Determine the Efficacy, Safety and Tolerability of AMG 162 in the Treatment of Postmenopausal Women With Low Bone Mineral Density - Full Text View

Sponsor:	Amgen
Information provided by:	Amgen
ClinicalTrials.gov Identifier:	NCT00043186

Purpose

To determine the effect of AMG 162 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 AMG 162 SC injections administered every 3 or 6 months for 12 months will significantly increase lumbar spine bone mineral density and will be well tolerated.

Condition	Intervention	Phase
Low Bone Mineral Density	Drug: Placebo Drug: Denosumab Drug: Active comparator	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
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

Resource links provided by NLM:

MedlinePlus related topics: Bone Density Minerals

Drug Information available for: Denosumab

U.S. FDA Resources

Further study details as provided by Amgen:

Primary Outcome Measures:

Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 for the Placebo and Denosumab Arms [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 12 calculated using ((month 12 value - baseline value) / baseline value ) x 100.

Secondary Outcome Measures:

Serum CTX Percent Change From Baseline at Month 12 [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Serum C-Telopeptide (CTX). Percent change from baseline to month 12 calculated using ((month 12 value - baseline value) / baseline value ) x 100.
Urine NTX/Creatinine Percent Change From Baseline at Month 12 [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Urinary N-telopeptide (uNTX)/Creatinine. Percent change from baseline to month 12 calculated using ((month 12 value - baseline value) / baseline value ) x 100.
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 12 for the Alendronate Arm [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 12 calculated using ((month 12 value - baseline value) / baseline value ) x 100.
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 24 [ Time Frame: From Baseline to 24 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 24 calculated using ((month 24 value - baseline value) / baseline value ) x 100.
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 36 [ Time Frame: From Baseline to 36 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 36 calculated using ((month 36 value - baseline value) / baseline value ) x 100.
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 42 [ Time Frame: From Baseline to 42 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 42 calculated using ((month 42 value - baseline value) / baseline value ) x 100.
Lumbar Spine Bone Mineral Density Percent Change From Baseline at Month 48 [ Time Frame: From Baseline to 48 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 48 calculated using ((month 48 value - baseline value) / baseline value ) x 100.
Serum CTX Percent Change From Baseline at Month 24 [ Time Frame: From Baseline to 24 months ] [ Designated as safety issue: No ]
Serum C-Telopeptide (CTX). Percent change from baseline to month 24 calculated using ((month 24 value - baseline value) / baseline value ) x 100.
Serum CTX Percent Change From Baseline at Month 36 [ Time Frame: From Baseline to 36 months ] [ Designated as safety issue: No ]
Serum C-Telopeptide (CTX). Percent change from baseline to month 36 calculated using ((month 36 value - baseline value) / baseline value ) x 100.
Serum CTX Percent Change From Baseline at Month 42 [ Time Frame: From Baseline to 42 months ] [ Designated as safety issue: No ]
Serum C-Telopeptide (CTX). Percent change from baseline to month 42 calculated using ((month 42 value - baseline value) / baseline value ) x 100.
Serum CTX Percent Change From Baseline at Month 48 [ Time Frame: From Baseline to 48 months ] [ Designated as safety issue: No ]
Serum C-Telopeptide (CTX). Percent change from baseline to month 48 calculated using ((month 48 value - baseline value) / baseline value ) x 100.
Urine NTX/Creatinine Percent Change From Baseline at Month 24 [ Time Frame: From Baseline to 24 months ] [ Designated as safety issue: No ]
Urinary N-telopeptide (uNTX)/Creatinine. Percent change from baseline to month 24 calculated using ((month 24 value - baseline value) / baseline value ) x 100.
Urine NTX/Creatinine Percent Change From Baseline at Month 36 [ Time Frame: From Baseline to 36 months ] [ Designated as safety issue: No ]
Urinary N-telopeptide (uNTX)/Creatinine. Percent change from baseline to month 36 calculated using ((month 36 value - baseline value) / baseline value ) x 100.
Urine NTX/Creatinine Percent Change From Baseline at Month 42 [ Time Frame: From Baseline to 42 months ] [ Designated as safety issue: No ]
Urinary N-telopeptide (uNTX)/Creatinine. Percent change from baseline to month 42 calculated using ((month 42 value - baseline value) / baseline value ) x 100.
Urine NTX/Creatinine Percent Change From Baseline at Month 48 [ Time Frame: From Baseline to 48 months ] [ Designated as safety issue: No ]
Urinary N-telopeptide (uNTX)/Creatinine. Percent change from baseline to month 48 calculated using ((month 48 value - baseline value) / baseline value ) x 100.
