A Study to Test the Efficacy, Safety and Tolerability of Romosozumab Treatment in Postmenopausal Chinese Women With Osteoporosis

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of Romosozumab Treatment in Postmenopausal Chinese Women With Osteoporosis

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05067335

Enrollment

327

Registered

2021-10-05

Start date

2021-10-21

Completion date

2023-11-09

Last updated

2024-12-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Osteoporosis

Keywords

Osteoporosis, Phase 3, Chinese Patients, Romosozumab

Brief summary

The purpose of the study is to evaluate the effect of treatment with romosozumab for 6 months compared with placebo on the percent changes in bone mineral density (BMD) at the lumbar spine, at the total hip and femoral neck in postmenopausal Chinese women with osteoporosis.

Interventions

DRUGRomosozumab

Subjects will receive romosozumab in a specified sequence during the treatment Period.

DRUGPlacebo

Subjects will receive Placebo in a specified sequence during the treatment Period.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

FEMALE

Age

55 Years to 90 Years

Healthy volunteers

Inclusion criteria

* Subject is considered reliable and capable of adhering to the protocol, visit schedule, and medication intake according to the judgment of the investigator * Subject is an ambulatory postmenopausal Chinese women, 55 to 90 years of age (inclusive) at the time of Screening. Postmenopause is defined as no spontaneous vaginal bleeding or spotting for 12 or more consecutive months prior to Screening * Subject has a bone mineral density (BMD) T-score ≤-2.50 at the lumbar spine, total hip, or femoral neck, as assessed by the central imaging vendor at the time of Screening based on DXA scans, and using data for Caucasian women from the National Health and Nutritional Examination Survey (NHANES, 1998) * Subject must have at least 1 of following independent risk factors for fracture: * History of fragility fracture (except hip fracture, a severe vertebral fracture or more than 2 moderate vertebral fractures) * Parental history of hip fracture * Low body weight (body mass index ≤19kg/m2) * Elderly (age ≥ 65 years) * Current smoker * Subject has at least 2 vertebrae in the L1 to L4 region and at least 1 hip that are evaluable by dual-energy x-ray absorptiometry (DXA), as assessed by the central imaging vendor

Exclusion criteria

* Subject has a BMD T-score of ≤-3.50 at the total hip or femoral neck, as assessed by the central imaging vendor at the time of Screening based on DXA scans, and using data for Caucasian women from NHANES 1998 * Subject has a known history of hip fracture * Subject has any severe (SQ3) or more than 2 moderate (SQ2) vertebral fractures, as assessed by the central imaging vendor based on the lateral spine x-ray at Screening * Subject has a history of myocardial infarction (MI) * Subject has a history of stroke * Subject has a vitamin D insufficiency, defined as 25 (OH) vitamin D levels \<20 ng/mL, as assessed by the central laboratory at Screening. Vitamin D repletion will be permitted and the subject may be retested once within the Screening Period * Subject has used oral bisphosphonates: * Any doses received within 3 months prior to randomization * More than 1 month of cumulative use between 3 and 12 months prior to randomization * More than 3 years of cumulative use, unless the last dose was received ≥5 years prior to randomization * Subject has used intravenous (iv) bisphosphonates: * zoledronic acid * Any doses received within 3 years prior to randomization * More than 1 dose received within 5 years prior to randomization * iv ibandronate, iv pamidronate, or iv alendronate (ALN) * Any doses received within 12 months prior to randomization * More than 3 years of cumulative use, unless the last dose was received ≥5 years prior to randomization * Subject has used denosumab or any cathepsin K inhibitor: ● Any doses received within 18 months prior to randomization * Subject has used tibolone, cinacalcet, or calcitonin: * Any doses received within 3 months prior to randomization * Subject has used teriparatide (TPTD) or any parathyroid hormone (PTH) derivative: * Any doses received within 3 months prior to randomization * More than 1 month of cumulative use between 3 and 12 months prior to randomization * Subject has used systemic oral or transdermal estrogen or selective estrogen receptor modulators (SERMs): ● More than 1 month of cumulative use within 6 months prior to randomization * Subject has used strontium ranelate or fluoride: ● More than 1 month of cumulative use within 5 years prior to randomization * Subject has used hormonal ablation therapy: ● More than 1 month of cumulative use within 6 months prior to randomization * Subject has used systemic glucocorticosteroids: ● ≥5mg prednisone equivalent per day for more than 14 days within 3 months prior to randomization * Subject has a history of osteonecrosis of the jaw (ONJ) or atypical femoral fracture (AFF) * Subject has evidence of any of the following: 1. Current, uncontrolled hyper- or hypothyroidism. Uncontrolled hyperthyroidism is defined as thyroid-stimulating hormone (TSH) and thyroxine (T4) outside of the normal range. Uncontrolled hypothyroidism is defined as TSH \>10 2. Current, uncontrolled hyperparathyroidism or history of hypoparathyroidism. Uncontrolled hyperparathyroidism is defined as PTH outside the normal range in subjects with concurrent hypercalcemia or PTH values \>20 % above upper limit of normal (ULN) in normocalcemic subjects 3. Current hypercalcemia or hypocalcemia, defined as albumin-adjusted serum calcium outside the normal range, as assessed by the central laboratory at the time of Screening. Albumin-adjusted serum calcium levels may be retested once in case of an elevated albumin-adjusted serum calcium level within 1.1xULN of the laboratory's reference ranges 4. Subject has ≥3xULN of any of the following: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or \>ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert's syndrome). If subject has elevations only in total bilirubin that are \>ULN and \<1.5xULN, fractionate bilirubin to identify possible undiagnosed Gilbert's syndrome (ie, direct bilirubin \<35 %)

