Extension Study to Evaluate the Long Term Safety and Efficacy of Denosumab in the Treatment of Osteoporosis

NCT00523341 | Completed Phase 3 Results

• 1 other identifier: 20060289
• Study Type: interventional
• Target: 4,550
• Locations: 0 countries
• Sites: N/A

Brief Summary

The primary objective was to describe the safety and tolerability of up to 10 years or 7 years denosumab administration as measured by adverse event monitoring, immunogenicity and safety laboratory parameters in participants who previously received denosumab or placebo, respectively.

Conditions

Osteopenia; Osteoporosis

Keywords

postmenopausal osteoporosis; low bone density; fractures; low bone mass

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Adverse Events (AEs)

  A serious adverse event (SAE) is defined as an adverse event that: • is fatal • is life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • is other significant medical hazard. Treatment-related adverse events includes only events for which the investigator indicated there was a reasonable possibility they may have been caused by study drug. The following were classified as adverse events of interest (events that are considered to be identified or potential risks of denosumab treatment): positively adjudicated osteonecrosis of the jaw, positively adjudicated atypical femoral fracture, hypocalcemia, adverse events potentially related to hypersensitivity, serious infection (including bacterial cellulitis), malignancy, cardiac disorders, vascular disorders, fracture healing complications, eczema, acute pancreatitis, and musculoskeletal pain.

  84 months

• Number of Participants With Laboratory Toxicities of Grade ≥ 3

  Laboratory toxicity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 indicates severe toxicity and Grade 4 indicates life-threatening toxicity.

  84 months

• Number of Participants With Antibodies to Denosumab

  Every 12 months through Month 84

Secondary Outcomes (45)

• Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit

  Baseline (of extension study) and months 12, 24, 36, 60 and 84

• Percent Change From Baseline in Total Hip Bone Mineral Density by Visit

  Baseline (of extension study) and months 12, 24, 36, 60 and 84

• Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit

  Baseline (of extension study) and months 12, 24, 36, 60 and 84

• Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit

  Baseline (of extension study) and months 12, 24, 36, 60 and 84

• Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit

  Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84

Study Arms (1)

Denosumab

EXPERIMENTAL

Participants received a 60 mg subcutaneous injection of denosumab every 6 months for seven years.

Biological: Denosumab

Interventions

Denosumab BIOLOGICAL

Administered by subcutaneous injection once every 6 months.

Also known as: AMG 162, Prolia

Denosumab

Eligibility Criteria

• Age: 60 Years - 94 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Subjects must sign the informed consent before any study specific procedures are performed and agree to receive denosumab 60 mg subcutaneous injection every 6 months
• Subjects must not have discontinued investigational product during the 20030216 study and must have attended the 20030216 study month 36 visit
• Subjects must be re-consented prior to (or at) the 24 month visit for participation beyond month 24.
• Permanently non-ambulatory subjects (use of an assistive device eg, cane, walker, etc. is permitted)
• Missed 2 or more investigational product doses during the 20030216 study
• Any disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or comply with study procedures
• Developed sensitivity to mammalian cell derived drug products during the 20030216 study
• Unable to tolerate calcium supplementation during the last 6 months of participation in the 20030216 study (between the month 30 and month 36 20030216 study visits)
• Currently receiving any investigational product other than denosumab or having received any investigational product during the 20030216 study
• Current use of the following osteoporosis agents: bisphosphonates, calcitonin, fluoride, parathyroid hormone, selective estrogen receptor modulators, systemic oral or transdermal estrogen (except vaginal preparations and estrogen creams which are acceptable), strontium, or tibolone
• For bone biopsy sub-study subjects only: known or suspected sensitivity or contraindication to tetracycline derivatives

Sponsors & Collaborators

• Amgen: lead

Related Publications (16)

• Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, Roux C, Torring O, Valter I, Wang AT, Brown JP. Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res. 2018 Feb;33(2):190-198. doi: 10.1002/jbmr.3337. Epub 2017 Nov 22.

  PMID: 29105841 BACKGROUND

• Dempster DW, Brown JP, Fahrleitner-Pammer A, Kendler D, Rizzo S, Valter I, Wagman RB, Yin X, Yue SV, Boivin G. Effects of Long-Term Denosumab on Bone Histomorphometry and Mineralization in Women With Postmenopausal Osteoporosis. J Clin Endocrinol Metab. 2018 Jul 1;103(7):2498-2509. doi: 10.1210/jc.2017-02669.

  PMID: 29672714 BACKGROUND

• Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, Czerwinski E, Fahrleitner-Pammer A, Kendler DL, Lippuner K, Reginster JY, Roux C, Malouf J, Bradley MN, Daizadeh NS, Wang A, Dakin P, Pannacciulli N, Dempster DW, Papapoulos S. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017 Jul;5(7):513-523. doi: 10.1016/S2213-8587(17)30138-9. Epub 2017 May 22.

  PMID: 28546097 BACKGROUND

• Ferrari S, Eastell R, Napoli N, Schwartz A, Hofbauer LC, Chines A, Wang A, Pannacciulli N, Cummings SR. Denosumab in postmenopausal women with osteoporosis and diabetes: Subgroup analysis of FREEDOM and FREEDOM extension. Bone. 2020 May;134:115268. doi: 10.1016/j.bone.2020.115268. Epub 2020 Feb 10.

  PMID: 32058020 BACKGROUND

• Ferrari S, Lewiecki EM, Butler PW, Kendler DL, Napoli N, Huang S, Crittenden DB, Pannacciulli N, Siris E, Binkley N. Favorable skeletal benefit/risk of long-term denosumab therapy: A virtual-twin analysis of fractures prevented relative to skeletal safety events observed. Bone. 2020 May;134:115287. doi: 10.1016/j.bone.2020.115287. Epub 2020 Feb 21.

