This is a Phase I Study Conducted in Healthy Volunteers
Conditions
Keywords
Denosumab, Healthy Volunteers
Brief summary
This study has been designed as a randomized, double-blind, parallel-group study and in healthy adult male subjects of age 28 years to 55 years old. The study will assess the PK, safety and tolerability of AVT03 compared to US-Xgeva when administered as a single 120 mg SC dose
Detailed description
The study will consist of screening period, a 196 day (28 weeks) treatment and assessment period, and an End of Study (EOS) visit on week 32 on Day 196. Subjects will undertake a screening visit between Day -28 and Day -1 to determine their eligibility for the study. Subjects who meet the eligibility criteria will be admitted to the study site on the day prior to dosing (Day -1), during which their continued eligibility will be assessed up to Day 1 prior to dosing. On Day 1, eligible subjects will be randomized and will receive a single dose of 120mg AVT03 or 120mg Xgeva as subcutaneous injection.
Interventions
BIOLOGICALAVT03
AVT03 will be given as 1 time subcutaneous injection
BIOLOGICALDenosumab
Xgeva (denosumab) will be given as 1 time subcutaneous injection
Sponsors
Alvotech Swiss AG
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double Blind
Eligibility
Sex/Gender
MALE
Age
28 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 2. Male subjects who are 28 to 55 years old, inclusive, at the time of signing the ICF. 3. Have a body weight of 50.0 to 90.0 kg (inclusive) and body mass index of 17.0 to 32 kg/m2 at Screening and Day -1.
Exclusion criteria
1. Evidence of clinically relevant pathology, especially prior diagnosis of bone disease, or any uncontrolled condition that will affect bone metabolism such as, but not limited to: osteoporosis, osteogenesis imperfecta, hyperparathyroidism,, non-controlled hyperthyroidism osteomalacia, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, current flare-up of osteoarthritis and/or gout, active malignancy, renal disease, Paget's disease of the bone, malabsorption syndrome. 2. Have osteonecrosis of the jaw (ONJ) or risk factors for ONJ such as invasive dental procedures (e.g., tooth extraction, dental implants, oral surgery) or intend to undergo such procedures during the study period, poor oral hygiene, periodontal, and/or pre-existing dental disease. 3. Have bone fractures, presence of active healing fractures, or recent bone fracture 4. Abnormal serum calcium. 5. Known vitamin D deficiency.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Co-primary PK Endpoint Cmax: Maximum Serum Concentration | Day 1 (pre-dose, 8h and 12h post-dose), Day 2 to Day 13 (daily), Day 15, Day 18, Day 22, Day 25, Day 29, Day 43, Day 57, Day 71, Day 85, Day 99, Day 112, Day 126, Day 141, Day 162 and Day 196 (week 28) / End of study | Samples will be collected for measurement |
| Co-primary PK endpoint_AUC0-t: Area Under the Serum Concentration-time Curve up to Time t, Where t is the Last Time Point With a Concentration Above the Lower Limit of Quantitation | Day 1 (pre-dose, 8h and 12h post-dose), Day 2 to Day 13 (daily), Day 15, Day 18, Day 22, Day 25, Day 29, Day 43, Day 57, Day 71, Day 85, Day 99, Day 112, Day 126, Day 141, Day 162 and Day 196 (week 28) / End of study | Samples will be collected for measurement |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK_ AUC0-inf: Comprised of AUC0-t and AUC Extrapolated From Time t to Time Infinity. | Day 1 (pre-dose, 8h and 12h post-dose), Day 2 to Day 13 (daily), Day 15, Day 18, Day 22, Day 25, Day 29, Day 43, Day 57, Day 71, Day 85, Day 99, Day 112, Day 126, Day 141, Day 162 and Day 196 (week 28) / End of study | Samples will be collected for measurement |
| Safety Incidence, Nature and Severity of Adverse Events. | Day 1(week 1) to Day 196 (week 28)] | — |
| Immunogenicity Presence of ADAs and Presence of nAbs Against AVT03 and Xgeva | Day 1, Day 8, Day 15, Day 29, Day 57, Day 71, Day 112, Day 141, Day 196/EoS | Samples will be collected for measurement |
Countries
Poland, South Africa, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental Arm AVT03 120mg AVT03 is the proposed biosimilar for Xgeva (denosumab). Subjects in this arm received a single 120mg dose of AVT03 as a subcutaneous injection
AVT03: AVT03 was given as 1 time subcutaneous injection | 104 |
| Active Comparator Xgeva 120mg Xgeva (denosumab) is the active comparator for AVT03. Subjects in this arm received a single 120mg dose of Xgeva (denosumab) as a subcutaneous injection
Denosumab: Xgeva (denosumab) was given as 1 time subcutaneous injection | 104 |
| Total | 208 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Experimental Arm AVT03 120mg | Active Comparator Xgeva 120mg | Total |
|---|---|---|---|
| Age, Continuous | 36.5 years STANDARD_DEVIATION 6.72 | 38.1 years STANDARD_DEVIATION 7.08 | 37.3 years STANDARD_DEVIATION 6.94 |
| Race/Ethnicity, Customized Asian (Japanese) | 12 Participants | 12 Participants | 24 Participants |
| Race/Ethnicity, Customized Black or African American | 28 Participants | 24 Participants | 52 Participants |
