Clinical trial NCT00471237: A Phase II Study Evaluating SB-751689 in Post-Menopausal Women With Osteoporosis.
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Osteoporosis
Keywords: bone mineral density,
Ronacaleret
teriparatide
alendronate,
Post-menopausal women,
osteoporosis,
SB-751689
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-05-09
Enrollment: 564
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Percent Change From Baseline in Bone Marrow Density (BMD) at Month 12 Measured by Dual-Energy X-Ray Absorptiometry (DXA) Scans of the Lumbar Spine (L1-L4)
timeFrame: Baseline (Day 0) and 12 Months
measure: Number of Participants With Hypercalcemia
timeFrame: Up to Month 12
measure: Number of Participants Withdrew Due to Hypercalcemia
timeFrame: Up to Month 12
measure: Number of Participant With Laboratory Abnormalities of Potential Clinical Concern at Any Post-baseline Visit
timeFrame: Up to Month 12
measure: Number of Participant With Vital Signs of Potential Clinical Concern at Any Post-baseline Visit
timeFrame: Up to 12 Months
measure: Number of Participant With Electrocardiogram (ECG) Findings Reported as Adverse Event
timeFrame: Up to 12 months
measure: Mean Change From Baseline in Height
timeFrame: Baseline (Day 0), Month 6, 12 and early withdrawal
measure: Mean Change From Baseline in Weight
timeFrame: Baseline (Day 0), Month 6, 12 and early withdrawal
Secondary outcomes:
measure: Percent Change From Baseline to Month 6 in BMD Measured by DXA Scans of the Lumbar Spine (L1-L4)
timeFrame: Baseline (Day 0) and Month 6
measure: Percent Change From Baseline to Months 6 and 12 in BMD Measured by DXA Scans of the Hip (Total Hip, Femoral Neck and Trochanter).
timeFrame: Baseline (Day 0), Month 6 and Month 12
measure: Number of Participants Who Remained the Same or Had Any Improvement in DXA BMD (> Baseline)
timeFrame: Baseline (Day 0), Month 5, 6 and 12
measure: Percent Change From Baseline to Month 12 in the Volumetric Integral, Cortical, and Trabecular Density (BMD) at the Hip and Lumbar Spine as Measured by Quantitative Computer Tomography (QCT) Scans
timeFrame: Baseline (Day 0) and Month 12
measure: Percent Change From Baseline to Month 12 in the Total Vertebra Integral VOI at the Lumbar Spine as Measured by QCT Scans
timeFrame: Baseline (Day 0) and Month 12
measure: Percent Change From Baseline to Month 12 in the Volumetric Integral, Cortical, and Trabecular Density (BMD) at the Hip as Measured by QCT Scans
timeFrame: Baseline (Day 0) and Month 12
measure: Percent Change From Baseline to Month 12 in Cortical Thickness at the Hip as Measured by QCT Scans
timeFrame: Baseline (Day 0) and Month 12
measure: Biochemical Markers of Bone Turnover: Levels of C-terminal Telopeptide α1 Chain of Type 1 Collagen (CTX1)
timeFrame: Baseline (Day 0), Week 4, Month 3, 6, and 12
measure: Biochemical Markers of Bone Turnover: Procollagen Type 1 N-terminal Propeptide (P1NP)
timeFrame: Baseline (Day 0), Week 4, Month 3, 6, and 12
measure: Biochemical Markers of Bone Turnover: Bone Specific Alkaline Phosphatase (BALP)
timeFrame: Baseline (Day 0), Week 4, Month 3, 6, and 12
measure: Blood Concentrations of Ronacaleret
timeFrame: Pre-dose (0.0 hour [h]) and 12 h post dose at Week 4, 20, 40 min, 1, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 1-4, 8-12, and 24 h at Month 3, 6 and 12
measure: Area Under the Concentration-time Curve Over the Dosing Interval (AUC 0-t) and Area Under the Concentration-time Curve Over the Dosing Interval (AUC 0-tau) of Ronacaleret
timeFrame: Pre-dose (0.0 h) and 12 h post dose at Week 4, 20, 40 min, 1, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 1-4, 8-12, and 24 h at Month 3, 6 and 12
measure: Maximum Blood Concentration (Cmax) of Ronacaleret
timeFrame: Pre-dose (0.0 h) and 12 h post dose at Week 4, 20, 40 min, 1, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 1-4, 8-12, and 24 h at Month 3, 6 and 12
measure: Time Required to Achieve Maximum Concentration of Ronacaleret in Blood (Tmax)
timeFrame: Pre-dose (0.0 h) and 12 h post dose at Week 4, 20, 40 min, 1, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 1-4, 8-12, and 24 h at Month 3, 6 and 12
Other outcomes:
Locations:
city: Oakland
country: United States
facility: GSK Investigational Site
state: California
city: Palm Desert
country: United States
facility: GSK Investigational Site
state: California
city: Walnut Creek
country: United States
facility: GSK Investigational Site
state: California
city: Decatur
country: United States
facility: GSK Investigational Site
state: Georgia
city: Bethesda
country: United States
facility: GSK Investigational Site
state: Maryland
city: Akron
country: United States
facility: GSK Investigational Site
state: Ohio
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Portland
country: United States
facility: GSK Investigational Site
state: Oregon
city: Duncansville
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: St Leonards
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Footscray
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Geelong
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Heidelberg
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Gent
country: Belgium
facility: GSK Investigational Site
city: Liege
country: Belgium
facility: GSK Investigational Site
city: Tienen
country: Belgium
facility: GSK Investigational Site
city: Ballerup
country: Denmark
facility: GSK Investigational Site
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hong Kong
country: Hong Kong
facility: GSK Investigational Site
city: Shatin
country: Hong Kong
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Suwon
country: Korea, Republic of
facility: GSK Investigational Site
city: Mexico, D.F.
country: Mexico
facility: GSK Investigational Site
city: Bergen
country: Norway
facility: GSK Investigational Site
city: Hamar
country: Norway
facility: GSK Investigational Site
city: Oslo
country: Norway
facility: GSK Investigational Site
city: Grudziadz
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Wroclaw
country: Poland
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Panorama
country: South Africa
facility: GSK Investigational Site
city: Rosebank
country: South Africa
facility: GSK Investigational Site
city: Somerset West
country: South Africa
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Fitzpatrick LA, Dabrowski CE, Cicconetti G, Gordon DN, Papapoulos S, Bone HG 3rd, Bilezikian JP. The effects of ronacaleret, a calcium-sensing receptor antagonist, on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mineral density. J Clin Endocrinol Metab. 2011 Aug;96(8):2441-9. doi: 10.1210/jc.2010-2855. Epub 2011 May 18.