A Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Romosozumab (AMG 785)

Study Overview
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Brief Summary
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The primary objective of this study was to assess the safety, tolerability, and immunogenicity potential of romosozumab following multiple subcutaneous (SC) administrations in healthy men and postmenopausal women with low bone mass.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Ascending Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 785 in Healthy Men and Postmenopausal Women With Low Bone Mass

Conditions
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Postmenopausal, 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 males and females between 45 to 80 years of age Postmenopausal females Low bone mineral density, defined by bone mineral density (BMD) T-scores between -1.0 and -2.5, inclusive, for the lumbar spine [L1-L4] or total evaluable vertebrae [if fewer than L1-L4] or total hip) 25-hydroxyvitamin D ≥ 20 ng/mL Weight ≤ 98 kg (216 lb) and/or height ≤ 196 cm (77 in) Exclusion Criteria: Osteoporosis defined by bone mineral density (BMD) T-scores < -2.5 for the lumbar spine (L1-L4) or total evaluable vertebrae (if fewer than L1-L4) or total hip Diagnosed with any condition that would affect bone metabolism Previous exposure to AMG 785

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

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: Sequential 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 2 weeks (Q2W) or once every 4 weeks (Q4W) for 3 months. | Drug: Placebo<br>* Administered by subcutaneous injection<br>|
| Experimental: Romosozumab<br>Participants were randomized to receive romosozumab administered by subcutaneous injection at doses of 1 mg/kg Q2W, 2 mg/kg Q4W, 2 mg/kg Q2W, or 3 mg/kg 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 |
| --- | --- | --- |
| Number of Participants With Adverse Events | Serious adverse events were any events that were fatal, were life-threatening (placed the participant at immediate risk of death), required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, were congenital anomalies or birth defects, or were other significant medical hazards. Relatedness to investigational product was assessed by the investigator by means of the question: Is there a reasonable possibility that the event may have been caused by the investigational product?' | 169 days | 
| Number of Participants Who Developed Antibodies to Romosozumab | All samples were tested for binding anti-romsozumab antibodies using an immunoassay; all antibody-positive samples were further tested in a bioassay to determine if the antibodies were neutralizing. Development of antibodies to romosozumab is defined as participants with a negative result at baseline and a positive result at any time postbaseline. | Blood samples for detection of anti-romosozumab antibodies were collected at day 1 (predose) and days 29 (predose), 57 (predose), 85, 113, 141, and 169. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Maximum Observed 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. | Q2W dose groups: First dose on days 1 (predose) to 15 (predose); Last dose on days 71 (predose) to 169. Q4W dose groups: First dose on days 1 (predose) to 29 (predose); Last dose on days 57 (predose) to 169. | 
| Maximum Observed Concentration (Cmax) of Romosozumab |  | Q2W dose groups: First dose on days 1 (predose) to 15 (predose); Last dose on days 71 (predose) to 169. Q4W dose groups: First dose on days 1 (predose) to 29 (predose); Last dose on days 57 (predose) to 169. | 
| Area Under the Concentration-time Curve for the Dosing Interval (AUC0-tau) for Romosozumab | Area under the serum romosozumab concentration-time curve from time 0 to tau (tau = 14 days for Q2W dose cohorts and 28 days for Q4W dose cohorts) | Q2W dose groups: First dose on days 1 (predose) to 15 (predose); Last dose on days 71 (predose) to 169. Q4W dose groups: First dose on days 1 (predose) to 29 (predose); Last dose on days 57 (predose) to 169. | 
