Osteoporosis, Postmenopausal
Conditions
Keywords
Postmenopausal Osteoporosis, Denosumab, Alvotech
Brief summary
This is a randomized, double-blind, parallel design, repeat dose, 2 arm, multicenter study comparing the efficacy, safety, immunogenicity, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of AVT03 and US-Prolia in postmenopausal women with osteoporosis.
Detailed description
After the screening activities, eligible subjects were randomized to receive either AVT03 60 mg or Prolia® 60 mg, administered as a subcutaneous (s.c.) injection on Day 1 and at Month 6. At Month 12, subjects in AVT03 treatment group will received a third dose of AVT03 60 mg administered s.c. while subjects in Prolia® treatment group will were be re-randomized 1:1 to receive either Prolia 60 mg or AVT03 60 mg administered as a subcutaneous injection. Afterwards, the subjects will be followed until the End of Study (EoS) Visit.
Interventions
BIOLOGICALAVT03
AVT03 (denosumab) is a recombinant fully human IgG2 monoclonal antibody to RANKL to be administered as a subcutaneous injection. Subjects in this arm received AVT03 60mg administered s.c. on Day 1 and at Month 6. At Month 12, subjects in the AVT03 arm received a third dose of AVT03 60 mg.
BIOLOGICALDenosumab
Prolia (denosumab) is a recombinant fully human IgG2 monoclonal antibody to RANKL developed to be administered as a subcutaneous injection. Subjects in this arm received 60mg of commercially available US-Prolia, administered s.c on Day 1 and at Month 6. At Month 12, subjects in the Prolia treatment group were re-randomized in a 1:1 ratio to receive either: * AVT03 60 mg administered s.c. on Day365. * Prolia 60 mg administered s.c. on Day365.
Sponsors
Alvotech Swiss AG
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Postmenopausal women with osteoporosis willing to sign an informed consent form (ICF)and able to undergo protocol related procedures. 2. A baseline dual-energy x-ray absorptiometry (DXA) scan with a T score ≤-2.5 and * 4.0 at the LS (L1 to L4)and/or, total hip, and/or femoral neck. 3. Age: ≥50 years. 4. Female subject is postmenopausal according to 1 of the following criteria: 1. Spontaneous amenorrhea for ≥12 consecutive months 2. Biochemical criteria of menopause, follicle-stimulating hormone, \>40 IU/L except surgically sterile 3. Having had bilateral oophorectomy ≥6 weeks prior to Screening 5. Willing to receive calcium plus vitamin D supplements. 6. At least 2 consecutive evaluable lumbar vertebrae and at least 1 evaluable hip.
Exclusion criteria
1. Evidence of clinically relevant pathology, especially prior diagnosis of bone disease, or any uncontrolled condition that will affect bone metabolism 2. History and/or presence of 1 severe or more than 1 moderate vertebral fractures confirmed by x-ray. 3. History of hip fracture 4. Presence of active healing fractures 5. Osteonecrosis of the jaw (ONJ) or risk factors for ONJ such as invasive dental procedures 6. Evidence of hypo/hypercalcemia at Screening 7. Known vitamin D deficiency 8. Known intolerance to calcium and vitamin D supplement.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in LS BMD at Month 12 to Demonstrate Comparable Efficacy of AVT03 and Prolia®. | Baseline to Month 12 | Percent Change From Baseline in LS BMD at Month 12 to demonstrate comparable efficacy of AVT03 and Prolia®. |
| To Demonstrate Comparable Profile of AVT03 and Prolia in Terms of Area Under the Percent Change From Baseline in Serum C-telopeptide of Type 1 Collagen (AUEC of %Cfb sCTX-1) | Baseline to Month 6 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of New Morphometric Vertebral Fractures | Month 12 and 18 | Incidence of new morphometric vertebral fractures at 12 and 18 months |
| Percent Change From Baseline in sCTX-1 | Month 3, Month 6, Month 9, Month 12 and Month 18 | Percent change from Baseline in sCTX-1 at 3, 6, 9, 12 and 18 months |
| Incidence, Nature and Severity of Adverse Events Including Adverse Drug Reactions | Month 18 | — |
| Percent Change From Baseline in LS BMD | Month 6, Month18 | Percent change from Baseline in LS BMD at 6 and 18 months |
| Frequency and Severity of Findings in Routine Safety Parameters | Month 18 | — |
| Frequency and Titer of Anti-drug Antibodies and Frequency of Neutralizing Antibodies Against AVT03 and Prolia | Month 18 | — |
| Serum Trough Concentration of AVT03 and Prolia | Month 18 | — |
| Frequency and Severity of Injection Site Reactions | Month 12 | — |
| Percent Change From Baseline in Hip and Femoral Neck BMD | Month 6, Month 12, Month 18 | Percent change from Baseline in hip and femoral neck BMD at Month 6, 12 and 18 months |
Countries
Bulgaria, Czechia, Georgia, Poland, South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AVT03 AVT03 is a proposed biosimilar for Prolia.
AVT03: AVT03 (denosumab) is a recombinant fully human IgG2 monoclonal antibody to RANKL to be administered as a subcutaneous injection. Subjects in this arm received AVT03 60mg administered s.c. on Day 1 and at Month 6. At Month 12, subjects in the AVT03 arm received a third dose of AVT03 60 mg. | 266 |
| Prolia Denosumab: Prolia (denosumab) is a recombinant fully human IgG2 monoclonal antibody to RANKL developed to be administered as a subcutaneous injection.