Total Hip Bone Mineral Density Percent Change From Baseline at Month 12 [ Time Frame: From Baseline to 12 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 12 calculated using ((month 12 value - baseline value) / baseline value ) x 100.
Total Hip Bone Mineral Density Percent Change From Baseline at Month 24 [ Time Frame: From Baseline to 24 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 24 calculated using ((month 24 value - baseline value) / baseline value ) x 100.
Total Hip Bone Mineral Density Percent Change From Baseline at Month 36 [ Time Frame: From Baseline to 36 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 36 calculated using ((month 36 value - baseline value) / baseline value ) x 100.
Total Hip Bone Mineral Density Percent Change From Baseline at Month 42 [ Time Frame: From Baseline to 42 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 42 calculated using ((month 42 value - baseline value) / baseline value ) x 100.
Total Hip Bone Mineral Density Percent Change From Baseline at Month 48 [ Time Frame: From Baseline to 48 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 48 calculated using ((month 48 value - baseline value) / baseline value ) x 100.
Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 12 [ Time Frame: From Baseline to 12 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 12 calculated using ((month 12 value - baseline value) / baseline value ) x 100.
Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 24 [ Time Frame: From Baseline to 24 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 24 calculated using ((month 24 value - baseline value) / baseline value ) x 100.
Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 36 [ Time Frame: From Baseline to 36 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 36 calculated using ((month 36 value - baseline value) / baseline value ) x 100.
Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 42 [ Time Frame: From Baseline to 42 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 42 calculated using ((month 42 value - baseline value) / baseline value ) x 100.
Distal 1/3 Radius Bone Mineral Density Percent Change From Baseline at Month 48 [ Time Frame: From Baseline to 48 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 48 calculated using ((month 48 value - baseline value) / baseline value ) x 100.
Total Body Bone Mineral Density Percent Change From Baseline at Month 12 [ Time Frame: From Baseline to 12 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 12 calculated using ((month 12 value - baseline value) / baseline value ) x 100.
Total Body Bone Mineral Density Percent Change From Baseline at Month 24 [ Time Frame: From Baseline to 24 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 24 calculated using ((month 24 value - baseline value) / baseline value ) x 100.
Total Body Bone Mineral Density Percent Change From Baseline at Month 36 [ Time Frame: From Baseline to 36 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 36 calculated using ((month 36 value - baseline value) / baseline value ) x 100.
Total Body Bone Mineral Density Percent Change From Baseline at Month 42 [ Time Frame: From Baseline to 42 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 42 calculated using ((month 42 value - baseline value) / baseline value ) x 100.
Total Body Bone Mineral Density Percent Change From Baseline at Month 48 [ Time Frame: From Baseline to 48 months ] [ Designated as safety issue: No ]
Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 48 calculated using ((month 48 value - baseline value) / baseline value ) x 100.
Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 12 [ Time Frame: From Baseline to 12 months ] [ Designated as safety issue: No ]
Bone specific alkaline phosphatase (BSAP). Percent change from baseline to month 12 calculated using ((month 12 value - baseline value) / baseline value ) x 100.
Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 24 [ Time Frame: From Baseline to 24 months ] [ Designated as safety issue: No ]
Bone specific alkaline phosphatase (BSAP). Percent change from baseline to month 24 calculated using ((month 24 value - baseline value) / baseline value ) x 100.
Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 36 [ Time Frame: From Baseline to 36 months ] [ Designated as safety issue: No ]
Bone specific alkaline phosphatase (BSAP). Percent change from baseline to month 36 calculated using ((month 36 value - baseline value) / baseline value ) x 100.
Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 42 [ Time Frame: From Baseline to 42 months ] [ Designated as safety issue: No ]
Bone specific alkaline phosphatase (BSAP). Percent change from baseline to month 42 calculated using ((month 42 value - baseline value) / baseline value ) x 100.
Bone Specific Alkaline Phosphatase Percent Change From Baseline at Month 48 [ Time Frame: From Baseline to 48 months ] [ Designated as safety issue: No ]
Bone specific alkaline phosphatase (BSAP). Percent change from baseline to month 48 calculated using ((month 48 value - baseline value) / baseline value ) x 100.

