Romosozumab (AMG 785) in Postmenopausal Women With Low Bone Mineral Density

NCT ID: NCT00896532

Last Updated: 2022-09-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 419 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-06-03
• Study Completion Date: 2016-02-18

Brief Summary

The primary objective was to determine the effect of treatment with romosozumab versus placebo at month 12 on the percent change from baseline in bone mineral density (BMD) at the lumbar spine in postmenopausal women with low bone density.

Detailed Description

This study included a 24-month treatment phase followed by rerandomization to a 12-month extension phase with denosumab or placebo, followed by a 12-month retreatment phase with romosozumab, followed by a 24-month follow-on phase with zoledronic acid or no intervention.

• 24-month Romosozumab Treatment Phase (months 1 to 24): Participants were randomized in a 1:1:1:1:1:1:1:1 ratio to receive 1 of 5 double-blind dosing regimens of romosozumab or placebo or open-label alendronate (ALN) or open-label teriparatide (TPTD) for the first 12 months of the study. At month 12, participants in the romosozumab and placebo groups continued their assigned treatment for an additional 12 months, participants in the TPTD group ended study participation, and participants in the ALN group transitioned to receive romosozumab 140 mg subcutaneously (SC) every month (QM) for an additional 12 months (months 12 to 24).
• 12-month Denosumab Extension Phase (months 24 to 36): At the end of the 24-month romosozumab treatment phase, eligible participants were randomized 1:1 within their original treatment group to receive either denosumab or placebo every 6 months (Q6M) for 12 months.
• 12-month Romosozumab Retreatment Phase (months 36 to 48): From months 36 to 48, participants initially randomized to romosozumab or placebo received romosozumab 210 mg SC QM. Participants who initially received ALN ended their participation at month 36 and were not retreated with romosozumab.
• 24-month Follow-on Phase (months 48 to 72): At month 48, participants received 1 dose of zoledronic acid 5 mg intravenously or no intervention for an additional 24 months.

Conditions

Low Bone Mineral Density; Postmenopausal Osteoporosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo

Participants received placebo matching to romosozumab once a month (QM) or once every 3 months (Q3M) administered subcutaneously (SC) for up to 24 months.

Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.

Group Type: PLACEBO_COMPARATOR

Denosumab

Intervention Type: DRUG

Denosumab 60 mg administered by subcutaneous injection Q6M

Placebo to Denosumab

Intervention Type: DRUG

Administered by subcutaneous injection Q6M

Zoledronic acid

Intervention Type: DRUG

Zoledronic acid 5 mg administered intravenously

Placebo to Romosozumab

Intervention Type: DRUG

Administered by subcutaneous injection QM or Q3M.

Alendronate

Participants received open-label alendronate (ALN) 70 mg orally (PO) every week (QW) for 12 months. At month 12 participants transitioned to receive romosozumab 140 mg subcutaneously every month for an additional 12 months (months 12 to 24).

Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. At month 36 participants ended study participation.

Group Type: ACTIVE_COMPARATOR

Denosumab

Intervention Type: DRUG

Denosumab 60 mg administered by subcutaneous injection Q6M

Placebo to Denosumab

Intervention Type: DRUG

Administered by subcutaneous injection Q6M

Alendronate

Intervention Type: DRUG

Administered orally once a week

Romosozumab

Intervention Type: DRUG

Administered by subcutaneous injection

Teriparatide

Participants received open-label teriparatide 20 μg subcutaneously every day (QD) for 12 months. At month 12 participants ended study participation.

Group Type: ACTIVE_COMPARATOR

Teriparatide

Intervention Type: DRUG

Teriparatide 20 μg administered by subcutaneous injection once a day

Romosozumab 70 mg QM

Participants received double-blind romosozumab 70 mg subcutaneously every month for 24 months.

Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.

Group Type: EXPERIMENTAL

Denosumab

Intervention Type: DRUG

Denosumab 60 mg administered by subcutaneous injection Q6M

Placebo to Denosumab

Intervention Type: DRUG

Administered by subcutaneous injection Q6M

Zoledronic acid

Intervention Type: DRUG

Zoledronic acid 5 mg administered intravenously

Romosozumab

Intervention Type: DRUG

Administered by subcutaneous injection

Romosozumab 140 mg Q3M

Participants received double-blind romosozumab 140 mg subcutaneously once every 3 months for 24 months.

Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.

Group Type: EXPERIMENTAL

Denosumab

Intervention Type: DRUG

Denosumab 60 mg administered by subcutaneous injection Q6M

Placebo to Denosumab

Intervention Type: DRUG

Administered by subcutaneous injection Q6M

Zoledronic acid

Intervention Type: DRUG

Zoledronic acid 5 mg administered intravenously

Romosozumab

Intervention Type: DRUG

Administered by subcutaneous injection

Romosozumab 140 mg QM

Participants received double-blind romosozumab 140 mg QM subcutaneously for 24 months.

Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.

Group Type: EXPERIMENTAL

Denosumab

Intervention Type: DRUG

Denosumab 60 mg administered by subcutaneous injection Q6M

Placebo to Denosumab

Intervention Type: DRUG

Administered by subcutaneous injection Q6M

Zoledronic acid

Intervention Type: DRUG

Zoledronic acid 5 mg administered intravenously

Romosozumab

Intervention Type: DRUG

Administered by subcutaneous injection

Romosozumab 210 mg Q3M

Participants received double-blind romosozumab 210 mg Q3M subcutaneously for 24 months.

Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.

Group Type: EXPERIMENTAL

Denosumab

Intervention Type: DRUG

Denosumab 60 mg administered by subcutaneous injection Q6M

Placebo to Denosumab

Intervention Type: DRUG

Administered by subcutaneous injection Q6M

Zoledronic acid

Intervention Type: DRUG

Zoledronic acid 5 mg administered intravenously

Romosozumab

Intervention Type: DRUG

Administered by subcutaneous injection

Romosozumab 210 mg QM

Participants received double-blind romosozumab 210 mg QM subcutaneously for 24 months.

Participants were then rerandomized to receive denosumab 60 mg or placebo to denosumab subcutaneously every 6 months from months 24 to 36. From months 36 to 48 participants received romosozumab 210 mg SC QM. At month 48 eligible participants received a single dose of open-label zoledronic acid 5 mg intravenously, or no intervention.

Group Type: EXPERIMENTAL

Denosumab

Intervention Type: DRUG

Denosumab 60 mg administered by subcutaneous injection Q6M

Placebo to Denosumab

Intervention Type: DRUG

Administered by subcutaneous injection Q6M

Zoledronic acid

Intervention Type: DRUG

Zoledronic acid 5 mg administered intravenously

Romosozumab

Intervention Type: DRUG

Administered by subcutaneous injection

Interventions

Denosumab

Denosumab 60 mg administered by subcutaneous injection Q6M

Intervention Type: DRUG

Placebo to Denosumab

Administered by subcutaneous injection Q6M

Intervention Type: DRUG

Zoledronic acid

Zoledronic acid 5 mg administered intravenously

Intervention Type: DRUG

Placebo to Romosozumab

Administered by subcutaneous injection QM or Q3M.

Intervention Type: DRUG

Alendronate

Administered orally once a week

Intervention Type: DRUG

Teriparatide

Teriparatide 20 μg administered by subcutaneous injection once a day

Intervention Type: DRUG

Romosozumab

Administered by subcutaneous injection

Intervention Type: DRUG

Other Intervention Names

Fosamax; Forsteo; AMG 785; EVENITY™; Prolia®; Aclasta

Eligibility Criteria

Inclusion Criteria

• Ambulatory, postmenopausal women, aged ≥ 55 to ≤ 85
• Low BMD measured by dual energy X-ray absorptiometry (DXA) and assessed by the central imaging vendor (equivalent to T-scores between -2.0 and -3.5)

• Normocalcemia at or after the Month 21 visit but before the Month 24 study visit

• Albumin adjusted serum calcium of the most recent blood draw at or after the Month 30 visit but before the Month 36 study visit. Calcium repletion is permitted and central laboratory analysis of albumin adjusted serum calcium may be repeated before the Month 36 study visit
• Participation in Group A or B during initial 24 month treatment phase
• Subject has reached M36 of the study
• Appropriate written informed consent must be obtained

• Subject has reached month 48 of the study
• During the 24 month AMG 785 treatment phase, subject was assigned to any AMG 785 treatment group
• During the 12 month denosumab extension phase, subject was assigned to the denosumab treatment group Exclusion for the 24 month follow-on phase (Month 48 to 72)
• New malignancy
• Use of proscribed meds during the 12 month re-treatment phase
• Partial informed consent withdrawal and discontinuation of investigational product at any time up to month 48 visit
• Incidence of a clinical vertebral fracture or fragility fracture of the wrist, humerus, hip or pelvis during the initial 24 month treatment phase of the study
• BMD T-score of ≤ -2.5 at the lumbar spine, total hip, or femoral neck based on local read of the DXA scans at month 48
• Intolerance to zoledronic acid

Exclusion Criteria

• History of vertebral fracture, or fragility fracture of the wrist, humerus, hip or pelvis after age 50
• Untreated hyper- or hypothyroidism
• Current hyper- or hypoparathyroidism, hypo- or hypercalcemia
• Elevated transaminases
• Significantly impaired renal function
• Positive for: human immunodeficiency virus (HIV), hepatitis-C or hepatitis-B surface antigen
• Malignancy
• History of solid organ or bone marrow transplants
• Use of agents affecting bone metabolism
• Contraindicated or intolerant of alendronate therapy
• Contraindicated or intolerant of teriparatide therapy

