CT-P41_3.1

CELLTRION, Inc.

23, Academy-ro, Yeonsu-gu, Incheon, Korea, Republic of, 22014

Head Clinical Planning Department, Celltrion, Inc, +82 328504167, JeeHye.Suh@celltrion.com

Head Clinical Planning Department, Celltrion, Inc, +82 328504167, JeeHye.Suh@celltrion.com

No

No

No

Final

16 Nov 2023

Yes

18 May 2023

Yes

16 Nov 2023

No

- To demonstrate the equivalence of CT-P41 to US licensed Prolia in terms of efficacy in postmenopausal women with osteoporosis as determined by percent change from baseline in BMD for lumbar spine (L1 to L4) at Week 52 - To demonstrate the PD similarity in terms of area under the effect curve (AUEC) of serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX) over the initial 6 months (from Day 1 predose to Week 26 predose) between CT-P41 and US-licensed Prolia

The study was performed following the ethical principles that have their origin in the Declaration of Helsinki (WMA 2013), the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) harmonised tripartite guideline E6 (R2): Good Clinical Practice (GCP), and all applicable regulations. All investigators agreed to conduct all aspects of this study by national, state, local laws and regulations. Hypersensitivity/allergic reactions monitoring was assessed before the start of the study drug administration (within 15 minutes) and at 1 hour (± 10 minutes) after the end of the study drug administration by additional vital sign measurements including blood pressure, heart and respiratory rates, and body temperature. If patients had signs and symptoms of hypersensitivity/allergic reactions at home (hives, difficulty breathing, or swelling of face, eyes, lips, or mouth or any symptoms of cardiac origin), patients or caregivers were to be advised to call the study center or get immediate help. In addition, hypersensitivity could be monitored by routine continuous clinical monitoring including patient-reported signs and symptoms. In case of hypersensitivity, emergency medication and equipment, such as adrenaline, antihistamines, corticosteroids, and respiratory support including inhalational therapy, oxygen, and artificial ventilation was available and any types of ECG could be performed. For patients who experience or develop life-threatening treatment-related hypersensitivity/allergic reactions, the study drug was to be stopped immediately and the patient was to be withdrawn from the study.

18 May 2021

No

Yes

Poland: 339

Estonia: 53

Latvia: 9

Ukraine: 78

479

401

0

0

0

0

0

0

202

277

0

TP I - Week 0 Day 1 to Week 52

Randomised - controlled

Yes

CT-P41

Solution for injection

Subcutaneous use

A total of 2 subcutaneous administration of 60 mg CT-P41 (proposed denosumab biosimilar) at Week 0 and Week 26 (26-week intervals) in TP I. CT-P41 was administered as 60 mg/mL single dose, solution for injection in a pre-filled syringe (PFS).

US-licensed Prolia

Solution for injection

Subcutaneous use

A total of 2 subcutaneous administrations of 60 mg US-licensed Prolia (denosumab) at Week 0 and Week 26 (26-week intervals) in TP I. US-licensed Prolia was administered as 60 mg/mL single dose, solution for injection in PFS.

TP II - Week 52 to Week 78

Randomised - controlled

Yes

CT-P41

Solution for injection

Subcutaneous use

Participants treated with CT-P41 in TP I continued the treatment with CT-P41 as a third dose at Week 52 in TP II

US-licensed Prolia

Solution for injection

Subcutaneous use

Participants treated with US-licensed Prolia in TP I were re-randomized to continue the treatment with US-licensed Prolia as a third dose at Week 52 in TP II

CT-P41 and US-licensed Prolia

Solution for injection

Subcutaneous use

Participants treated with US-licensed Prolia in TP I were re-randomized to switch to CT-P41 as a third dose at Week 52 in TP II

CT-P41

US-licensed Prolia

CT-P41

US-licensed Prolia

CT-P41 maintenance

US-licensed Prolia maintenance

Switched to CT-P41

Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA) and assessments of the lumbar spine (L1 to L4) were performed at a central imaging vendor. To evaluate the difference between 2 groups in the primary efficacy endpoint, the percent change from baseline in BMD for lumbar spine (L1 to L4) by DXA at Week 52 was analyzed using an analysis of covariance (ANCOVA) model coupled with multiple imputation assuming the data to be missing at random (MAR). The total number of participants in full analysis set (FAS) was 239 and 238 in the CT-P41 and US-licensed Prolia groups, respectively.

Primary

baseline (screening), Week 52 predose

An ANCOVA was performed with the treatment as a fixed effect and age, baseline BMD T-score at the lumbar spine, and prior bisphosphonates therapy (yes versus no) as covariates.

CT-P41 v US-licensed Prolia

434

Pre-specified

-0.139

2-sided

The AUEC of serum Concentration of serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX) was calculated by non-compartmental analysis method from the concentration-time data. The effect used in the AUEC was based on the percent change from baseline (or also defined as % inhibition). Serum concentration below the LLoQ was set to the LLoQ in the PD parameter estimation.

Primary

Baseline (Week 0 Day 1), up to Week 26

An ANCOVA was performed with the natural log-transformed AUEC of s-CTX as the dependent variable, treatment as a fixed effect and age, baseline BMD T-score at the lumbar spine, prior bisphosphonates therapy (Yes versus No), and baseline s-CTX level as covariates.

