A Study to Evaluate the Effect of Romosozumab (AMG 785) on Bone Quality of the Forearm in Postmenopausal Women With Low Bone Mass

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of romosozumab on parameters of bone quality of the forearm using peripheral quantitative computed tomography (pQCT) following multiple subcutaneous dose administrations of romosozumab in postmenopausal women with low bone mass.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multiple Dose Study to Evaluate the Effect of AMG 785 on Parameters of Bone Quality of the Forearm Using pQCT in Postmenopausal Women With Low Bone Mineral Density

Conditions
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Osteopenia

Intervention / Treatment
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* Drug: Romosozumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy females between 55 to 80 years of age Postmenopausal females (based on medical history) defined as 12 continuous months of spontaneous amenorrhea Women 60 years of age and older will be considered postmenopausal Women 55-59 must have a serum follicle-stimulating hormone result > 40 mIU/mL and serum estradiol ≤ 20 pg/mL Low bone mineral density (BMD), defined as a BMD T-score between -1.0 and -2.5 at the lumbar spine (L1-L4) and/or femoral neck Weight ≤ 98 kg (216 lb) and/or height ≤ 196 cm (77 in) 25-hydroxyvitamin D ≥ 20 ng/mL at screening Willing and able to take ≥ 500 mg calcium and ≥ 400 IU (but ≤ 1,000 IU) vitamin D daily Exclusion Criteria: Osteoporosis, defined as a BMD T-score ≤ -2.5 at the lumbar spine or femoral neck History of vertebral fracture, or fragility fracture of the wrist, humerus, hip or pelvis Diagnosed with any condition that will affect bone metabolism Subjects with fewer than 2 evaluable vertebrae; metal in forearms bilaterally that would not allow for at least one evaluable forearm Administration of the following medications within 6 months before study drug administration. This includes all routes of administration, for example intranasal and topical skin patches, unless otherwise noted: Hormone replacement therapy [(eg, estrogen, estrogen-like compounds such as raloxifene). Infrequent use of estrogen vaginal creams (< 3 times per week) is allowed.] Calcitonin Parathyroid hormone (or any derivative) Glucocorticosteroids (inhaled or topical corticosteroids administered more than 2 weeks before the enrollment date are allowed) Anabolic steroids Calcitriol, and available analogues Administration of daily, weekly, or monthly bisphosphonates (BP) unless meeting the following criteria: < 2 weeks of BP use requires a 2-month washout period 2 weeks to 3 months of BP use requires a 9-month washout period 3 to 6 months of BP use requires a 1-year washout period > 6 months of BP use requires a 3-year washout period; Greatly differing levels of physical activity or constant levels of intense physical exercise during the 6 months before study drug administration Known sensitivity to mammalian-derived drug preparations Known to be hepatitis B surface antigen, hepatitis C virus or human Immunodeficiency virus (HIV) positive or a known diagnosis of acquired immunodeficiency syndrome (AIDS) Any organic or psychiatric disorder, which, in the opinion of the investigator, poses a risk to subject safety and may prevent the subject from completing the study or interfere with the interpretation of the study results Unavailable for follow-up assessment or any concerns for subject's compliance with the protocol procedures Any other condition that might reduce the chance of obtaining data required by the protocol or that might compromise the ability to give truly informed consent History or evidence of a clinically significant disorder, condition or disease that, in the opinion of the Investigator or Amgen physician would pose a risk to subject safety or interfere with the study evaluation, procedures or completion Clinically significant abnormality during the screening physical examination, electrocardiogram (ECG) or laboratory evaluation Participation in another clinical study within 4 weeks of screening or within 5 times the half-life of the investigational agent in the other clinical study, if known Has donated or lost 400 mL or more of blood or plasma within 8 weeks of study drug administration Previous AMG 785 exposure