  PMID: 32092479 BACKGROUND

• Kendler DL, Chines A, Brandi ML, Papapoulos S, Lewiecki EM, Reginster JY, Munoz Torres M, Wang A, Bone HG. The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies. Osteoporos Int. 2019 Jan;30(1):71-78. doi: 10.1007/s00198-018-4687-2. Epub 2018 Sep 22.

  PMID: 30244369 BACKGROUND

• Watts NB, Brown JP, Papapoulos S, Lewiecki EM, Kendler DL, Dakin P, Wagman RB, Wang A, Daizadeh NS, Smith S, Bone HG. Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension. J Bone Miner Res. 2017 Jul;32(7):1481-1485. doi: 10.1002/jbmr.3119. Epub 2017 Apr 3.

  PMID: 28277603 BACKGROUND

• Watts NB, Grbic JT, Binkley N, Papapoulos S, Butler PW, Yin X, Tierney A, Wagman RB, McClung M. Invasive Oral Procedures and Events in Postmenopausal Women With Osteoporosis Treated With Denosumab for Up to 10 Years. J Clin Endocrinol Metab. 2019 Jun 1;104(6):2443-2452. doi: 10.1210/jc.2018-01965.

  PMID: 30759221 BACKGROUND

• Adachi JD, Bone HG, Daizadeh NS, Dakin P, Papapoulos S, Hadji P, Recknor C, Bolognese MA, Wang A, Lin CJF, Wagman RB, Ferrari S. Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study. BMC Musculoskelet Disord. 2017 Apr 27;18(1):174. doi: 10.1186/s12891-017-1520-6.

  PMID: 28449657 BACKGROUND

• Bilezikian JP, Lin CJF, Brown JP, Wang AT, Yin X, Ebeling PR, Fahrleitner-Pammer A, Franek E, Gilchrist N, Miller PD, Simon JA, Valter I, Zerbini CAF, Libanati C, Chines A. Long-term denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus: analyses from the FREEDOM Extension cross-over group. Osteoporos Int. 2019 Sep;30(9):1855-1864. doi: 10.1007/s00198-019-05020-8. Epub 2019 Jun 14.

  PMID: 31201481 BACKGROUND

• Ferrari S, Butler PW, Kendler DL, Miller PD, Roux C, Wang AT, Huang S, Wagman RB, Lewiecki EM. Further Nonvertebral Fracture Reduction Beyond 3 Years for Up to 10 Years of Denosumab Treatment. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3450-3461. doi: 10.1210/jc.2019-00271.

  PMID: 31125092 BACKGROUND

• Ferrari S, Libanati C, Lin CJF, Brown JP, Cosman F, Czerwinski E, de Gregomicronrio LH, Malouf-Sierra J, Reginster JY, Wang A, Wagman RB, Lewiecki EM. Relationship Between Bone Mineral Density T-Score and Nonvertebral Fracture Risk Over 10 Years of Denosumab Treatment. J Bone Miner Res. 2019 Jun;34(6):1033-1040. doi: 10.1002/jbmr.3722. Epub 2019 May 29.

  PMID: 30919997 BACKGROUND

• Broadwell A, Chines A, Ebeling PR, Franek E, Huang S, Smith S, Kendler D, Messina O, Miller PD. Denosumab Safety and Efficacy Among Participants in the FREEDOM Extension Study With Mild to Moderate Chronic Kidney Disease. J Clin Endocrinol Metab. 2021 Jan 23;106(2):397-409. doi: 10.1210/clinem/dgaa851.

  PMID: 33211870 BACKGROUND

• Cosman F, Huang S, McDermott M, Cummings SR. Multiple Vertebral Fractures After Denosumab Discontinuation: FREEDOM and FREEDOM Extension Trials Additional Post Hoc Analyses. J Bone Miner Res. 2022 Nov;37(11):2112-2120. doi: 10.1002/jbmr.4705. Epub 2022 Oct 12.

  PMID: 36088628 BACKGROUND

• Bone HG, Chapurlat R, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Mellstrom D, Radominski SC, Reginster JY, Resch H, Ivorra JA, Roux C, Vittinghoff E, Daizadeh NS, Wang A, Bradley MN, Franchimont N, Geller ML, Wagman RB, Cummings SR, Papapoulos S. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab. 2013 Nov;98(11):4483-92. doi: 10.1210/jc.2013-1597. Epub 2013 Aug 26.

  PMID: 23979955 DERIVED

• Papapoulos S, Chapurlat R, Libanati C, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Man Z, Mellstrom D, Radominski SC, Reginster JY, Resch H, Roman Ivorra JA, Roux C, Vittinghoff E, Austin M, Daizadeh N, Bradley MN, Grauer A, Cummings SR, Bone HG. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res. 2012 Mar;27(3):694-701. doi: 10.1002/jbmr.1479.

  PMID: 22113951 DERIVED

Related Links

• AmgenTrials clinical trials website

MeSH Terms

Conditions

Bone Diseases, Metabolic; Osteoporosis; Osteoporosis, Postmenopausal; Fractures, Bone

Interventions

Denosumab

Condition Hierarchy (Ancestors)

Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Study Director
• Organization: Amgen Inc.

866-572-6436

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 30, 2007
• First Posted: August 31, 2007
• Study Start: August 7, 2007
• Primary Completion: July 19, 2015
• Study Completion: July 19, 2015
• Last Updated: November 7, 2022
• Results First Posted: July 12, 2016

Record last verified: 2022-11