Healthy Volunteer
Conditions
Keywords
denosumab, bioequivalence
Brief summary
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.
Interventions
DRUGDenosumab CP4
Denosumab produced by a process referred to as CP4, administered subcutaneously.
DRUGDenosumab CP2
Denosumab produced by a process referred to as CP2, administered subcutaneously.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Drug Concentration (Cmax) of Denosumab | Day 1 predose up to day 127 | 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. |
| Area Under the Drug Concentration-time Curve From Time 0 to 18 Weeks Post-dose (AUC0-18 Weeks) of Denosumab | Day 1 predose up to day 127 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Serum C-telopeptide (CTX1) Percent Inhibition-Time Curve From Time 0 to 18 Weeks Post-dose (AUEC0-18 Weeks) | Day 1 predose up to day 127 | 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. |
| Maximum Percent Inhibition (Imax) of Serum CTX1 | Day 1 predose up to day 127 | 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. |
| Half-life (T1/2) of Denosumab | Day 1 predose up to day 127 | 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. |
| Number of Participants With Adverse Events | From the first dose of denosumab through day 126 | 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. |
| Number of Participants Who Developed Anti-denosumab Antibodies | Predose on day 1, and days 29, 67 and 127 | — |
| Time to Reach Maximum Percent Inhibition (Tmax) of Serum CTX1 | Day 1 predose up to day 127 | 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. |
| Time to Maximum Observed Concentration (Tmax) of Denosumab | Day 1 predose up to day 127 | 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. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 2 centers in the United States.
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive a single 120-mg dose of denosumab either as a 1.7 mL single injection of 70 mg/mL denosumab produced using the new CP4 process or as a 1.7 mL single injection of 70 mg/mL denosumab produced from the current CP2 process.
Participants by arm
| Arm | Count |
|---|---|
| Denosumab CP4 Participants received a single dose of 120 mg denosumab manufactured using the new CP4 process subcutaneously on day 1. | 71 |
| Denosumab CP2 Participants received a single dose of 120 mg denosumab manufactured using the current CP2 process subcutaneously on day 1. | 71 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Decision by Sponsor | 1 | 1 |
| Overall Study | Lost to Follow-up | 4 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Denosumab CP2 | Total | Denosumab CP4 |
|---|---|---|---|
| Age, Continuous | 37.6 years STANDARD_DEVIATION 11.3 | 38.3 years STANDARD_DEVIATION 11.1 | 38.9 years STANDARD_DEVIATION 10.9 |
| Race/Ethnicity, Customized Asian | 4 participants | 9 participants | 5 participants |
| Race/Ethnicity, Customized Black (or African American) | 24 participants | 48 participants | 24 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 23 participants | 43 participants | 20 participants |
| Race/Ethnicity, Customized Multiple | 1 participants | 4 participants | 3 participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 48 participants | 99 participants | 51 participants |
| Race/Ethnicity, Customized White | 42 participants | 81 participants | 39 participants |
| Sex: Female, Male Female | 33 Participants | 62 Participants | 29 Participants |
| Sex: Female, Male Male | 38 Participants | 80 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 26 / 71 | 24 / 71 |
| serious Total, serious adverse events | 0 / 71 | 1 / 71 |
Outcome results
Primary
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.
Time frame: Day 1 predose up to day 127
Population: The PK concentration analysis set; 2 participants were excluded from all PK analyses because insufficient samples were available for calculation of PK variables and a further 11 participants were excluded from the analysis of AUC0-18 weeks because all samples after week 16 were missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Denosumab CP4 | Area Under the Drug Concentration-time Curve From Time 0 to 18 Weeks Post-dose (AUC0-18 Weeks) of Denosumab | 579 day*μg/mL | Standard Deviation 190 |
| Denosumab CP2 | Area Under the Drug Concentration-time Curve From Time 0 to 18 Weeks Post-dose (AUC0-18 Weeks) of Denosumab | 555 day*μg/mL | Standard Deviation 166 |
90% CI: [0.934, 1.131]
Primary
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.
Time frame: Day 1 predose up to day 127
Population: The pharmacokinetic (PK) concentration analysis set includes all participants who received denosumab and had at least one PK sample collected. Two participants were excluded from all PK analyses because insufficient samples were available (≥ 3 missing consecutive samples) for calculation of PK variables.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Denosumab CP4 | Maximum Observed Drug Concentration (Cmax) of Denosumab | 12.7 μg/mL | Standard Deviation 3.53 |
| Denosumab CP2 | Maximum Observed Drug Concentration (Cmax) of Denosumab | 11.8 μg/mL | Standard Deviation 3.51 |
90% CI: [0.995, 1.181]
Secondary
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.
