Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Denosumab (AMG 162) in Japanese Postmenopausal Women

A Randomized, Double-blind, Placebo-controlled, Single-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AMG 162 Administered Subcutaneously to Japanese Postmenopausal Women

The primary objective was to evaluate the safety and tolerability of denosumab (AMG 162) after a single subcutaneous administration in Japanese postmenopausal women.

Study Overview

• Status: Completed
• Conditions: Osteoporosis
• Intervention / Treatment: Drug: Placebo; Biological: Denosumab

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ambulatory women between the ages of 40 and 64 years, inclusive
• postmenopausal, defined as amenorrheic for at least 24 months
• clinically acceptable physical exam
• clinical laboratory tests (complete blood count [CBC], blood chemistries, urinalysis) within normal limits or clinically acceptable to the investigator/sponsor at the time of screening with the exception of aspartate transaminase (AST) and alkaline phosphatase (ALT), which must be < 1.25 times the upper limit of normal, or gamma-glutamyl transpeptidase (GGT), which must be < 1.5 times the upper limit of normal
• normal or clinically acceptable electrocardiogram (ECG) (12-lead reporting ventricular rate and PR, QRS, QT, and QTc intervals)
• body mass index between 17 and 27
• willing to sign an approved informed consent form before any study-specific assessments and oral consultations are performed

Exclusion Criteria:

• administration of medications within 6 months before investigational product administration that are known to effect bone metabolism, including but not limited to the following: calcitonin, parathyroid hormone (or any derivative), supplemental vitamin D (> 1000 IU/day), glucocorticosteroids (inhaled or topical corticosteroids administered more than 2 weeks before the date of informed consent were allowed), anabolic steroids, calcitriol and available analogues, diuretics
• administration of the following medications within 12 months before study drug administration: bisphosphonates, fluoride for osteoporosis
• diagnosed with any condition that affects bone metabolism
• greatly differing levels of physical activity compared with the 6 months before investigational product administration or constant levels of intense physical activities
• routine alcohol intake of ≥ 2 drinks/day, on average, within 6 months of investigational product administration
• known sensitivity to any drugs
• positive test results for hepatitis B surface antigen, hepatitis C virus, human immunodeficiency virus antigen/antibody, syphilis
• receiving or received any investigational drug (or was currently using an investigational device) within 4 months before receiving investigational product
• donated any amount of blood within 16 weeks, or over 400 mL (Note: not 400 mL but 200 mL, for the subjects who were to be enrolled into cohorts 4 or 5) within 1 year of the start day of screening
• subject had previously entered this study
• any other condition that might have reduced the chance of obtaining data (eg, known poor compliance) required by the protocol or that might have compromised the ability to give truly informed consent

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants received a single subcutaneous injection of placebo to denosumab on day 1.	Drug: Placebo; Administered by subcutaneous injection
Experimental: Denosumab; Participants received a single subcutaneous dose of denosumab on day 1. Doses included 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg.	Biological: Denosumab; Administered by subcutaneous injection; Other Names: Prolia; AMG 162

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants With Adverse Events	From day 1 up to 4 months for participants assigned to the 0.03 or 0.1 mg/kg dose cohorts, up to 6 months for participants assigned to the 0.3 mg/kg dose cohort and for up to 9 months for participants assigned to the 1.0 or 3.0 mg/kg dose cohorts

