Bioequivalence Study of Denosumab CP4 Drug Product and Commercially Available Denosumab CP2 Drug Product

A Double-Blind, Randomized, Single-Dose, Parallel-Group Study in Healthy Volunteers to Assess the Bioequivalence of a 120 mg Denosumab Subcutaneous Dose When Administered as Denosumab CP4 Drug Product or as Commercially Available Denosumab CP2 Drug Product

To evaluate the bioequivalence based on pharmacokinetics (PK) of a single 120 mg subcutaneous dose of denosumab administered to healthy volunteers using denosumab CP4 or denosumab CP2 drug products.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteer
• Intervention / Treatment: Drug: Denosumab CP4; Drug: Denosumab CP2

• Study Type: Interventional
• Enrollment (Actual): 146
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Cypress, California, United States, 90630
      • Research Site
  • Texas
    • San Antonio, Texas, United States, 78209
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion:

• Healthy male and female, ages ≥ 18 to ≤ 65 years (inclusive)
• Body weight > 60 to < 100 kg at time of screening
• Clinically acceptable physical exams and laboratory tests (blood hematology, blood chemistry, urinalysis) and no history or evidence of any clinically significant medical disorder that would pose a risk to subject safety or interfere with study evaluations or procedures
• Normal or clinically acceptable electrocardiogram (ECG) (12-lead reporting heart rate and PR, QRS, QT, and QTc intervals) at screening
• Willing to be confined to the research facility for 2 consecutive nights
• Subject will be available for follow-up assessments

Exclusion Criteria:

Prior diagnosis of bone disease, or any condition that will affect bone metabolism such as, but not limited to: osteoporosis, osteogenesis imperfecta, hyperparathyroidism, hyperthyroidism, hypothyroidism, osteomalacia, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, current flare-up of osteoarthritis and/or gout, active malignancy, renal disease (defined as glomerular filtration rate [GFR] < 45 mL/min), Paget's disease of the bone, recent bone fracture (within 6 months), malabsorption syndrome

• Presents with any psychiatric disorder, which may prevent the subject from completing the study or interfere with the interpretation of the study results
• Significant changes in physical activity during the 6 months before study drug administration or constant levels of intense physical exercise
• Prior use of any non-Amgen approved medications within 4 weeks or 5-half lives (whichever time period is longer) of study drug administration and for the duration of the study. This includes medications such as, but not limited to: bisphosphonates, fluoride, hormone replacement therapy (ie, estrogen) or selective estrogen receptor modulator, such as ralaxofene, calcitonin, strontium, parathyroid hormone or derivatives, supplemental vitamin D [>1000 IU/day], glucocorticosteroids, anabolic steroids, calcitriol, diuretics, over the counter medications, herbal supplements
• Positive for human immunodeficiency virus (HIV) at screening or known diagnosis of acquired immune deficiency syndrome (AIDS)
• Positive hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B) or detectable hepatitis C virus ribonucleic acid (RNA) by polymerase chain reaction (PCR) at screening (indicative of active hepatitis C - screening is generally done by hepatitis C antibody [HepCAb], followed by hepatitis C virus RNA by PCR if HepCAb is positive)
• Known sensitivity to any of the products to be administered during the study
• Prior denosumab administration
• Receiving or has received any investigational drug (or is currently using an investigational device) within 30 days before receiving study drug, or at least 10 times the respective elimination half-life (whichever period is longer) and for the duration of the study
• Women with a positive pregnancy test at screening or day-1
• Men and women of reproductive potential who are unwilling to practice a highly effective method of birth control while on study through 5 months after receiving the last dose of study drug. Highly effective methods of birth control include sexual abstinence (men, women); vasectomy; or a condom with spermicide (men) in combination with either barrier methods, hormonal birth control or intrauterine device (women)
• Women who are lactating/breastfeeding or who plan to breastfeed while on study through 5 half-lives after receiving the dose of study drug
• Women planning to become pregnant while on study through 5 months after receiving the dose of study drug
• Men with partners who are pregnant or planning to become pregnant while the subject is on study through 5 months after receiving the last dose of study drug
• Unwilling or unable to limit alcohol consumption throughout the course of the study. Alcohol is prohibited 24 hours prior to screening, 24 hours prior to check-in on day -1, and throughout confinement. Alcohol is also limited to no more than 2 drinks per day during the outpatient period of the study through completion of day 127 (EOS). A standard drink is equivalent to 12 ounces of regular beer, 8 to 9 ounces of malt liquor, 5 ounces of wine, or 1.5 ounces of 80 proof distilled spirits
• Positive urine screen for alcohol and/or drugs with a high potential for abuse at screening or day -1. Rescreening of the subject within 48 hours of a positive result is permitted
• Any other condition that might reduce the chance of obtaining data required by protocol or that might compromise the ability to give truly informed consent and/or comply with study procedures
• Osteonecrosis of the jaw (ONJ) or risk factors for ONJ such as invasive dental procedures (eg, tooth extraction, dental implants, oral surgery in the past 6 months), poor oral hygiene, periodontal, and/or pre-existing dental disease
• Recent tooth extraction (within 6 months of screening visit)
• Evidence of hypocalcemia at screening
• Known vitamin D deficiency
• Known intolerance to calcium or vitamin D supplements

