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

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

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.

Study Overview

• Status: Completed
• Conditions: Osteopenia; Postmenopausal
• Intervention / Treatment: Drug: Placebo; Drug: Romosozumab

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 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; Administered by subcutaneous injection
Experimental: Romosozumab; 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; Administered by subcutaneous injection; Other Names: AMG 785; EVENITY™

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2007
• Primary Completion (Actual): December 2, 2008
• Study Completion (Actual): December 2, 2008

Study Registration Dates

• First Submitted: January 25, 2013
• First Submitted That Met QC Criteria: April 3, 2013
• First Posted (Estimated): April 8, 2013

Study Record Updates

• Last Update Posted (Actual): August 30, 2023
• Last Update Submitted That Met QC Criteria: August 28, 2023
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic
• Other Study ID Numbers: 20060221