Design outcomes

Primary

Measure	Time frame	Description
Percent Change From Baseline in Bone Mineral Density (BMD) at the Lumbar Spine to the End of Double-Blind Period	From Baseline (Day 1) to the end of the Double-blind Period (Month 6)	Percent change from baseline in BMD at the lumbar spine was assessed by dual-energy x-ray absorptiometry (DXA) at 6 months. Missing postbaseline BMD other than due to COVID-19 were imputed using the last observation carried forward (LOCF) approach. Missing or out of window (exceed 70 days since previous IMP) post-baseline DXA BMD due to COVID-19 were set to missing and imputed by multiple imputation under missing at random approach. LSM = least square mean.
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Double-Blind Period	From Baseline to the end of the Double-blind Period (Month 6)	An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a IMP, whether or not related to the IMP. TEAEs are defined as all AEs started on or worsened in severity on or after the date of receiving first dose of IMP and before or on the end of study (EOS) date.
Percentage of Participants With Treatment-emergent Adverse Events for Romosozumab During Overall Period	From Month 7 up to Month 12 (Placebo/Romo) and From Day 1 up to Month 12 (Romo/Romo) + 3-month SFU (up to Month 15)	An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with use of a IMP, whether or not related to IMP. TEAEs are defined as all AEs started on or worsened in severity on or after date of receiving first dose of IMP and before or on EOS date except lipid-type AEs starting on date of first dose of IMP and not worsening (and not deemed IMP related by the investigator). As pre-specified in Protocol and SAP, TEAEs were assessed and reported for 6 months for participants in placebo/romosozumab arm (Open-label Period) and for a total of 12 months for participants in romosozumab/romosozumab arm (Double-blind Period + Open-label Period combined) + 3 months of Safety follow-up for both arms (Up to Month 15) during overall period.