• Incidence of a clinical vertebral fracture or fragility fracture of the wrist, humerus, hip or pelvis during the initial 24 month treatment phase of the study
• A BMD loss of ≥ 7.0% from baseline at any time up to the Month 18 visit of the initial 24-month treatment phase
• Malignancy
• History of osteonecrosis of the jaw
• Use of proscribed medication during the initial 24 month treatment phase
• Contraindicated or intolerant of denosumab therapy

• New malignancy
• Use of proscribed medication during the 12 month extension phase

• Minimum Eligible Age: 55 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MD

Role: STUDY_DIRECTOR

Amgen

References

Genant HK, Engelke K, Bolognese MA, Mautalen C, Brown JP, Recknor C, Goemaere S, Fuerst T, Yang YC, Grauer A, Libanati C. Effects of Romosozumab Compared With Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women With Low Bone Mass. J Bone Miner Res. 2017 Jan;32(1):181-187. doi: 10.1002/jbmr.2932. Epub 2016 Sep 20.

Reference Type: BACKGROUND

PMID: 27487526 (View on PubMed)

Keaveny TM, Crittenden DB, Bolognese MA, Genant HK, Engelke K, Oliveri B, Brown JP, Langdahl BL, Yan C, Grauer A, Libanati C. Greater Gains in Spine and Hip Strength for Romosozumab Compared With Teriparatide in Postmenopausal Women With Low Bone Mass. J Bone Miner Res. 2017 Sep;32(9):1956-1962. doi: 10.1002/jbmr.3176. Epub 2017 Jun 26.

Reference Type: BACKGROUND

PMID: 28543940 (View on PubMed)

Kendler DL, Bone HG, Massari F, Gielen E, Palacios S, Maddox J, Yan C, Yue S, Dinavahi RV, Libanati C, Grauer A. Bone mineral density gains with a second 12-month course of romosozumab therapy following placebo or denosumab. Osteoporos Int. 2019 Dec;30(12):2437-2448. doi: 10.1007/s00198-019-05146-9. Epub 2019 Oct 18.

Reference Type: BACKGROUND

PMID: 31628490 (View on PubMed)

McClung MR, Brown JP, Diez-Perez A, Resch H, Caminis J, Meisner P, Bolognese MA, Goemaere S, Bone HG, Zanchetta JR, Maddox J, Bray S, Grauer A. Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study. J Bone Miner Res. 2018 Aug;33(8):1397-1406. doi: 10.1002/jbmr.3452. Epub 2018 May 22.

Reference Type: BACKGROUND

PMID: 29694685 (View on PubMed)

McClung MR, Bolognese MA, Brown JP, Reginster JY, Langdahl BL, Maddox J, Shi Y, Rojeski M, Meisner PD, Grauer A. A single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab. Osteoporos Int. 2020 Nov;31(11):2231-2241. doi: 10.1007/s00198-020-05502-0. Epub 2020 Jul 4.

Reference Type: BACKGROUND

PMID: 32623487 (View on PubMed)

McClung MR, Bolognese MA, Brown JP, Reginster JY, Langdahl BL, Shi Y, Timoshanko J, Libanati C, Chines A, Oates MK. Skeletal responses to romosozumab after 12 months of denosumab. JBMR Plus. 2021 Jun 3;5(7):e10512. doi: 10.1002/jbm4.10512. eCollection 2021 Jul.

Reference Type: BACKGROUND

PMID: 34258507 (View on PubMed)

Poole KE, Treece GM, Pearson RA, Gee AH, Bolognese MA, Brown JP, Goemaere S, Grauer A, Hanley DA, Mautalen C, Recknor C, Yang YC, Rojeski M, Libanati C, Whitmarsh T. Romosozumab Enhances Vertebral Bone Structure in Women With Low Bone Density. J Bone Miner Res. 2022 Feb;37(2):256-264. doi: 10.1002/jbmr.4465. Epub 2021 Dec 16.

Reference Type: BACKGROUND

PMID: 34738660 (View on PubMed)

McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, Langdahl BL, Reginster JY, Zanchetta JR, Wasserman SM, Katz L, Maddox J, Yang YC, Libanati C, Bone HG. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014 Jan 30;370(5):412-20. doi: 10.1056/NEJMoa1305224. Epub 2014 Jan 1.

Reference Type: DERIVED

PMID: 24382002 (View on PubMed)

Related Links

http://www.amgentrials.com

AmgenTrials clinical trials website

Other Identifiers

2008-005991-28

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

20060326

Identifier Type: -

Identifier Source: org_study_id