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Drug Product CP4; Participants received a single dose of 120 mg denosumab manufactured using the new CP4 process subcutaneously on day 1.	Drug: Denosumab CP4; Denosumab produced by a process referred to as CP4, administered subcutaneously.
Experimental: Drug Product CP2; Participants received a single dose of 120 mg denosumab manufactured using the current CP2 process subcutaneously on day 1.	Drug: Denosumab CP2; Denosumab produced by a process referred to as CP2, administered subcutaneously.; Other Names: XGEVA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Drug Concentration (Cmax) of Denosumab	Serum denosumab concentration-time data were analyzed by non-compartmental methods. Serum concentrations below the LLOQ (20.0 ng/mL) were set to 0 before data analysis.	Day 1 predose up to day 127
Area Under the Drug Concentration-time Curve From Time 0 to 18 Weeks Post-dose (AUC0-18 Weeks) of Denosumab	Serum denosumab concentration-time data were analyzed by non-compartmental methods. Serum concentrations below the LLOQ (20.0 ng/mL) were set to 0 before data analysis.	Day 1 predose up to day 127

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Maximum Observed Concentration (Tmax) of Denosumab	Serum denosumab concentration-time data were analyzed by non-compartmental methods. Serum concentrations below the LLOQ (20.0 ng/mL) were set to 0 before data analysis.	Day 1 predose up to day 127
Half-life (T1/2) of Denosumab	Serum denosumab concentration-time data were analyzed by non-compartmental methods. Serum concentrations below the LLOQ (20.0 ng/mL) were set to 0 before data analysis.	Day 1 predose up to day 127
Area Under the Serum C-telopeptide (CTX1) Percent Inhibition-Time Curve From Time 0 to 18 Weeks Post-dose (AUEC0-18 Weeks)	Serum CTX1 concentration-time data were analyzed by non-compartmental methods. Serum CTX1 concentrations below the LLOQ (0.0490 ng/mL) were set to 0.0490 ng/mL before data analysis. AUEC0-18 weeks was estimated using the linear-log trapezoidal method.	Day 1 predose up to day 127
Maximum Percent Inhibition (Imax) of Serum CTX1	Serum CTX1 concentration-time data were analyzed by non-compartmental methods. Serum CTX1 concentrations below the LLOQ (0.0490 ng/mL) were set to 0.0490 ng/mL before data analysis.	Day 1 predose up to day 127
Time to Reach Maximum Percent Inhibition (Tmax) of Serum CTX1	Serum CTX1 concentration-time data were analyzed by non-compartmental methods. Serum CTX1 concentrations below the LLOQ (0.0490 ng/mL) were set to 0.0490 ng/mL before data analysis.	Day 1 predose up to day 127
Number of Participants With Adverse Events	A treatment-related adverse event (TRAE) is any treatment-emergent adverse event (AE) that per investigator review has a reasonable possibility of being caused by the investigational product.	From the first dose of denosumab through day 126
Number of Participants Who Developed Anti-denosumab Antibodies		Predose on day 1, and days 29, 67 and 127

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: January 31, 2014
• First Submitted That Met QC Criteria: January 31, 2014
• First Posted (Estimate): February 4, 2014

Study Record Updates

• Last Update Posted (Actual): December 29, 2017
• Last Update Submitted That Met QC Criteria: July 18, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: denosumab, bioequivalence
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: 20120186