A Phase II Study Evaluating SB-751689 in Post-Menopausal Women With Osteoporosis.
Condition: Osteoporosis
MeSH terms: Osteoporosis
Intervention: Ronacaleret; Teriparatide; Alendronate
Intervention description: 100mg, 200mg, 300mg, 400mg; PTH (1-34); Bisphosphonate
Intervention MeSH terms: Alendronate; Teriparatide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 564.0
Sex: Female
Minimum age: 18 Years
Maximum age: 79 Years
Healthy volunteers: No
Keywords: bone mineral density,; Ronacaleret; teriparatide; alendronate,; Post-menopausal women,; osteoporosis,; SB-751689

Summary:

      This is a 12 month study designed to evaluate the safety and effectiveness of SB-751689 in
      the treatment of osteoporosis in post-menopausal women, in comparison with 2 active
      comparators and placebo.
    

Eligibility criteria:

        Inclusion:

          -  Informed consent: Subject is willing and able to provide written informed consent.

          -  Menopausal status: Ambulatory female aged < 80 years at screening and >5 years
             postmenopausal.

          -  T-Score: A subject with either no or only one prevalent vertebral fracture is eligible
             for inclusion if she satisfies one of the following T-score requirements:

        If no prevalent vertebral fracture subject must have an absolute BMD value consistent with
        a T-score of less than or equal to -2.5 and greater than -4.0 at either the femoral neck,
        total hip, trochanter, or lumbar spine, or If one prevalent vertebral fracture subject must
        have an absolute BMD value consistent with a T-score of less than or equal to -2.0 and
        greater than -4.0 at either the femoral neck, total hip, trochanter, or lumbar spine.

          -  Suitable vertebra: Two or more vertebra in the range of L1 to L4 that are suitable for
             BMD measurement by DXA.

          -  Protocol compliance: Subject who, in the opinion of the investigator, is willing and
             able to comply with the requirements of the protocol.

        Exclusion:

          -  T-Score: Has an absolute BMD value consistent with a T-score less than or equal to
             -4.0 at either the femoral neck, total hip, trochanter, or lumbar spine.

          -  Vertebral fractures: Has >1 prevalent vertebral fracture at the screening visit.

          -  Non-vertebral fractures: Any previous non-vertebral osteoporosis related/fragility
             fracture after age 40.

          -  Spine deformity: Significant spine deformity which would preclude DXA/QCT assessments.

          -  BMI: BMI ≥33kg/m2.

          -  Bone metabolic diseases: Other than osteoporosis, history or concurrent diseases
             affecting bone metabolism (e.g., osteomalacia, hyperparathyroidism, hyperthyroidism).

          -  GI disease: History of major upper gastrointestinal disease

          -  Malabsorption: Active or history of malabsorption (e.g., history of celiac disease,
             irritable bowel syndrome or inflammatory bowel disease).

          -  Liver disease: Past or current history of liver disease or known hepatic or biliary
             abnormalities, (with the exception of previously documented diagnosis of Gilbert's
             syndrome).

          -  Rheumatoid arthritis: Active disease or history of rheumatoid arthritis.

          -  Nephrolithiasis: History of or active nephrolithiasis (kidney stones).

          -  Osteosarcoma risk: Subjects at increased risk of osteosarcoma such as those with
             Paget's disease of bone or any prior external beam or implant radiation therapy
             involving the skeleton.

          -  Malignancy: Malignant disease diagnosed within the previous 5 years (except resected
             basal cell cancer).

          -  Biological abnormalities: Any clinically relevant biological abnormality found and/or
             volunteered at screening (other than those related to the disease under investigation)
             which, in the opinion of the investigator, is clinically significant and would
             preclude safe participation in this study.

          -  Surgical and medical conditions: Presence of the following conditions within six
             months prior to screening: myocardial infarction, coronary bypass surgery, coronary
             artery angioplasty, unstable angina, cardiac arrhythmia, clinically evident congestive
             heart failure, or cerebrovascular accident.

          -  Glomerular filtration rate: Glomerular filtration rate (GFR) <35 mL/min as calculated
             by the Modification of Diet in Renal Disease (MDRD) equation as follows: GFR
             (mL/min/1.73 m2) = 186 x (Serum creatinine mg/dL)-1.154 x (Age)-0.203 x (0.742 if
             female) x (1.210 if African American) (conventional units).

          -  QT/QTc prolongation: A marked baseline prolongation of QT/QTc interval (e.g., QTc
             interval ≥450 msec on the Screening ECG).

          -  Torsades de Pointes: A history of risk factors for Torsades de Pointes (e.g., heart
             failure, hypokalemia, family history of Long QT Syndrome).

