Randomized, double blind, parallel group, single dose, 3 arm study to investigate and compare the PK, PD, safety and immunogenicity profile of MB09 with EU/US-Xgeva® in healthy male subjects. During the course of the study, the similarity in pharmacokinetics will be assessed by sampling the levels of drug in the blood, and by comparing these levels among the different administration arms. Pharmacodynamics, safety, tolerability, and immunologic response to the administered drugs will also be evaluated throughout.
The primary PK parameter endpoints are AUC0-last and Cmax for denosumab. The secondary PK endpoints will include all other PK parameters for denosumab, including AUC0-∞, Tmax, CL and t1/2. For the primary PK Analysis, an analysis of variance (ANOVA) model with treatment and stratification factors as fixed effects will be performed on the natural log transformed values of Cmax, AUC0 last, and AUC0-∞. Estimates of geometric mean ratios together with the corresponding 90% confidence intervals (CI) will be derived for the comparisons of the PK parameters as follows: * MB09 versus EU-Xgeva® * MB09 versus US-Xgeva® * EU-Xgeva® versus US-Xgeva® Bioequivalence will be concluded if the 90% CIs for the test to reference ratios of the geometric least square means for AUC0-last and Cmax are entirely contained within the \[80%, 125%\] interval. For the PD Analysis, an analysis of covariance (ANCOVA) model with treatment and stratification factors as fixed effects and logged pre-dose sCTX concentrations fitted as a covariate will be performed on the natural log-transformed values of AUEC0 253 and AUIC0 253. Adverse events will be coded using MedDRA Version 24. All AE data will be presented in a data listing. Treatment-emergent AEs will be summarised by treatment and overall, as well as by severity and relationship to study drug. Serious AEs and AEs leading to discontinuation of study drug will also be presented in the data listings and summarised by treatment and overall. The incidence of ADA to denosumab and the neutralizing potential and titre of positive ADAs will be reported. All immunogenicity data will be presented in the data listings.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
257
Single dose of 35mg SC administered
Single dose of 35mg SC administered
Single dose of 35mg SC administered
Biokinetica - Early Phase Institute
Józefów, Poland
AUC0-last
Area under the plasma concentration versus time curve from time zero to the last quantifiable concentration
Time frame: Day 1 to Day 253
Cmax
Maximum observed plasma concentration
Time frame: Day 1 to Day 253
AUC0-∞
Area under the plasma concentration versus time curve from time zero extrapolated to infinity
Time frame: Day 1 to Day 253
Tmax
Time to reach Cmax
Time frame: Day 1 to Day 253
CL
Clearance
Time frame: Day 1 to Day 253
t1/2
Terminal half-life
Time frame: Day 1 to Day 253
Pharmacodynamics (sCTX) AUEC0-253
Observed concentration of serum C-terminal telopeptide of Type 1 collagen (sCTX) parameter will be calculated as PD endpoint. AUC0-253: area under the plasma concentration versus time curve from time 0 to day 253
Time frame: Day 1 to Day 253
Incidence of Treatment Emergent Adverse Events (TEAEs)
A treatment-emergent adverse event is defined as any event not present before exposure to study drug or any event already present that worsens in intensity or frequency after exposure.
Time frame: Day 1 to Day 253
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Incidence of Anti-denosumab Antibodies (ADA)
The incidence of ADA to denosumab and the neutralizing potential and titre of positive ADA. The immunogenicity endpoint included denosumab anti-drug antibodies (ADA).
Time frame: Day 1 to Day 253
Incidence of Neutralizing Antibodies (NAb)
The incidence the neutralizing potential and titre of positive ADA.
Time frame: Day 1 to Day 253