Enrollment:	412
Study Start Date:	May 2002
Study Completion Date:	June 2007
Primary Completion Date:	April 2007 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 30 mg sc q 3 months AMG 162: 30 mg SC every 3 months until month 21; placebo SC every 6 months at month 24 and month 30; 60 mg SC every 6 months at month 36 and month 42	Drug: Denosumab AMG 162: 14 60, and 100 mg SC every 6 months until month 21 (alternating with placebo every 3 months); 60 mg SC every 6 months beginning month 24 through 42 AMG 162: 210 mg SC every 6 months until month 21; (alternating with placebo every 3 months); placebo every 6 months beginning month 24 through 42 AMG 162: 30 mg SC every 3 months until month 21; placebo SC every 6 months at month 24 and month 30; 60 mg SC every 6 months at month 36 and month 42 AMG 162: 6 and 14 mg SC every 3 months until month 21; 60 mg SC every 6 months beginning month 24 through 42
Experimental: 210 mg AMG 162: 210 mg SC every 6 months until month 21; (alternating with placebo every 3 months); placebo every 6 months beginning month 24 through 42	Drug: Denosumab AMG 162: 14 60, and 100 mg SC every 6 months until month 21 (alternating with placebo every 3 months); 60 mg SC every 6 months beginning month 24 through 42 AMG 162: 210 mg SC every 6 months until month 21; (alternating with placebo every 3 months); placebo every 6 months beginning month 24 through 42 AMG 162: 30 mg SC every 3 months until month 21; placebo SC every 6 months at month 24 and month 30; 60 mg SC every 6 months at month 36 and month 42 AMG 162: 6 and 14 mg SC every 3 months until month 21; 60 mg SC every 6 months beginning month 24 through 42
Experimental: 6 and 14 mg q 3 months AMG 162: 6 and 14 mg SC every 3 months until month 21; 60 mg SC every 6 months beginning month 24 through 42	Drug: Denosumab AMG 162: 14 60, and 100 mg SC every 6 months until month 21 (alternating with placebo every 3 months); 60 mg SC every 6 months beginning month 24 through 42 AMG 162: 210 mg SC every 6 months until month 21; (alternating with placebo every 3 months); placebo every 6 months beginning month 24 through 42 AMG 162: 30 mg SC every 3 months until month 21; placebo SC every 6 months at month 24 and month 30; 60 mg SC every 6 months at month 36 and month 42 AMG 162: 6 and 14 mg SC every 3 months until month 21; 60 mg SC every 6 months beginning month 24 through 42
Placebo Comparator: blinded control group placebo sc every 3 months until month 21 then beginning at month 24 every 6 months until month 42	Drug: Placebo placebo sc every 3 months until month 21 then beginning at month 24 every 6 months until month 42
Active Comparator: open label reference group Fosamax 70 mg oral weekly for 24 months. No treatment through month 48	Drug: Active comparator Fosamax 70 mg oral weekly for 24 months. No treatment through month 48
Experimental: 14, 60 & 100 mg AMG 162: 14 60, and 100 mg SC every 6 months until month 21 (alternating with placebo every 3 months); 60 mg SC every 6 months beginning month 24 through 42	Drug: Denosumab AMG 162: 14 60, and 100 mg SC every 6 months until month 21 (alternating with placebo every 3 months); 60 mg SC every 6 months beginning month 24 through 42 AMG 162: 210 mg SC every 6 months until month 21; (alternating with placebo every 3 months); placebo every 6 months beginning month 24 through 42 AMG 162: 30 mg SC every 3 months until month 21; placebo SC every 6 months at month 24 and month 30; 60 mg SC every 6 months at month 36 and month 42 AMG 162: 6 and 14 mg SC every 3 months until month 21; 60 mg SC every 6 months beginning month 24 through 42

