A Phase II Study Evaluating SB-751689 in Post-Menopausal Women With Osteoporosis.

This study has been terminated.
(Terminated for futility by sponsor after a pre-planned interim review of data)
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00471237
First received: May 7, 2007
Last updated: March 27, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Osteoporosis
Drug: Ronacaleret
Drug: Teriparatide
Drug: Alendronate
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Study CR9108963: A 12-month, Randomized, Double-blind, Parallel-group, Placebo and Active-controlled Dose-range Finding Study of the Efficacy and Safety of SB-751689 in Post-menopausal Women With Osteoporosis

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Data from this study, along with other data, will be used to select a dose of SB-751689 for further evaluation based on the effect seen on bone mineral density, safety and tolerability, in comparison with placebo and 2 active comparators. [ Time Frame: 12 Months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Bone mineral density of the lumbar spine and hip, volumetric bone mineral density at the hip and spine, biomarkers of bone turnover [ Time Frame: 12 Months ] [ Designated as safety issue: No ]

Enrollment: 569
Study Start Date: May 2007
Study Completion Date: December 2008
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Placebo
All subjects will take calcium (500-660mg elemental daily) and vitamin D (at least 400IU daily) supplements once daily in the evening throughout the study
Active Comparator: Alendronate
All subjects will take calcium (500-660mg elemental daily) and vitamin D (at least 400IU daily) supplements once daily in the evening throughout the study
Drug: Alendronate
Bisphosphonate
Active Comparator: Teriparatide
Open-label arm. All subjects will take calcium (500-660mg elemental daily) and vitamin D (at least 400IU daily) supplements once daily in the evening throughout the study
Drug: Teriparatide
PTH (1-34)
Experimental: Ronacaleret
4 arms, 100mg, 200mg, 300mg, 400mg. All subjects will take calcium (500-660mg elemental daily) and vitamin D (at least 400IU daily) supplements once daily in the evening throughout the study.
Drug: Ronacaleret
100mg, 200mg, 300mg, 400mg
Other Name: SB-751689

  Eligibility

Ages Eligible for Study:   18 Years to 79 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00471237

  Show 49 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Publications:
Fitzpatrick LA, Dabrowski CE, Cicconetti G, Gordon DN, Fuerst T, Engelke K, Genant HK. Ronacaleret, a calcium-sensing receptor antagonist, increases trabecular but not cortical bone in postmenopausal women. J Bone Miner Res. 2012 Feb;27(2):255-62. doi: 10.1002/jbmr.554.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00471237     History of Changes
Other Study ID Numbers: CR9108963
Study First Received: May 7, 2007
Last Updated: March 27, 2014
Health Authority: Spain: Agencia Española del Medicamento y Productos Sanitarios
Argentina: Ministry of Health - A.N.M.A.T
Belgium: Agence Fédérale des Médicaments et des Produits de la Santé
Norway: Statens Legemiddelverk
Russia: Russian Ministry of Health
Denmark: Lægemiddelstyrelsen
Germany: Federal Institute for Drugs and Medical Devices
Hong Kong: Department of Health
South Africa: Medicines Control Council
Poland: URZ.D REJESTRACJI PRODUKTÓW LECZNICZYCH, WYROBÓW MEDYCZNYCH I PRODUKTÓW BIOBÓJCZYCH,CEBK
Mexico: Ministry of Health
Australia: Department of Health and Ageing Therapeutic Goods Administration
South Korea: Food and Drug Administration
United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
bone mineral density,
Ronacaleret
teriparatide
alendronate,
Post-menopausal women,
osteoporosis,
SB-751689

Additional relevant MeSH terms:
Osteoporosis
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Alendronate
Teriparatide
Bone Density Conservation Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 26, 2014