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants were randomized to receive matching placebo administered by subcutaneous injection once every 4 weeks (Q4W) for 3 months. | Drug: Placebo<br>* Administered by subcutaneous injection<br>|
| Experimental: Romosozumab<br>Participants were randomized to receive 3 mg/kg romosozumab administered by subcutaneous injection once every 4 weeks (Q4W) for 3 months. | Drug: Romosozumab<br>* Administered by subcutaneous injection<br>* Other names: EVENITY™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Polar Cross-sectional Moment of Inertia at the Distal Radius | The polar moment of inertia is a geometric measurement used to predict bone quality, specifically the ability to resist torsion (twisting), and is highly correlated with fracture load at the distal radius. The polar cross-sectional moment of inertia was assessed using peripheral quantitative computed tomography (pQCT), a 3-dimensional imaging technology which can be used for volumetric analysis of appendicular skeletal sites such as the arms and the legs. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Total Bone Area at the Distal Radius | Total bone area was assessed using peripheral quantitative computed tomography (pQCT), a 3-dimensional imaging technology which can be used for volumetric analysis of appendicular skeletal sites such as the arms and the legs. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Total Bone Mineral Content at the Distal Radius | Total bone mineral content was assessed using peripheral quantitative computed tomography (pQCT). The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Total Bone Mineral Density at the Distal Radius | Total bone mineral density was assessed using peripheral quantitative computed tomography (pQCT). The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Cortical Bone Area at the Distal Radius | Cortical bone area was assessed using peripheral quantitative computed tomography (pQCT). The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Cortical Bone Mineral Content at the Distal Radius | Cortical bone mineral content was assessed using peripheral quantitative computed tomography (pQCT). The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Cortical Bone Mineral Density at the Distal Radius | Cortical bone mineral density was assessed using peripheral quantitative computed tomography (pQCT). The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Endocortical Circumference at the Distal Radius | Endocortical circumference was derived from pQCT measurements based on applying a circular ring model to the cortical shell. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Periosteal Circumference at the Distal Radius | Periosteal circumference was derived from pQCT measurements based on applying a circular ring model to the cortical shell. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Cortical Thickness at the Distal Radius | Cortical thickness was derived from pQCT measurements based on applying a circular ring model to the cortical shell. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Polar Section Modulus at the Distal Radius | Polar section modulus is a measurement of bone strength and was derived from pQCT measurements. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Polar Strength Strain Index at the Distal Radius | The polar strength strain index is a measurement of bone strength and was derived from pQCT measurements. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Axial Moment of Inertia at the Distal Radius | Axial moment of inertia is an indicator of the ability of bone to resist bending, and was derived from pQCT measurements based on a circular ring model. The distal slice was acquired at 20% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Total Bone Area at the Ultradistal Radius | Total bone area was assessed using peripheral quantitative computed tomography (pQCT), a 3-dimensional imaging technology which can be used for volumetric analysis of appendicular skeletal sites such as the arms and the legs. The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Total Bone Mineral Content at the Ultradistal Radius | Total bone mineral content was assessed using peripheral quantitative computed tomography (pQCT). The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Total Bone Mineral Density at the Ultradistal Radius | Total bone mineral density was assessed using peripheral quantitative computed tomography (pQCT). The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Trabecular Bone Area at the Ultradistal Radius | Trabecular bone area was assessed using peripheral quantitative computed tomography (pQCT). The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Trabecular Bone Mineral Content at the Ultradistal Radius | Trabecular bone mineral content was assessed using peripheral quantitative computed tomography (pQCT). The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Trabecular Bone Mineral Density at the Ultradistal Radius | Trabecular bone mineral density was assessed using peripheral quantitative computed tomography (pQCT). The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Polar Strength Strain Index at the Ultradistal Radius | The polar strength strain index is a measurement of bone strength and was derived from pQCT measurements. The ultradistal slice was acquired at 4% of the length of the ulna proximal to the radial endplate. Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Bone Mineral Density at the One-third Radius | Bone mineral density was assessed using dual energy x-ray absorptiometry (DXA). Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Bone Mineral Density at the Total Wrist | Bone mineral density was assessed using dual energy x-ray absorptiometry (DXA). Scans were analyzed by a central reader. | Baseline and days 29, 57, 85, 127, and 169 | 
| Percent Change From Baseline in Bone Mineral Density at the Total Lumbar Spine | Bone mineral density was assessed using dual energy x-ray absorptiometry (DXA). Scans were analyzed by a central reader. | Baseline and days 85 and 169 | 
| Percent Change From Baseline in Serum Procollagen Type 1 N-terminal Propeptide (P1NP) |  | Baseline and days 4, 15, 29, 57, 62, 71, 85, 99, 127, and 169 | 
| Percent Change From Baseline in Serum C-Telopeptide (sCTX) |  | Baseline and days 4, 15, 29, 57, 62, 71, 85, 99, 127, and 169 | 
| Time to Maximum Serum Concentration (Tmax) of Romosozumab | Serum concentrations of romosozumab were measured by a validated enzyme-linked immunosorbent assay. The lower limit of quantification (LLOQ) was 50 ng/mL. | First Dose: Day 1 (predose) and on days 4, 15, and 29 (predose). Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169 | 
| Maximum Serum Concentration (Cmax) of Romosozumab | Serum concentrations of romosozumab were measured by a validated enzyme-linked immunosorbent assay. The lower limit of quantification (LLOQ) was 50 ng/mL. | First Dose: Day 1 (predose) and on days 4, 15, and 29 (predose). Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169 | 
| Area Under the Serum Concentration-time Curve From Time 0 to Tau (AUC0-28) | Serum concentrations of romosozumab were measured by a validated enzyme-linked immunosorbent assay. The lower limit of quantification (LLOQ) was 50 ng/mL. The area under the serum drug concentration-time curve from time zero to tau (tau = 28 days) (AUC0-28) was calculated by the linear trapezoidal method. | First Dose: Day 1 (predose) and on days 4, 15, and 29 (predose). Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169 | 
| Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) | Serum concentrations of romosozumab were measured by a validated enzyme-linked immunosorbent assay. The lower limit of quantification (LLOQ) was 50 ng/mL. | Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169 | 
| Apparent Clearance (CL/F) of Romosozumab | Serum concentrations of romosozumab were measured by a validated enzyme-linked immunosorbent assay. The lower limit of quantification (LLOQ) was 50 ng/mL. | Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169 | 
| Terminal Half-life (t1/2,z) of Romosozumab | Serum concentrations of romosozumab were measured by a validated enzyme-linked immunosorbent assay. The lower limit of quantification (LLOQ) was 50 ng/mL. | Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169 | 
| Accumulation Ratio | Accumulation ratio was calculated as the ratio of AUC0-28 after the last dose to AUC0-28 after the first dose. | First Dose: Day 1 (predose) and on days 4, 15, and 29 (predose). Last Dose: Days 57 (predose), 62, 71, 85, 99, 127, and 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amgen, Postmenopausal, Bone Density