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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Healthy Volunteer

Intervention / Treatment
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* Drug: Denosumab CP4
* Drug: Denosumab CP2


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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denosumab, bioequivalence