CT-P41 v US-licensed Prolia

448

Pre-specified

94.94

2-sided

Bone mineral density was assessed by DXA and assessments of the lumbar spine (L1 to L4) were performed at a central imaging vendor. To evaluate the difference between 2 groups in the primary efficacy endpoint, the percent change from baseline in BMD for lumbar spine (L1 to L4) by DXA at Week 52 was analyzed using an ANCOVA model coupled with multiple imputation assuming the data to be MAR.

Primary

baseline (screening), Week 52 predose

An ANCOVA was performed with the treatment as a fixed effect and age, baseline BMD T-score at the lumbar spine, and prior bisphosphonates therapy (yes versus no) as covariates.

CT-P41 v US-licensed Prolia

417

Pre-specified

-0.28

2-sided

Bone mineral density was assessed by DXA and assessments of the lumbar spine (L1 to L4), total hip, and femoral neck were performed at a central imaging vendor.

Secondary

baseline (screening), Week 52 predose

Bone mineral density was assessed by DXA and assessments of the lumbar spine (L1 to L4), total hip, and femoral neck BMD were performed at a central imaging vendor.

Secondary

baseline (screening), Week 78

Efficacy analysis of new vertebral fractures included only vertebral fractures occurring from T4 to L4 and confirmed by the central imaging vendor. A new vertebral fracture was defined as an increase of ≥1 grade in any vertebra from T4 to L4 that was normal at screening. The nonvertebral fractures endpoint included fractures other than those of the vertebrae, excluding the skull, facial bones, mandible, metacarpals, and phalanges (fingers or toes) since they are not associated with decreased BMD, and excluded pathologic fractures and those associated with severe trauma acquired from a fall (from a height higher than a stool, chair, or first rung of a ladder) or otherwise. Only nonvertebral fractures confirmed by the central imaging vendor were included in the efficacy analysis. The fractures occurring at the site of femur neck, femur intertrochanter, or femur subtrochanter were considered as a hip fracture.

Secondary

up to Week 52 predose

Efficacy analysis of new vertebral fractures included only vertebral fractures occurring from T4 to L4 and confirmed by the central imaging vendor. A new vertebral fracture was defined as an increase of ≥1 grade in any vertebra from T4 to L4 that was normal at screening. The nonvertebral fractures endpoint included fractures other than those of the vertebrae, excluding the skull, facial bones, mandible, metacarpals, and phalanges (fingers or toes) since they are not associated with decreased BMD, and excluded pathologic fractures and those associated with severe trauma acquired from a fall (from a height higher than a stool, chair, or first rung of a ladder) or otherwise. Only nonvertebral fractures confirmed by the central imaging vendor were included in the efficacy analysis. The fractures occurring at the site of femur neck, femur intertrochanter, or femur subtrochanter were considered as a hip fracture.

Secondary

from Week 52 to Week 78

The Ctrough, a concentration before the next study drug administration, was calculated by non-compartmental analysis method from the concentration-time data. All serum concentrations below the lower limit of quantification (LLoQ) was set to 0 in the descriptive summaries of pharmacokinetics (PK) parameter estimation. In TP I, the Ctrough of denosumab at Weeks 0 and 26 was assessed as the serum concentration at Weeks 26 and 52 before the study drug administration, respectively.

Secondary

Week 0 Day 1 predose, Week 26 predose

The Ctrough, a concentration before the next study drug administration, was calculated by non-compartmental analysis method from the concentration-time data. All serum concentrations below the LLoQ was set to 0 in the descriptive summaries of PK parameter estimation. In TP II, the Ctrough of denosumab at Week 52 was assessed as the serum concentration at Week 78.

Secondary

Week 52

Samples that were positive in the ADA confirmatory assay were analyzed further to conduct a NAb assessment. The test outcomes for the screening assay were ‘Positive’ or ‘Negative’. The number of patients with at least one ADA/NAb positive result after the first study drug administration of each treatment period including scheduled and unscheduled visits (Treatment Period I: Week 0 / Treatment Period II: Week 52) regardless of their ADA status at baseline were presented.

Secondary

up to Week 52 predose

Samples that were positive in the ADA confirmatory assay were analyzed further to conduct a NAb assessment. The test outcomes for the screening assay were ‘Positive’ or ‘Negative’. The number of patients with at least one ADA/NAb positive result after the first study drug administration of each treatment period including scheduled and unscheduled visits (Treatment Period I: Week 0 / Treatment Period II: Week 52) regardless of their ADA status at baseline were presented.

Secondary

from Week 52 to Week 78

Through Week 78 • TP I: Adverse event (AE) start date before the study drug administration in TP II • TP II: AE start date on or after the date of study drug administration in TP II.

Among the 240 and 239 in the CT-P41 and US-licensed Prolia groups who initiated TP I, 1 subject each terminated the study participation before the treatment initiation. Since the AE results in TP I were summarized in the safety set who received at least 1 dose of the study drug during TP I, the total number of subjects exposed was 239 and 238.

26.0

CT-P41

US-licensed Prolia

CT-P41 Maintenance

US-licensed Prolia Maintenance

Switched to CT-P41