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

Phase 1

Completed

• Conditions: Osteoporosis
• Interventions: Drug: Placebo; Biological: Denosumab

• Registration Number: NCT03822078
• Lead Sponsor: Amgen

Brief Summary

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

Detailed Description

Not available

Study Timeline

• Study Start: 2003-09-30
• Primary Completion: 2004-12-24
• Study Completion: 2004-12-24
• Study First Submitted: 2019-01-28
• Study First Submitted QC: 2019-01-28
• Study First Posted: 2019-01-30
• Status Verified: 2019-05
• Results First Submitted: 2019-05-21
• Results First Submitted QC: 2019-05-21
• Last Update Submitted: 2019-05-21
• Results First Posted: 2019-07-24
• Last Update Posted: 2019-07-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Not specified
• Target Recruitment: 45

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants received a single subcutaneous injection of placebo to denosumab on day 1.
Denosumab	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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)
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
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).
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
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
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)