Secondary

Measure	Time frame	Description
Percent Change From Baseline in Bone Mineral Density at the Total Hip at Month 12	Baseline, Month 12	Percent change from Baseline in BMD at the total hip was assessed by DXA at 12 months. Missing postbaseline BMD other than due to COVID-19 were imputed using the LOCF approach. Missing or out of window (exceed 70 days since previous IMP) post-baseline DXA BMD due to COVID-19 were set to missing and imputed by multiple imputation under missing at random approach. For Placebo/Romosozumab Treatment group, only the post Month 6 value was used for imputation for Open-label Period, the values in the Double-blind Period were not carried forward into the Open-label Period.
Percent Change From Baseline in Bone Mineral Density at the Total Hip to the End of Double-Blind Period	From Baseline to the end of the Double-blind Period (Month 6)	Percent change from baseline in BMD at the total hip was assessed by DXA at 6 months. Missing postbaseline BMD other than due to COVID-19 were imputed using the LOCF approach. Missing or out of window (exceed 70 days since previous IMP) post-baseline DXA BMD due to COVID-19 were set to missing and imputed by multiple imputation under missing at random approach.
Percent Change From Baseline in Bone Mineral Density at the Femoral Neck at Month 12	Baseline, Month 12	Percent change from Baseline in BMD at the femoral neck was assessed by DXA at 12 months. Missing postbaseline BMD other than due to COVID-19 were imputed using the LOCF approach. Missing or out of window (exceed 70 days since previous IMP) post-baseline DXA BMD due to COVID-19 were set to missing and imputed by multiple imputation under missing at random approach. For Placebo/Romosozumab Treatment group, only the post Month 6 value was used for imputation for Open-label Period, the values in the Double-blind Period were not carried forward into the Open-label Period.
Percent Change From Baseline in Bone Mineral Density at the Femoral Neck to the End of the Double-Blind Period	From Baseline to the end of the Double-blind Period (Month 6)	Percent change from baseline in BMD at the femoral neck was assessed by DXA at 6 months. Missing postbaseline BMD other than due to COVID-19 were imputed using the LOCF approach. Missing or out of window (exceed 70 days since previous IMP) post-baseline DXA BMD due to COVID-19 were set to missing and imputed by multiple imputation under missing at random approach.
Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 12	Baseline, Month 12	Percent change from Baseline in BMD at the lumbar spine was assessed by DXA at 12 months. Missing postbaseline BMD other than due to COVID-19 were imputed using the LOCF approach. Missing or out of window (exceed 70 days since previous IMP) post-baseline DXA BMD due to COVID-19 were set to missing and imputed by multiple imputation under missing at random approach. For Placebo/Romosozumab Treatment group, only the post Month 6 value was used for imputation for Open-label Period, the values in the Double-blind Period were not carried forward into the Open-label Period.

Countries

China

Participant flow

Recruitment details

The study started to enroll participants in October 2021 and concluded in November 2023.

Pre-assignment details

Participant flow refers to the Randomized Set.

Participants by arm

Arm	Count
Placebo Participants randomized to this arm received a matching placebo subcutaneously (sc) every month (QM) during the 6-month Double-blind (DB) Period.	109
Romosozumab Participants randomized to this arm received romosozumab (Romo) 210 milligrams (mg) sc QM during the 6-month Double-blind Period.	218
Total	327

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Double-blind Period: Day 1 - Month 6	Adverse Event	1	2	0	0
Double-blind Period: Day 1 - Month 6	Patient Voluntary Withdrawal	1	0	0	0
Double-blind Period: Day 1 - Month 6	Protocol Violation	1	1	0	0
Double-blind Period: Day 1 - Month 6	The Patient Withdrew Early Due To Their Own Reasons	0	1	0	0
Double-blind Period: Day 1 - Month 6	Withdrawal by Subject	6	10	0	0
Open-label Period: Month 7 - 12	Adverse Event	0	0	3	2
Open-label Period: Month 7 - 12	Did not receive Open-label IMP at Month 6 and then discontinued	0	0	1	0
Open-label Period: Month 7 - 12	Lost to Follow-up	0	0	1	0
Open-label Period: Month 7 - 12	Subject Was Unable To Comply With Study Procedures Due To Prolonged Withdrawal From Medication	0	0	1	0
Open-label Period: Month 7 - 12	Withdrawal by Subject	0	0	0	3

Baseline characteristics

Characteristic	Placebo	Romosozumab	Total
Age, Continuous	67.3 Years STANDARD_DEVIATION 6.1	67.0 Years STANDARD_DEVIATION 5.7	67.1 Years STANDARD_DEVIATION 5.8
Age, Customized 18 - <65 yrs	31 Participants	63 Participants	94 Participants
Age, Customized 65 - <85 yrs	76 Participants	154 Participants	230 Participants
Age, Customized >=85 yrs	2 Participants	1 Participants	3 Participants
Race/Ethnicity, Customized Asian	109 Participants	218 Participants	327 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	109 Participants	218 Participants	327 Participants
Sex: Female, Male Female	109 Participants	218 Participants	327 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
deaths Total, all-cause mortality	0 / 109	0 / 218	0 / 98	1 / 218
other Total, other adverse events	25 / 109	59 / 218	59 / 98	155 / 218
serious Total, serious adverse events	5 / 109	8 / 218	9 / 98	25 / 218