Subjects will receive 60mg of commercially available US-Prolia, administered s.c on Day 1 and at Month 6. At Month 12, subjects in the Prolia treatment group will be re-randomized in a 1:1 ratio to receive either:
* AVT03 60 mg administered s.c. on Day365.
* Prolia 60 mg administered s.c. on Day365. | 266 |
| Total | 532 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Baseline to Month 12 | Adverse Event | 7 | 2 | 0 |
| Baseline to Month 12 | Death | 3 | 1 | 0 |
| Baseline to Month 12 | Physician Decision | 1 | 0 | 0 |
| Baseline to Month 12 | Protocol Violation | 2 | 3 | 0 |
| Baseline to Month 12 | Withdrawal by Subject | 11 | 16 | 0 |
| Month 12 to Month 18 | Death | 1 | 0 | 0 |
| Month 12 to Month 18 | Lost to Follow-up | 1 | 0 | 1 |
| Month 12 to Month 18 | Other reasons | 0 | 0 | 1 |
| Month 12 to Month 18 | Withdrawal by Subject | 3 | 2 | 1 |
Baseline characteristics
| Characteristic | AVT03 | Prolia | Total |
|---|---|---|---|
| Age, Continuous | 65.2 years STANDARD_DEVIATION 6.94 | 64.5 years STANDARD_DEVIATION 7.04 | 64.9 years STANDARD_DEVIATION 7 |
| BMI at screening | 25.12 kg/m^2 STANDARD_DEVIATION 3.547 | 25.2 kg/m^2 STANDARD_DEVIATION 3.605 | 25.16 kg/m^2 STANDARD_DEVIATION 3.573 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 11 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 6 Participants | 11 Participants |
| Race (NIH/OMB) White | 246 Participants | 249 Participants | 495 Participants |
| Region of Enrollment Bulgaria | 14 participants | 11 participants | 25 participants |
| Region of Enrollment Czechia | 28 participants | 33 participants | 61 participants |
| Region of Enrollment Georgia | 33 participants | 37 participants | 70 participants |
| Region of Enrollment Poland | 144 participants | 144 participants | 288 participants |
| Region of Enrollment South Africa | 47 participants | 41 participants | 88 participants |
| Sex: Female, Male Female | 266 Participants | 266 Participants | 532 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 266 | 1 / 266 | 1 / 242 | 0 / 122 | 0 / 122 |
| other Total, other adverse events | 178 / 266 | 178 / 266 | 99 / 242 | 39 / 122 | 39 / 122 |
| serious Total, serious adverse events | 9 / 266 | 10 / 266 | 6 / 242 | 3 / 122 | 2 / 122 |
Outcome results
Primary
Percent Change From Baseline in LS BMD at Month 12 to Demonstrate Comparable Efficacy of AVT03 and Prolia®.
Percent Change From Baseline in LS BMD at Month 12 to demonstrate comparable efficacy of AVT03 and Prolia®.
Time frame: Baseline to Month 12
Population: The number of evaluable subjects with data at Month 12 per group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AVT03 | Percent Change From Baseline in LS BMD at Month 12 to Demonstrate Comparable Efficacy of AVT03 and Prolia®. | 5.3 Percent Change From Baseline in LS BMD | Standard Error 0.87 |
| Prolia | Percent Change From Baseline in LS BMD at Month 12 to Demonstrate Comparable Efficacy of AVT03 and Prolia®. | 5.18 Percent Change From Baseline in LS BMD | Standard Error 0.872 |
Primary
To Demonstrate Comparable Profile of AVT03 and Prolia in Terms of Area Under the Percent Change From Baseline in Serum C-telopeptide of Type 1 Collagen (AUEC of %Cfb sCTX-1)
Time frame: Baseline to Month 6
Population: The number of evaluable subjects with data at Month 12 per group.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AVT03 | To Demonstrate Comparable Profile of AVT03 and Prolia in Terms of Area Under the Percent Change From Baseline in Serum C-telopeptide of Type 1 Collagen (AUEC of %Cfb sCTX-1) | 2345.55 percentage change from baseline*days | Standard Error 1.011 |
| Prolia | To Demonstrate Comparable Profile of AVT03 and Prolia in Terms of Area Under the Percent Change From Baseline in Serum C-telopeptide of Type 1 Collagen (AUEC of %Cfb sCTX-1) | 2342.87 percentage change from baseline*days | Standard Error 1.011 |
Secondary
Frequency and Severity of Findings in Routine Safety Parameters
Time frame: Month 18
Secondary
Frequency and Severity of Injection Site Reactions
Time frame: Month 12
Secondary
Frequency and Titer of Anti-drug Antibodies and Frequency of Neutralizing Antibodies Against AVT03 and Prolia
Time frame: Month 18
Secondary
Incidence, Nature and Severity of Adverse Events Including Adverse Drug Reactions
Time frame: Month 18
Secondary
Incidence of New Morphometric Vertebral Fractures
Incidence of new morphometric vertebral fractures at 12 and 18 months
Time frame: Month 12 and 18
Secondary
Percent Change From Baseline in Hip and Femoral Neck BMD
Percent change from Baseline in hip and femoral neck BMD at Month 6, 12 and 18 months
Time frame: Month 6, Month 12, Month 18
Secondary
Percent Change From Baseline in LS BMD
Percent change from Baseline in LS BMD at 6 and 18 months
Time frame: Month 6, Month18
Secondary
Percent Change From Baseline in sCTX-1
Percent change from Baseline in sCTX-1 at 3, 6, 9, 12 and 18 months
Time frame: Month 3, Month 6, Month 9, Month 12 and Month 18
Secondary
Serum Trough Concentration of AVT03 and Prolia
Time frame: Month 18