Secondary Outcome Measures

Outcome Measure	Time Frame
Area Under the Serum Concentration Time Curve From Time 0 to Time of Last Quantifiable Serum Concentration (AUC0-t) of Denosumab	Day 1 predose and 5 minutes, 1, 4, 8, 12, 24, hours, days 3, 4, 5, 6, 8, 11, 15, 22, 29, 43, 57, 71, 85, 99, 113, also days 141 and 169 for participants in the 0.3, 1.0, or 3.0 mg/kg cohorts and days 197, 225, and 253 for the 1.0 or 3.0 mg/kg dose cohorts
Maximum Observed Concentration of Denosumab (Cmax)	Day 1 predose and 5 minutes, 1, 4, 8, 12, 24, hours, days 3, 4, 5, 6, 8, 11, 15, 22, 29, 43, 57, 71, 85, 99, 113, also days 141 and 169 for participants in the 0.3, 1.0, or 3.0 mg/kg cohorts and days 197, 225, and 253 for the 1.0 or 3.0 mg/kg dose cohorts
Time to Maximum Observed Concentration (Tmax) of Denosumab	Day 1 predose and 5 minutes, 1, 4, 8, 12, 24, hours, days 3, 4, 5, 6, 8, 11, 15, 22, 29, 43, 57, 71, 85, 99, 113, also days 141 and 169 for participants in the 0.3, 1.0, or 3.0 mg/kg cohorts and days 197, 225, and 253 for the 1.0 or 3.0 mg/kg dose cohorts
Apparent Clearance (CL/F) of Denosumab	Day 1 predose and 5 minutes, 1, 4, 8, 12, 24, hours, days 3, 4, 5, 6, 8, 11, 15, 22, 29, 43, 57, 71, 85, 99, 113, also days 141 and 169 for participants in the 0.3, 1.0, or 3.0 mg/kg cohorts and days 197, 225, and 253 for the 1.0 or 3.0 mg/kg dose cohorts
Mean Residence Time (MRT) From Time 0 to Time of Last Quantifiable Serum Concentration	Day 1 predose and 5 minutes, 1, 4, 8, 12, 24, hours, days 3, 4, 5, 6, 8, 11, 15, 22, 29, 43, 57, 71, 85, 99, 113, also days 141 and 169 for participants in the 0.3, 1.0, or 3.0 mg/kg cohorts and days 197, 225, and 253 for the 1.0 or 3.0 mg/kg dose cohorts
Percent Change From Baseline in Urinary N-Telopeptide Corrected for Urine Creatinine (N-Tx/Cr)	Baseline and day 2, 3, 4, 5, 6, 8, 11, 15, 22, 29, 43, 57, 71, 85, 99, 113 (for all dose cohorts), 141, 169 (0.3, 1.0, and 3.0 mg/kg cohorts only), 197, 225, 253, 281, and 309 (1.0 and 3.0 mg/kg cohorts only).
Percent Change From Baseline in Bone-Specific Alkaline Phosphatase (BSAP)	Baseline and day 8, 15, 22, 29, 43, 57, 71, 85, 99, 113 (for all dose cohorts), 141, 169 (0.3, 1.0, and 3.0 mg/kg cohorts only), 197, 225, and 253, 281, and 309 (1.0 and 3.0 mg/kg cohorts only)
Percent Change From Baseline in Intact Parathyroid Hormone (iPTH)	Baseline and day 2, 3, 5, 8, 15, 29, 57, 85, 99, 113 (for all dose cohorts), 141, 169 (0.3, 1.0, and 3.0 mg/kg cohorts only), 197, 225, 253, 281, and 309 (1.0 and 3.0 mg/kg cohorts only)

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Kumagai Y, Hasunuma T, Padhi D. A randomized, double-blind, placebo-controlled, single-dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of denosumab administered subcutaneously to postmenopausal Japanese women. Bone. 2011 Nov;49(5):1101-7. doi: 10.1016/j.bone.2011.08.007. Epub 2011 Aug 12.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2003
• Primary Completion (Actual): December 24, 2004
• Study Completion (Actual): December 24, 2004

Study Registration Dates

• First Submitted: January 28, 2019
• First Submitted That Met QC Criteria: January 28, 2019
• First Posted (Actual): January 30, 2019

Study Record Updates

• Last Update Posted (Actual): July 24, 2019
• Last Update Submitted That Met QC Criteria: May 21, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Postmenopausal; Denosumab
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: 20030164

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes