-driven manner until at least 440 participants experienced a nonvertebral fracture or if the superiority of romosozumab was proven for nonvertebral fractures at the primary analysis.

Official Title
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A Multicenter, International, Randomized, Double-blind, Alendronate-controlled Study to Determine the Efficacy and Safety of Romosozumab in the Treatment of Postmenopausal Women With Osteoporosis

Conditions
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Postmenopausal Women With Osteoporosis

Intervention / Treatment
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* Biological: Romosozumab
* Drug: Alendronate
* Drug: Placebo to Romosozumab
* Drug: Placebo to Alendronate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women who meet at least one of the following bone mineral density (BMD) and fracture criteria: BMD T-score at the total hip or femoral neck of ≤ -2.50 and EITHER: at least 1 moderate (semiquantitative grade [SQ]2) or severe (SQ3) vertebral fracture OR at least 2 mild (SQ1) vertebral fractures OR BMD T-score at the total hip or femoral neck of ≤ -2.00 and EITHER: at least 2 moderate (SQ2) or severe (SQ3) vertebral fractures OR a fracture of the proximal femur that occurred within 3 to 24 months prior to randomization. Exclusion Criteria: History of metabolic or bone disease (except osteoporosis) Use of agents affecting bone metabolism Vitamin D insufficiency History of solid organ or bone marrow transplants Hyper- or hypocalcemia Hyper- or hypothyroidism Hyper- or hypoparathyroidism Possible signs of intolerance to alendronate