Outcome results

Primary

Percentage of Participants With Treatment-emergent Adverse Events for Romosozumab During Overall Period

An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with use of a IMP, whether or not related to IMP. TEAEs are defined as all AEs started on or worsened in severity on or after date of receiving first dose of IMP and before or on EOS date except lipid-type AEs starting on date of first dose of IMP and not worsening (and not deemed IMP related by the investigator). As pre-specified in Protocol and SAP, TEAEs were assessed and reported for 6 months for participants in placebo/romosozumab arm (Open-label Period) and for a total of 12 months for participants in romosozumab/romosozumab arm (Double-blind Period + Open-label Period combined) + 3 months of Safety follow-up for both arms (Up to Month 15) during overall period.

Time frame: From Month 7 up to Month 12 (Placebo/Romo) and From Day 1 up to Month 12 (Romo/Romo) + 3-month SFU (up to Month 15)

Population: The SS consisted of all randomized study participants who received at least 1 dose of IMP. The SS for open label period consisted of all randomized study participants who received at least 1 dose of IMP during open label period.

Arm	Measure	Value (NUMBER)
Placebo	Percentage of Participants With Treatment-emergent Adverse Events for Romosozumab During Overall Period	80.6 percentage of participants
Romosozumab	Percentage of Participants With Treatment-emergent Adverse Events for Romosozumab During Overall Period	88.1 percentage of participants

Primary

Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Double-Blind Period

An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a IMP, whether or not related to the IMP. TEAEs are defined as all AEs started on or worsened in severity on or after the date of receiving first dose of IMP and before or on the end of study (EOS) date.

Time frame: From Baseline to the end of the Double-blind Period (Month 6)

Population: The Safety Set (SS) consisted of all randomized study participants who received at least 1 dose of IMP.

Arm	Measure	Value (NUMBER)
Placebo	Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Double-Blind Period	70.6 percentage of participants
Romosozumab	Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Double-Blind Period	72.9 percentage of participants

Primary

Percent Change From Baseline in Bone Mineral Density (BMD) at the Lumbar Spine to the End of Double-Blind Period

Percent change from baseline in BMD at the lumbar spine was assessed by dual-energy x-ray absorptiometry (DXA) at 6 months. Missing postbaseline BMD other than due to COVID-19 were imputed using the last observation carried forward (LOCF) approach. Missing or out of window (exceed 70 days since previous IMP) post-baseline DXA BMD due to COVID-19 were set to missing and imputed by multiple imputation under missing at random approach. LSM = least square mean.

Time frame: From Baseline (Day 1) to the end of the Double-blind Period (Month 6)

Population: The Full Analysis Set (FAS) consisted of all randomized study participants who received at least 1 dose of investigational medicinal product (IMP) and provided at least 1 Baseline and post-Baseline BMD measurement.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Placebo	Percent Change From Baseline in Bone Mineral Density (BMD) at the Lumbar Spine to the End of Double-Blind Period	0.44 percent change	Standard Error 0.442
Romosozumab	Percent Change From Baseline in Bone Mineral Density (BMD) at the Lumbar Spine to the End of Double-Blind Period	9.81 percent change	Standard Error 0.323

Comparison: The ANCOVA model was used and included treatment group, Baseline DXA BMD value, machine type (hologic or lunar) at Baseline, age strata group (stratification factor), region, and interaction of Baseline DXA BMD value and machine type at Baseline as independent variables.p-value: <0.00195% CI: [8.34, 10.39]ANCOVA

Secondary

Percent Change From Baseline in Bone Mineral Density at the Femoral Neck at Month 12

Percent change from Baseline in BMD at the femoral neck was assessed by DXA at 12 months. Missing postbaseline BMD other than due to COVID-19 were imputed using the LOCF approach. Missing or out of window (exceed 70 days since previous IMP) post-baseline DXA BMD due to COVID-19 were set to missing and imputed by multiple imputation under missing at random approach. For Placebo/Romosozumab Treatment group, only the post Month 6 value was used for imputation for Open-label Period, the values in the Double-blind Period were not carried forward into the Open-label Period.

Time frame: Baseline, Month 12