Eligibility

Ages Eligible for Study:	up to 80 Years
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

4.1 Inclusion Criteria 4.1.1 Women not more than 80 years old on date of randomization 4.1.2 At least 1 year postmenopausal on date of randomization 4.1.3 Ambulatory 4.1.4 If ≤ 60 years old or post bilateral oophorectomy based on medical history, will require serum FSH > 50mU/mL or serum estradiol < 20 pg/mL to be eligible; 4.1.5 Low bone mineral density (BMD t-score ≤ -1.8 at any one of the following sites: lumbar spine, femoral neck, or total hip; BMD t-scores must not be lower than -4.0 at the lumbar spine, or -3.5 at the femoral neck or total hip). Refer to Table 3 in Section 7.11.1 for Hologic and Lunar densitometer-specific BMD values, and more specific information.

4.1.6 Ethical - Before any study specific procedure, including the screening DXA, the subject must give informed consent for participation in the study (see Section 12.2).

4.2 Exclusion Criteria 4.2.1 Fluoride treatment for osteoporosis within the last 2 years before the enrollment date; 4.2.2 Bisphosphonate use within the last 12 months before the enrollment date; 4.2.3 Administration of the following medications within the last 6 months before enrollment date:

Tibolone
Parathyroid hormone (or any derivative)
Systemic glucocorticosteroids (> 5 mg oral prednisone equivalent per day for more than 10 days)
Inhaled corticosteroids (> 2,000 µg per day for more than 10 days)
Anabolic steroids or testosterone 4.2.4 Administration of the following medications within the last 3 months before the enrollment date:

a) Systemic hormone replacement therapy b) Selective estrogen receptor modulators (SERMs) c) Calcitonin d) Calcitriol 4.2.5 Evidence of any of the following conditions per subject self report or medical chart review:

Current hyper- or hypothyroidism (stable on thyroid replacement therapy is allowed, if the TSH is within the normal range)
Current hyper- or hypoparathyroidism
Albumin-adjusted serum calcium < 8.5 mg/dL
Osteomalacia
Rheumatoid arthritis
Paget's disease
Malignancy within the last 5 years prior to enrollment (except cervical carcinoma in situ or basal cell carcinoma)
Renal disease (creatinine clearance <= 35 mL/min using the following equation):

Creatinine Clearance = 0.85 [(140 - age in years) x (weight in kg)] [72 x serum creatinine (mg/dL)]
Any bone disease, other than osteoporosis, which may interfere with the interpretation of the findings (e.g., osteogenesis imperfecta or osteopetrosis)
Malabsorption syndrome
Weight, height or girth which may preclude accurate DXA measurements
Less than 2 lumbar vertebrae (L1-L4) evaluable by DXA
Recent long bone fracture (within 6 months)
Osteoporosis-related fracture (i.e., crush or wedge vertebral fracture or hip fracture) known or suspected to have occurred within 2 years of randomization.
More than one single, grade 1 vertebral fracture. 4.2.6 Currently enrolled or has participated within the previous 30 days in other investigational device or drug trial(s). For some trials, this may be allowed after discussion and written approval from Amgen.

4.2.7 Known sensitivity to mammalian-derived drug preparations (e.g., Herceptin).

4.2.8 Any organic or psychiatric disorder, serum chemistry, or hematology, which, in the opinion of the investigator, may prevent the subject from completing the study or interfere with the interpretation of the study results.

4.2.9 Self-reported alcohol or drug abuse within the previous 12 months. 4.2.10 Any disorder that compromises ability to give truly informed consent for participation in this study.

4.2.11 Prior administration of AMG 162. 4.2.12 Known sensitivity or contraindication to Fosamax. 4.2.13 Known sensitivity or contraindication to tetracycline derivatives (biopsy subset subjects only).

Responsible Party:	Global Development Leader, Amgen Inc.
ClinicalTrials.gov Identifier:	NCT00043186 History of Changes
Other Study ID Numbers:	20010223
Study First Received:	August 6, 2002
Results First Received:	December 22, 2009
Last Updated:	June 25, 2010
Health Authority:	United States: Food and Drug Administration