          -  Liver chemistries: Liver chemistries [aspartate aminotransferase (AST), alanine
             aminotransferase (ALT) or total bilirubin] exceeding 2-fold the upper limit of the
             laboratory-specified reference range, at screening.

          -  Abnormal serum calcium: Serum calcium (total or albumin-adjusted) outside the central
             laboratory reference range at the screening visit.

          -  Abnormal PTH: PTH (intact or whole) outside the normal range.

          -  Abnormal creatine phosphokinase: Creatine phosphokinase (CPK) outside the normal
             range.

          -  Abnormal alkaline phosphatase: Alkaline phosphatase outside of the normal range.

          -  Thyroid hormone replacement: Subjects receiving thyroid hormone replacement therapy
             must have a TSH level checked. Subjects will be excluded if TSH levels are <0.1 or
             >10.0mIU/L. However, subjects will not be excluded if TSH is in the range 0.1-4.5
             mIU/L. If TSH is >4.5 and ≤10.0mIU/mL, measure T4 and exclude the subject only if the
             T4 is outside the normal range.

          -  Vitamin D deficiency: Vitamin D deficiency (serum 25-hydroxy vitamin D < 20ng/mL,
             equivalent to 50nmol/L) at screening. Subjects can undergo vitamin D repletion as per
             local practice and be re-screened once only for vitamin D levels within the 6-week
             screening period. They will remain excluded if the re-screened value is < 20ng/mL.

          -  Previous strontium or IV bisphosphonate: Any previous treatment with strontium
             ranelate or intravenous bisphosphonate.

          -  Oral bisphosphonates: Any previous treatment with an oral bisphosphonate as follows:

        any treatment within the last six months

          -  one month cumulative treatment within the last 12 months

          -  three months cumulative treatment within the past two years, or

          -  two years cumulative treatment within the past five years.

               -  Fluoride: Treatment with fluoride (dose greater than 10mg/day) within the
                  previous 5 years for osteoporosis.

               -  Digoxin: Current therapy with digoxin.

               -  Bone metabolism drugs: Treatment with other drugs affecting bone metabolism
                  within the last six months prior to screening:

        Chronic systemic corticosteroid [e.g., glucocorticoid, mineralocorticoid] treatment of no
        more than 2 intra-articular injections within the past year or use of oral, parenteral, or
        long-term, high-dose inhaled corticosteroids. Treatment with any topical corticosteroid
        will not exclude the subject from participating.

        Hormones [e.g., estrogens/"natural estrogen preparations"(except for nonsystemic vaginal
        treatment), 19-norprogestins, SERMs such as raloxifene, anabolic steroids/androgens such as
        dehydroepiandrosterone (DHEA) or its sulfated form (DHEAS), nandrolone, tibolone, active
        vitamin D analogs/metabolites such as 1,25-dihydroxy vitamin D (calcitriol) or
        1alpha-hydroxyvitamin D3 (1-alpha hydroxycholecalciferol), calcitonin].

        Calcineurin inhibitors [e.g., cyclosporine, tacrolimus] or methotrexate.

          -  Previous anabolic agents: Treatment with PTH, PTH analogues or similar anabolic agent
             for osteoporosis within the last two years.

          -  Contraindications: Contraindications to therapy with calcium or vitamin D.

          -  Pregnancy: Women who are pregnant are not allowed in this study.

          -  Interfering medications: Vitamin A in excess of 10,000 IU per day, heparin, or
             lithium, or anticonvulsant medications except benzodiazepines.

          -  Investigational drug exposure: Administration of any investigational drug within 90
             days preceding the first dose of the study drug.

          -  Substance abuse: History or current evidence of drug or alcohol abuse within the
             previous 12 months.

          -  Problems swallowing: Inability to swallow a tablet whole.

        The following exclusion criteria do not apply to subjects allocated to the open-label
        teriparatide group:

          -  Calcium channel blockers: Current therapy with calcium channel blockers diltiazem and
             verapamil.

          -  Oral Azole Antifungals: Current therapy with any oral azole antifungal.

          -  Immunosuppressants: Current therapy with cyclosporine or oral tacrolimus.

          -  Ritonavir: Current therapy with ritonavir.

          -  Quinidine: Current therapy with quinidine.

          -  Macrolide Antibiotics: Subjects anticipated to require chronic use of macrolide
             antibiotics.

          -  Alendronate Contraindications: Contraindications to therapy with alendronate.
             Additional Exclusion Criteria for Subjects Recruited at QCT Sites

          -  Hip surgery: History of hip surgery resulting in a metal implant on either the left or
             right side that would cause an artefact on a QCT scan.

        Additional Exclusion Criteria for Teriparatide Subjects

          -  Teriparatide contraindications: Contraindications to therapy with teriparatide
             according to locally approved datasheet.