| Race/Ethnicity, Customized Caucasian/White | 64 Participants | 68 Participants | 132 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 104 Participants | 104 Participants | 208 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 104 | 1 / 104 |
| other Total, other adverse events | 66 / 104 | 67 / 104 |
| serious Total, serious adverse events | 1 / 104 | 3 / 104 |
Outcome results
Primary
Co-primary PK endpoint_AUC0-t: Area Under the Serum Concentration-time Curve up to Time t, Where t is the Last Time Point With a Concentration Above the Lower Limit of Quantitation
Samples will be collected for measurement
Time frame: Day 1 (pre-dose, 8h and 12h post-dose), Day 2 to Day 13 (daily), Day 15, Day 18, Day 22, Day 25, Day 29, Day 43, Day 57, Day 71, Day 85, Day 99, Day 112, Day 126, Day 141, Day 162 and Day 196 (week 28) / End of study
Population: A total of 4 participants were excluded from the PK population analyses set (1 participant in the AVT03 group and 3 participants in the Xgeva group) due to limited duration of PK data.\[
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Experimental Arm AVT03 120mg | Co-primary PK endpoint_AUC0-t: Area Under the Serum Concentration-time Curve up to Time t, Where t is the Last Time Point With a Concentration Above the Lower Limit of Quantitation | 15501387.9 ng·h/mL | Geometric Coefficient of Variation 27 |
| Active Comparator Xgeva 120mg | Co-primary PK endpoint_AUC0-t: Area Under the Serum Concentration-time Curve up to Time t, Where t is the Last Time Point With a Concentration Above the Lower Limit of Quantitation | 14366056.2 ng·h/mL | Geometric Coefficient of Variation 29 |
Primary
Co-primary PK Endpoint Cmax: Maximum Serum Concentration
Samples will be collected for measurement
Time frame: Day 1 (pre-dose, 8h and 12h post-dose), Day 2 to Day 13 (daily), Day 15, Day 18, Day 22, Day 25, Day 29, Day 43, Day 57, Day 71, Day 85, Day 99, Day 112, Day 126, Day 141, Day 162 and Day 196 (week 28) / End of study
Population: A total of 4 participants were excluded from the PK population analyses set (1 participant in the AVT03 group and 3 participants in the Xgeva group) due to limited duration of PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Experimental Arm AVT03 120mg | Co-primary PK Endpoint Cmax: Maximum Serum Concentration | 12761.4 ng/mL | Geometric Coefficient of Variation 34 |
| Active Comparator Xgeva 120mg | Co-primary PK Endpoint Cmax: Maximum Serum Concentration | 12259.8 ng/mL | Geometric Coefficient of Variation 32 |
Secondary
Immunogenicity Presence of ADAs and Presence of nAbs Against AVT03 and Xgeva
Samples will be collected for measurement
Time frame: Day 1, Day 8, Day 15, Day 29, Day 57, Day 71, Day 112, Day 141, Day 196/EoS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental Arm AVT03 120mg | Immunogenicity Presence of ADAs and Presence of nAbs Against AVT03 and Xgeva | Neutralizing Antibodies | 41 Participants |
| Experimental Arm AVT03 120mg | Immunogenicity Presence of ADAs and Presence of nAbs Against AVT03 and Xgeva | Binding (ADA) | 104 Participants |
| Active Comparator Xgeva 120mg | Immunogenicity Presence of ADAs and Presence of nAbs Against AVT03 and Xgeva | Neutralizing Antibodies | 43 Participants |
| Active Comparator Xgeva 120mg | Immunogenicity Presence of ADAs and Presence of nAbs Against AVT03 and Xgeva | Binding (ADA) | 102 Participants |
Secondary
PK_ AUC0-inf: Comprised of AUC0-t and AUC Extrapolated From Time t to Time Infinity.
Samples will be collected for measurement
Time frame: Day 1 (pre-dose, 8h and 12h post-dose), Day 2 to Day 13 (daily), Day 15, Day 18, Day 22, Day 25, Day 29, Day 43, Day 57, Day 71, Day 85, Day 99, Day 112, Day 126, Day 141, Day 162 and Day 196 (week 28) / End of study
Population: A total of 4 participants were excluded from the PK population analyses set (1 participant in the AVT03 group and 3 participants in the Xgeva group) due to limited duration of PK data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Experimental Arm AVT03 120mg | PK_ AUC0-inf: Comprised of AUC0-t and AUC Extrapolated From Time t to Time Infinity. | 15559245.8 ng·h/mL | Geometric Coefficient of Variation 28 |
| Active Comparator Xgeva 120mg | PK_ AUC0-inf: Comprised of AUC0-t and AUC Extrapolated From Time t to Time Infinity. | 14555779.3 ng·h/mL | Geometric Coefficient of Variation 29 |
Secondary
Safety Incidence, Nature and Severity of Adverse Events.
Time frame: Day 1(week 1) to Day 196 (week 28)]
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental Arm AVT03 120mg | Safety Incidence, Nature and Severity of Adverse Events. | Any TEAE | 66 participants |
| Experimental Arm AVT03 120mg | Safety Incidence, Nature and Severity of Adverse Events. | TESAEs | 1 participants |
| Active Comparator Xgeva 120mg | Safety Incidence, Nature and Severity of Adverse Events. | Any TEAE | 67 participants |
| Active Comparator Xgeva 120mg | Safety Incidence, Nature and Severity of Adverse Events. | TESAEs | 3 participants |