Time frame: Day 1 predose up to day 127
Population: The pharmacodynamic (PD) analysis set includes all participants who received denosumab and had at least one sCTX1 sample collected.~Eleven participants were excluded from the analysis of AUEC0-18 weeks because no samples after week 16 were collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Denosumab CP4 | Area Under the Serum C-telopeptide (CTX1) Percent Inhibition-Time Curve From Time 0 to 18 Weeks Post-dose (AUEC0-18 Weeks) | 8380 day*percent inhibition | Standard Deviation 2050 |
| Denosumab CP2 | Area Under the Serum C-telopeptide (CTX1) Percent Inhibition-Time Curve From Time 0 to 18 Weeks Post-dose (AUEC0-18 Weeks) | 8190 day*percent inhibition | Standard Deviation 2250 |
Secondary
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.
Time frame: Day 1 predose up to day 127
Population: The PK concentration analysis set; 2 participants were excluded from all PK analyses because insufficient samples were available for calculation of PK variables and a further 11 participants were excluded from the analysis of T1/2 because all samples after week 16 were missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Denosumab CP4 | Half-life (T1/2) of Denosumab | 23.9 days | Standard Deviation 10.1 |
| Denosumab CP2 | Half-life (T1/2) of Denosumab | 22.4 days | Standard Deviation 10.2 |
Secondary
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.
Time frame: Day 1 predose up to day 127
Population: The pharmacodynamic analysis set includes all participants who received denosumab and had at least one sCTX1 sample collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Denosumab CP4 | Maximum Percent Inhibition (Imax) of Serum CTX1 | 69.8 percent inhibition | Standard Deviation 17 |
| Denosumab CP2 | Maximum Percent Inhibition (Imax) of Serum CTX1 | 70.3 percent inhibition | Standard Deviation 13.7 |
Secondary
Number of Participants Who Developed Anti-denosumab Antibodies
Time frame: Predose on day 1, and days 29, 67 and 127
Population: All participants who received denosumab
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Denosumab CP4 | Number of Participants Who Developed Anti-denosumab Antibodies | 0 participants |
| Denosumab CP2 | Number of Participants Who Developed Anti-denosumab Antibodies | 0 participants |
Secondary
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.
Time frame: From the first dose of denosumab through day 126
Population: All participants who received denosumab
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Denosumab CP4 | Number of Participants With Adverse Events | Any adverse event | 26 participants |
| Denosumab CP4 | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Denosumab CP4 | Number of Participants With Adverse Events | AEs leading to discontinuation of denosumab | 0 participants |
| Denosumab CP4 | Number of Participants With Adverse Events | Fatal adverse events | 0 participants |
| Denosumab CP4 | Number of Participants With Adverse Events | Treatment-related adverse events (TRAEs) | 4 participants |
| Denosumab CP4 | Number of Participants With Adverse Events | Treatment-related serious adverse events | 0 participants |
| Denosumab CP4 | Number of Participants With Adverse Events | TRAEs leading to discontinuation of denosumab | 0 participants |
| Denosumab CP4 | Number of Participants With Adverse Events | Treatment-related fatal adverse events | 0 participants |
| Denosumab CP2 | Number of Participants With Adverse Events | Treatment-related fatal adverse events | 0 participants |
| Denosumab CP2 | Number of Participants With Adverse Events | Any adverse event | 24 participants |
| Denosumab CP2 | Number of Participants With Adverse Events | Treatment-related adverse events (TRAEs) | 6 participants |
| Denosumab CP2 | Number of Participants With Adverse Events | Serious adverse events | 1 participants |
| Denosumab CP2 | Number of Participants With Adverse Events | TRAEs leading to discontinuation of denosumab | 0 participants |
| Denosumab CP2 | Number of Participants With Adverse Events | AEs leading to discontinuation of denosumab | 0 participants |
| Denosumab CP2 | Number of Participants With Adverse Events | Treatment-related serious adverse events | 0 participants |
| Denosumab CP2 | Number of Participants With Adverse Events | Fatal adverse events | 0 participants |
Secondary
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.
Time frame: Day 1 predose up to day 127
Population: The pharmacokinetic (PK) concentration analysis set includes all participants who received denosumab and had at least one PK sample collected. Two participants were excluded from all PK analyses because insufficient samples were available (≥ 3 missing consecutive samples) for calculation of PK variables.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Denosumab CP4 | Time to Maximum Observed Concentration (Tmax) of Denosumab | 6.9 days |
| Denosumab CP2 | Time to Maximum Observed Concentration (Tmax) of Denosumab | 7.0 days |
Secondary
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.
Time frame: Day 1 predose up to day 127
Population: The pharmacodynamic analysis set includes all participants who received denosumab and had at least one sCTX1 sample collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Denosumab CP4 | Time to Reach Maximum Percent Inhibition (Tmax) of Serum CTX1 | 3.01 days |
| Denosumab CP2 | Time to Reach Maximum Percent Inhibition (Tmax) of Serum CTX1 | 3.96 days |