Clinical trial NCT00043186: Determine the Efficacy, Safety and Tolerability of Denosumab (AMG 162) in the Treatment of Postmenopausal Women With Low Bone Mineral Density
Official title: A Randomized, Double-Blind, Placebo-controlled, Multi-dose Phase 2 Study to Determine the Efficacy, Safety and Tolerability of AMG 162 in the Treatment of Postmenopausal Women With Low Bone Mineral Density
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Low Bone Mineral Density
Keywords: bone loss
osteoporosis
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2002-08-07
Enrollment: 412
Sex: FEMALE
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To determine the effect of denosumab treatment compared with placebo over 12 months on bone mineral density (BMD) of the lumbar spine in postmenopausal women with low BMD. The clinical hypothesis is that denosumab subcutaneous injections administered every 3 or 6 months for 12 months will significantly increase lumbar spine bone mineral density and will be well tolerated.


Eligibility criteria: Inclusion Criteria

* women not more than 80 years of age on date of randomization
* ≥ 1 year postmenopausal on date of randomization
* ambulatory
* if ≤ 60 years of age, or had or would require a bilateral oophorectomy, serum follicle stimulating hormone (FSH) \> 50 mU/mL or serum estradiol \< 20 pg/mL
* low BMD (BMD T-score ≤ -1.8 at any 1 of the following sites: lumbar spine, femoral neck, or total hip; BMD T-scores must not have been \< -4.0 at the lumbar spine or - 3.5 at the femoral neck or total hip)
* before any study-specific procedure, including the screening dual X-ray absorptiometry (DXA) scan, gave informed consent for participation in the study.

Exclusion Criteria

* fluoride treatment for osteoporosis within the 2 years before the enrollment date
* bisphosphonate use within the 12 months before the enrollment date
* administration of the following medications within the 6 months before the enrollment date

  * tibolone
  * Parathyroid hormone (PTH) (or any derivative)
  * systemic glucocorticosteroids (\> 5 mg oral prednisone equivalent per day for \> 10 days)
  * inhaled corticosteroids (\> 2000 μg per day for \> 10 days)
  * anabolic steroids or testosterone
* administration of the following medications within the 3 months before the enrollment date

  * systemic hormone replacement therapy
  * selective estrogen receptor modulators
  * calcitonin
  * calcitriol
* current hyper- or hypothyroidism (allowed if stable on thyroid replacement therapy and thyroid-stimulating hormone was within the normal range)
* current hyper- or hypoparathyroidism
* albumin-adjusted serum calcium \< 8.5 mg/dL (\< 2.125 mol/L)
* osteomalacia
* rheumatoid arthritis
* Paget's disease
* malignancy within the 5 years before enrollment (except cervical carcinoma in situ or basal cell carcinoma, which were acceptable)
* renal disease; ie, creatinine clearance ≤ 35 mL/min
* any bone disease, other than osteoporosis, which could interfere with the interpretation of the findings (eg, osteogenesis imperfecta or osteopetrosis)
* malabsorption syndrome
* weight, height, or girth that could preclude accurate DXA measurements
* \< 2 lumbar vertebrae (L1 through L4) evaluable by DXA
* recent long bone fracture (within 6 months)
* osteoporotic-related fracture (ie, crush or wedge vertebral fracture or hip fracture) known or suspected to have occurred within 2 years of randomization
* \> 1 single, grade 1 vertebral fracture
* currently enrolled in or had participated within the previous 30 days in other investigational device or drug trial(s) (For some trials, this may have been allowed after discussion and written approval from Amgen.)
* known sensitivity to mammalian-derived drug preparations (eg, Herceptin®)
* any organic or psychiatric disorder, serum chemistry, or hematology that, in the opinion of the investigator, could have prevented the subject from completing the study or have interfered with the interpretation of the study results
* self-reported alcohol or drug abuse within the previous 12 months
* any disorder that compromised the ability to give truly informed consent for participation in the study
* previous administration of denosumab
* known sensitivity or contraindication to alendronate
* known sensitivity or contraindication to tetracycline derivatives (subjects in the biopsy substudy only).

Primary outcomes:
measure: Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 for the Placebo and Denosumab Arms
timeFrame: Baseline and Month 12
Secondary outcomes:
measure: Serum CTX Percent Change From Baseline at Month 12
timeFrame: Baseline and Month 12
measure: Urine NTX/Creatinine Percent Change From Baseline at Month 12
timeFrame: Baseline and Month 12
measure: Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 for the Alendronate Arm
timeFrame: Baseline and Month 12
measure: Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 24
timeFrame: Baseline and 24 months
measure: Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 36
timeFrame: Baseline and 36 months
measure: Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 42
timeFrame: Baseline and 42 months
measure: Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 48
timeFrame: Baseline and 48 months
measure: Serum CTX Percent Change From Baseline at Month 24
timeFrame: Baseline and 24 months
measure: Serum CTX Percent Change From Baseline at Month 36
timeFrame: Baseline and 36 months
measure: Serum CTX Percent Change From Baseline at Month 42
timeFrame: Baseline and 42 months
measure: Serum CTX Percent Change From Baseline at Month 48
timeFrame: Baseline and 48 months
measure: Urine NTX/Creatinine Percent Change From Baseline at Month 24
timeFrame: Baseline and 24 months
measure: Urine NTX/Creatinine Percent Change From Baseline at Month 36
timeFrame: Baseline and 36 months
measure: Urine NTX/Creatinine Percent Change From Baseline at Month 42
timeFrame: Baseline and 42 months
measure: Urine NTX/Creatinine Percent Change From Baseline at Month 48
timeFrame: Baseline and 48 months
measure: Total Hip Bone Mineral Density Percent Change From Baseline at Month 12
timeFrame: Baseline and 12 months
measure: Total Hip Bone Mineral Density Percent Change From Baseline at Month 24
timeFrame: Baseline and 24 months
measure: Total Hip Bone Mineral Density Percent Change From Baseline at Month 36
timeFrame: Baseline and 36 months
measure: Total Hip Bone Mineral Density Percent Change From Baseline at Month 42
timeFrame: Baseline and 42 months
measure: Total Hip Bone Mineral Density Percent Change From Baseline at Month 48
timeFrame: Baseline and 48 months
measure: Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12
timeFrame: Baseline and 12 months
measure: Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 24
timeFrame: Baseline and 24 months
measure: Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 36
timeFrame: Baseline and 36 months
measure: Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 42
timeFrame: Baseline and 42 months
measure: Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 48
timeFrame: Baseline and 48 months
measure: Total Body Bone Mineral Density Percent Change From Baseline at Month 12
timeFrame: Baseline and 12 months
measure: Total Body Bone Mineral Density Percent Change From Baseline at Month 24
timeFrame: Baseline and 24 months
measure: Total Body Bone Mineral Density Percent Change From Baseline at Month 36
timeFrame: Baseline and 36 months
measure: Total Body Bone Mineral Density Percent Change From Baseline at Month 42
timeFrame: Baseline and 42 months
measure: Total Body Bone Mineral Density Percent Change From Baseline at Month 48
timeFrame: Baseline and 48 months
measure: Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 12
timeFrame: Baseline and 12 months
measure: Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 24
timeFrame: Baseline and 24 months
measure: Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 36
timeFrame: Baseline and 36 months
measure: Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 42
timeFrame: Baseline and 42 months
measure: Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 48
timeFrame: Baseline and 48 months
Other outcomes:
Locations:
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Beck TJ, Lewiecki EM, Miller PD, Felsenberg D, Liu Y, Ding B, Libanati C. Effects of denosumab on the geometry of the proximal femur in postmenopausal women in comparison with alendronate. J Clin Densitom. 2008 Jul-Sep;11(3):351-9. doi: 10.1016/j.jocd.2008.04.001. Epub 2008 May 20.
citation: Lewiecki EM, Miller PD, McClung MR, Cohen SB, Bolognese MA, Liu Y, Wang A, Siddhanti S, Fitzpatrick LA; AMG 162 Bone Loss Study Group. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res. 2007 Dec;22(12):1832-41. doi: 10.1359/jbmr.070809.
citation: McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, Lain D, Kivitz AJ, Holloway DL, Zhang C, Peterson MC, Bekker PJ; AMG 162 Bone Loss Study Group. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006 Feb 23;354(8):821-31. doi: 10.1056/NEJMoa044459.
citation: Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008 Aug;43(2):222-229. doi: 10.1016/j.bone.2008.04.007. Epub 2008 Apr 26.
citation: Peterson MC, Riggs MM. A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling. Bone. 2010 Jan;46(1):49-63. doi: 10.1016/j.bone.2009.08.053. Epub 2009 Sep 2.