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 90 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 |
| --- | --- |
| Active Comparator: Alendronate/Alendronate<br>Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. | Drug: Alendronate<br>* Alendronate 70 mg tablet taken once a week<br>* Other names: Fosamax;Drug: Placebo to Romosozumab<br>* Administered by subcutaneous injection once a month during the double-blind treatment phase.<br>|
| Experimental: Romosozumab/Alendronate<br>Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study. | Biological: Romosozumab<br>* Romosozumab 210 mg administered by subcutaneous injection once a month during the double-blind treatment phase.<br>* Other names: Evenity;Drug: Alendronate<br>* Alendronate 70 mg tablet taken once a week<br>* Other names: Fosamax;Drug: Placebo to Alendronate<br>* Matching placebo tablet taken once a week during the double-blind treatment phase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With New Vertebral Fractures Through Month 24 | All fracture assessments were performed by blinded central imaging readers. New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height. Incident vertebral fractures were confirmed by a second independent reader using the Semiquantitative method. | 24 months | 
| Percentage of Participants With a Clinical Fracture at the Primary Analysis | All fracture assessments were performed by blinded central imaging readers. Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded. | The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Nonvertebral Fracture at the Primary Analysis | A nonvertebral fracture was defined as a documented fracture excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded. | The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3). | 
| Percentage of Participants With Any Fracture at the Primary Analysis | All fractures include any osteoporotic nonvertebral fractures that are not associated with high trauma severity or pathologic fractures and new or worsening vertebral fractures regardless of trauma severity or pathologic fractures. | The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3). | 
| Percentage of Participants With a New or Worsening Vertebral Fracture Through Month 24 | A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4 according to the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height. Incident vertebral fractures were confirmed by a second independent reader using the Semiquantitative method. | 24 months | 
| Percentage of Participants With a Major Nonvertebral Fracture at the Primary Analysis | Major nonvertebral fractures included a subset of nonvertebral fractures including pelvis, distal femur (ie, femur excluding hip), proximal tibia (ie, tibia excluding ankle), ribs, proximal humerus (ie, humerus excluding elbow), forearm, and hip. | The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3). | 
| Percentage of Participants With a Hip Fracture at the Primary Analysis | Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter. | The primary analysis was performed when clinical fracture events had been confirmed in at least 330 patients and all participants had completed the month 24 visit. The median follow-up was 2.7 years (interquartile range, 2.2 to 3.3). | 
| Percentage of Participants With Multiple New or Worsening Vertebral Fractures Through Month 24 | A new or worsening vertebral fracture was identified when there was a ≥ 1 grade increase from the previous grade in any vertebra from T4 to L4 according to the Genant Semiquantitative Scoring method. A participant had multiple new or worsening vertebral fractures when there were ≥ 2 vertebrae from T4 to L4 with ≥ 1 grade increase from the previous grade. The multiple new or worsening vertebral fractures need not have occurred at the same visit. Incident vertebral fractures were confirmed by a second independent reader. | 24 months | 
| Percentage of Participants With a Clinical Fracture Through Month 24 | Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded. | 24 months | 
| Percentage of Participants With a Nonvertebral Fracture Through Month 24 | A nonvertebral fracture was defined as a documented fracture excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded. | 24 months | 
| Percentage of Participants With a Hip Fracture Through Month 24 | Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter. | 24 months | 
| Percentage of Participants With a Clinical Vertebral Fracture Through Month 24 | A clinical vertebral fracture is a new or worsening vertebral fracture assessed at either a scheduled or unscheduled visit and associated with any signs and/or symptoms of back pain indicative of a fracture, regardless of trauma severity or whether it is pathologic. | 24 months | 
| Percentage of Participants With a Clinical Fracture Through Month 12 | Clinical fractures included clinical vertebral and nonvertebral fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges) that were associated with signs and/or symptoms indicative of a fracture. Clinical vertebral fractures were included regardless of trauma severity or pathologic fractures; nonvertebral fractures associated with high trauma severity or pathologic fractures were excluded. | 12 months | 
| Percentage of Participants With New Vertebral Fractures Through Month 12 | New vertebral fractures occurred when there was ≥ 1 grade increase from the previous grade of 0 in any vertebra from T4 to L4 using the Genant Semiquantitative Scoring method based on assessment of x-rays according to the following scale: Grade 0 (Normal) = no fracture; Grade 1 (Mild) = mild fracture, 20 to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2 (Moderate) = moderate fracture, 25 to 40% reduction in anterior, middle, and/or posterior height; Grade 3 (Severe) = severe fracture, greater than 40% reduction in anterior, middle, and/or posterior height. Incident vertebral fractures were confirmed by a second independent reader. | 12 months | 
| Percentage of Participants With Any Fracture Through Month 12 | All fractures include any osteoporotic nonvertebral fractures that are not associated with high trauma severity or pathologic fractures and new or worsening vertebral fractures regardless of trauma severity or pathologic fractures. | 12 months | 
| Percentage of Participants With a Nonvertebral Fracture Through Month 12 | A nonvertebral fracture was defined as a fracture present on a copy of radiographs or other diagnostic images such as computerized tomography (CT) or magnetic resonance imaging confirming the fracture within 14 days of reported fracture image date recorded by the study site, and/or documented in a copy of the radiology report, surgical report, or discharge summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges. In addition, fractures associated with high trauma severity or pathologic fractures were excluded. | 12 months | 
| Percentage of Participants With a Hip Fracture Through Month 12 | Hip fractures were defined as a subset of nonvertebral fractures including fractures of the femur neck, femur intertrochanter, and femur subtrochanter. | 12 months | 
| Percentage of Participants With a Major Osteoporotic Fracture Through Month 12 | Major osteoporotic fractures included clinical vertebral fractures and fractures of the hip, forearm and humerus. Fractures associated with high trauma severity or pathologic fractures were excluded. | 12 months | 
| Percentage of Participants With a Clinical Vertebral Fracture Through Month 12 | A clinical vertebral fracture is a new or worsening vertebral fracture assessed at either a scheduled or unscheduled visit and associated with any signs and/or symptoms of back pain indicative of a fracture, regardless of trauma severity or whether it is pathologic. | 12 months | 
| Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 24 | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. | Baseline and month 24 | 
| Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 24 | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. | Baseline and month 24 | 
| Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at at Month 24 | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. | Baseline and month 24 | 
| Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 12 | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. | Baseline and month 12 | 
| Percent Change From Baseline in Bone Mineral Density at the Total Hip at Month 12 | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. | Baseline and month 12 | 
| Percent Change From Baseline in Bone Mineral Density at the Femoral Neck at Month 12 | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. | Baseline and month 12 | 
| Percent Change From Baseline in Bone Mineral Density of the Lumbar Spine at Month 36 | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. | Baseline and month 36 | 
| Percent Change From Baseline in Bone Mineral Density of the Total Hip at Month 36 | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. | Baseline and month 36 | 
| Percent Change From Baseline in Bone Mineral Density of the Femoral Neck at Month 36 | Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). DXA scans were analyzed by a central imaging center. | Baseline and month 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoporosis, Osteoporosis-postmenopausal, Bone Diseases-Metabolic, Bone Diseases, Musculoskeletal Diseases