Denosumab China Phase III Study
Condition: Osteoporosis, Postmenopausal
MeSH terms: Osteoporosis; Osteoporosis, Postmenopausal
Intervention: Denosumab; Placebo; Elemental Calcium; Vitamin D
Intervention description: Injection; Injection; Oral, at least 600 mg; Oral, at least 400 IU
Intervention MeSH terms: Vitamin D; Denosumab; Calcium
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 486.0
Sex: Female
Minimum age: 60 Years
Maximum age: 90 Years
Healthy volunteers: No

Summary:

      This study is to evaluate the efficacy and safety of denosumab 60 milligrams (mg) for 12
      month treatment in Chinese postmenopausal women with osteoporosis at increased risk of
      fracture.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject is willing and able to provide written informed consent.

          -  Of Chinese origin - defined as being born in China, having four ethnic Chinese
             grandparents.

          -  Ambulatory woman between the age of 60 and 90 years, inclusive.

          -  The subject has a BMD absolute value consistent with a T-score<-2.5 and >-4.0 at
             either the lumbar spine or total hip.

          -  All subjects must have at least one of following additional the risk factors:

        history of fracture parental history of hip fracture increased bone turnover rate at
        screening (s-CTX >1.0 SD above the mean in healthy premenopausal women) low body weight
        (BMI≤19kg/m2) elderly (age≥70y) current smoker

          -  Postmenopausal defined as >5 years postmenopausal, which can be >5 years of
             spontaneous amenorrhea or >5 years post surgical bilateral oophorectomy. Use follicle
             stimulating hormone (FSH) levels >40 mIU/mL to confirm surgical postmenopausal status,
             where bilateral oophorectomy status is uncertain.

        Exclusion Criteria:

          -  Bone/metabolic disease:

        Any metabolic bone disease, e.g., osteomalacia or osteogenesis imperfecta, which may
        interfere with the interpretation of the findings.

        Paget's disease Cushing's disease Hyperprolactinemia

          -  Current hyperparathyroidism or hypoparathyroidism by medical record

          -  Thyroid condition: Hyperthyroidism or hypothyroidism. Only subjects with
             hypothyroidism who are on stable thyroid hormone replacement therapy may be allowed
             per the following criteria:

        If TSH level is below normal range, subject is not eligible for the study. If TSH level is
        elevated (>5.5 μIU/mL and ≤10.0 μIU/mL), serum T4 should be measured.

        If serum T4 is within normal range, subject is eligible. If serum T4 is outside of normal
        range, subject is not eligible for the study. If TSH level is > 10.0 μIU/mL, subject is not
        eligible.

          -  Rheumatoid arthritis

          -  Malignancy:

        Malignancy (except fully resected cutaneous basal cell or squamous cell carcinoma, cervical
        or breast ductal carcinoma in situ) within the last 5years.

          -  Malabsorption syndrome: malabsorption syndrome or any gastrointestinal disorders
             associated with malabsorption, for example Crohn's Disease and chronic pancreatitis.

          -  Renal disease - severe renal impairment

          -  Liver disease:

        Cirrhosis of the liver Unstable liver disease (as defined by the presence of ascites,
        encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent
        jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or
        asymptomatic gallstones). Chronic stable hepatitis B and C are acceptable if the subject
        otherwise meets study entry criteria (e.g., presence of hepatitis B surface antigen or
        positive Hepatitis C test result within 3 months of Screening).

          -  Drug or alcohol abuse: Evidence of alcohol or substance-abuse within the last 12
             months which the investigator believes would interfere with understanding or
             completing the study.

          -  Biological abnormalities:

        Any disorder that compromises the ability of the subject to give written informed consent
        or to comply with study procedures.

        Any physical or psychiatric disorder which, in the opinion of the investigator, will
        prevent the subject from completing the study or interfere with the interpretation of the
        study results.

        Known to have tested positive for human immunodeficiency virus (HIV).

          -  Vitamin D deficiency: Vitamin D deficiency (25-(OH) vitamin D level <20 ng/mL).
             Vitamin D repletion will be permitted and after repletion subjects may be re-tested
             once for 25-(OH) vitamin D levels.

          -  Oral/Dental Conditions Prior history or current evidence of osteomyelitis or
             osteonecrosis of the jaw. Active dental or jaw condition which requires oral surgery.
             Planned invasive dental procedure. Non-healed dental or oral surgery.

        Concomitant Medications:

          -  Previous strontium or IV bisphosphonate: Administration of intravenous (IV)
             bisphosphonate, fluoride, or strontium for osteoporosis within the last 5 years.

          -  Oral bisphosphonate: Oral bisphosphonate treatment for osteoporosis:

        If used for ≥3 years cumulatively, subject is ineligible.

        If used for >3-months but <3 years cumulatively:

        If the last dose was <1 year before enrolment, subject is ineligible. If the last dose was
        ≥1 year before enrolment, subject is eligible. If used ≤3 months, cumulatively, subject is
        eligible.

          -  Bone metabolism drugs: Administration of any of the following treatments within the
             last 6 weeks:

        Parathyroid hormone (PTH) or PTH derivatives, e.g., teriparatide. Anabolic steroids or
        testosterone. Glucocorticosteroids (>5 mg prednisone equivalent per day for more than 10
        days).

        Systemic hormone replacement therapy. Selective estrogen receptor modulators (SERMs), e.g.,
        raloxifene Tibolone. Calcitonin. Calcitriol or vitamin D derivatives. Other bone active
        drugs including anti-convulsives (except benzodiazepines) and heparin.

        Chronic systemic ketoconazole, androgens, ACTH, cinacalcet, aluminum, lithium, protease
        inhibitors, methotrexate, gonadotropin-releasing hormone agonists.

          -  Investigational drug exposure: Currently enrolled in an investigational device or drug
             trial(s) or it has not been at least 30 days since the last study visit in an
             investigational device or drug trial(s), or subject is receiving other investigational
             agent(s).

          -  Sensitivity: Known sensitivity to mammalian cell-derived drug products.

          -  Clinically significant hypersensitivity to denosumab Abnormal laboratory values

          -  General: Any laboratory abnormality which, in the opinion of the investigator, will
             prevent the subject from completing the study or interfere with the interpretation of
             the study results.

          -  Abnormal serum calcium: current hypocalcemia or hypercalcemia. Albumin adjusted serum
             calcium levels must be within normal limits of the central laboratory.

          -  Liver transaminases:

        Serum aspartate aminotransferase (AST) ≥2.0 x upper limits of normal (ULN). Serum alanine
        aminotransferase (ALT) ≥2.0 x ULN. Alkaline phosphatase and bilirubin ≥1.5 x ULN (isolated
        bilirubin ≥1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%.

          -  DXA measurements:

        Less than two lumbar vertebrae evaluable for DXA measurements. Height, weight, or girth
        which may preclude accurate DXA measurements.

          -  Subjects with a history of greater than 2 vertebral fractures.

          -  Subjects at very high risk of fracture who must be treated with active drugs in the
             opinion of investigator.