Clinical trial NCT00523341: Extension Study to Evaluate the Long Term Safety and Efficacy of Denosumab in the Treatment of Osteoporosis
Official title: An Open Label, Single Arm, Extension Study to Evaluate the Long Term Safety and Sustained Efficacy of Denosumab (AMG162) in the Treatment of Postmenopausal Osteoporosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Osteopenia
Osteoporosis
Keywords: postmenopausal osteoporosis
low bone density
fractures
low bone mass
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2007-08-31
Enrollment: 4550
Sex: FEMALE
Minimum age (years): 60
Maximum age (years): 94
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Postmenopausal women who have attended the 20030216 (NCT00089791) study month 36 visit will be eligible to participate if they meet the inclusion and exclusion criteria given below.

Inclusion Criteria

* 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.

Exclusion Criteria

* 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

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs)
timeFrame: 84 months
measure: Number of Participants With Laboratory Toxicities of Grade ≥ 3
timeFrame: 84 months
measure: Number of Participants With Antibodies to Denosumab
timeFrame: Every 12 months through Month 84
Secondary outcomes:
measure: Percent Change From Baseline in Lumbar Spine Bone Mineral Density by Visit
timeFrame: Baseline (of extension study) and months 12, 24, 36, 60 and 84
measure: Percent Change From Baseline in Total Hip Bone Mineral Density by Visit
timeFrame: Baseline (of extension study) and months 12, 24, 36, 60 and 84
measure: Percent Change From Baseline in Femoral Neck Bone Mineral Density by Visit
timeFrame: Baseline (of extension study) and months 12, 24, 36, 60 and 84
measure: Percent Change From Baseline in 1/3 Radius Bone Mineral Density by Visit
timeFrame: Baseline (of extension study) and months 12, 24, 36, 60 and 84
measure: Percent Change From Study 20030216 Baseline in Lumbar Spine Bone Mineral Density by Visit
timeFrame: Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
measure: Percent Change From Study 20030216 Baseline in Total Hip BMD by Visit
timeFrame: Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
measure: Percent Change From Study 20030216 Baseline in Femoral Neck BMD by Visit
timeFrame: Study 20030216 baseline and extension study months 12, 24, 36, 60 and 84
measure: Percent Change From Study 20030216 Baseline in 1/3 Radius BMD by Visit
timeFrame: Study 20030216 baseline and extension study months 12, 24, 36, 60, and 84
measure: Number of Participants With New Vertebral Fractures
timeFrame: 84 months
measure: Number of Participants With Non-Vertebral Fractures
timeFrame: 84 months
measure: Percent Change From Baseline in C-Telopeptide 1 (CTX-1) by Visit
timeFrame: Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
measure: Percent Change From Baseline in Procollagen Type 1 N-telopeptide (P1NP) by Visit
timeFrame: Baseline (of extension study), day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
measure: Percent Change From Study 20030216 Baseline in CTX-1 by Visit
timeFrame: Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
measure: Percent Change From Study 20030216 Baseline in P1NP by Visit
timeFrame: Study 20030216 Baseline and extension study day 10, and months 6, 12, 24, 36, 48, 60, 72, and 84
measure: Percent Change From Baseline in Albumin-adjusted Serum Calcium at Day 10
timeFrame: Baseline (of extension study) and day 10
measure: Serum Denosumab Concentration
timeFrame: Baseline (pre-dose in extension study), day 10, and Months 3, 4 and 6 (pre-dose)
measure: Bone Histomorphometry: Cancellous Bone Volume
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Trabecular Number
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Trabecular Separation
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Trabecular Thickness
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Cortical Width
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Cancellous Bone Volume by TRAP Histomorphometry
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Surface Density
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Osteoblast - Osteoid Interface
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Osteoid Surface
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Osteoid Thickness
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Wall Thickness
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Eroded Surface/Bone Surface
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Osteoclast Number - Length Based
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Osteoclast Number - Surface Based
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Osteoclast Number by TRAP - Length Based
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Osteoclast Number by TRAP - Surface Based
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Single-label Surface
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Double-label Surface
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Mineralizing Surface
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Mineral Apposition Rate
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Adjusted Apposition Rate
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Bone Formation Rate - Surface Based
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Bone Formation Rate - Volume Based
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Formation Period
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Activation Frequency
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Osteoid Volume
timeFrame: Month 24 and month 84
measure: Bone Histomorphometry: Mineralization Lag Time
timeFrame: Month 24 and month 84
measure: Bone Histology at Month 24
timeFrame: Month 24
measure: Bone Histology at Month 84
timeFrame: Month 84
Other outcomes:
Locations:
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.