| Half-life Associated With the Terminal Phase of Elimination (T1/2) for Romosozumab |  | Q2W dose groups: days 71 (predose) to 169; Q24 dose groups: days 57 (predose) to 169. | 
| Accumulation Ratio (AR) for Romosozumab | The accumulation ratio (AR) was calculated as the ratio of AUC0-tau after the last dose to AUC0-tau after the first dose. | Q2W dose groups: First dose on days 1 (predose) to 15 (predose); Last dose on days 71 (predose) to 169. Q4W dose groups: First dose on days 1 (predose) to 29 (predose); Last dose on days 57 (predose) to 169. | 
| Percent Change From Baseline in Bone Mineral Density of the Total Spine | Bone mineral density was determined by dual energy X-ray absorptiometry (DXA) scans of the lumbar spine (L1-L4) and assessed by a central lab. | Baseline and days 29, 85, 127, and 169 | 
| Percent Change From Baseline in Bone Mineral Density at the Total Hip | Bone mineral density was determined by dual energy X-ray absorptiometry (DXA) scans and assessed by a central lab. | Baseline and days 29, 85, 127, and 169 | 
| Percent Change From Baseline in Bone Mineral Density at the Femoral Hip | Bone mineral density was determined by dual energy X-ray absorptiometry (DXA) scans and assessed by a central lab. | Baseline and days 29, 85, 127, and 169 | 
| Percent Change From Baseline in Bone Mineral Density at the Distal One-third Radius | Bone mineral density was determined by dual energy X-ray absorptiometry (DXA) scans and assessed by a central lab. | Baseline and days 29, 85, 127, and 169 | 
| Percent Change From Baseline in Bone Mineral Density at the Total Wrist | Bone mineral density was determined by dual energy X-ray absorptiometry (DXA) scans and assessed by a central lab. | Baseline and days 29, 85, 127, and 169 | 
| Percent Change From Baseline in Bone Mineral Density of the Whole Body | Bone mineral density was determined by dual energy X-ray absorptiometry (DXA) scans and assessed by a central lab. | Baseline and days 29, 85, 127, and 169 | 
| Percent Change From Baseline in Procollagen Type 1 N-terminal Propeptide (P1NP) |  | Baseline and days 2, 4, 6, 8, 15, 22, 29, 36, 43, 50 (Q2W only), 57, 58 (Q4W only), 60 (Q4W only), 62 (Q4W only), 64, 71, 72 (Q2W only), 74 (Q2W only), 76 (Q2W only), 78, 85, 99, 113, 127, 141, 155 and 169 | 
| Percent Change From Baseline in Osteocalcin |  | Baseline and days 2, 4, 6, 8, 15, 22, 29, 36, 43, 50 (Q2W only), 57, 58 (Q4W only), 60 (Q4W only), 62 (Q4W only), 64, 71, 72 (Q2W only), 74 (Q2W only), 76 (Q2W only), 78, 85, 99, 113, 127, 141, 155 and 169 | 
| Percent Change From Baseline in Bone-specific Alkaline Phosphatase (BSAP) |  | Baseline and days 2, 4, 6, 8, 15, 22, 29, 36, 43, 50 (Q2W only), 57, 58 (Q4W only), 60 (Q4W only), 62 (Q4W only), 64, 71, 72 (Q2W only), 74 (Q2W only), 76 (Q2W only), 78, 85, 99, 113, 127, 141, 155 and 169 | 
| Percent Change From Baseline in Serum C-telopeptide (sCTX) |  | Baseline and days 2, 4, 6, 8, 15, 22, 29, 36, 43, 50 (Q2W only), 57, 58 (Q4W only), 60 (Q4W only), 62 (Q4W only), 64, 71, 72 (Q2W only), 74 (Q2W only), 76 (Q2W only), 78, 85, 99, 113, 127, 141, 155 and 169 | 
| Percent Change From Baseline in Intact Parathyroid Hormone (iPTH) |  | Baseline and days 2, 4, 6, 8, 15, 22, 29, 36, 43, 50 (Q2W only), 57, 58 (Q4W only), 60 (Q4W only), 62 (Q4W only), 64, 71, 72 (Q2W only), 74 (Q2W only), 76 (Q2W only), 78, 85, 99, 113, 127, 141, 155 and 169 | 
| Percent Change From Baseline in Sclerostin |  | Baseline and days 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155 and 169 | 
| Change From Baseline in Ionized Calcium |  | Baseline and day 169 (or earlier for participants who discontinued before day 169) |