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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: Ronacaleret
* Drug: Teriparatide
* Drug: Alendronate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Placebo<br>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<br>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<br>* Bisphosphonate<br>|
| Active Comparator: Teriparatide<br>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<br>* PTH (1-34)<br>|
| Experimental: Ronacaleret<br>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<br>* 100mg, 200mg, 300mg, 400mg<br>* Other names: SB-751689;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | DXA scanners from Hologic and GE Lunar was used to measure BMD by a DXA scan. At least two vertebrae (L1-L4) that were suitable for measurement of BMD were evaluated. The same scanner was used throughout the study for all measurements for a given participant. DXA scans were sent to a central reading facility for quality control and central analysis. Assessments performed on Day 0 were considered as Baseline. Percent change from Baseline was computed as (change from baseline / baseline value) * 100%. Percent change from Baseline in areal bone mineral density (aBMD) was reported. | Baseline (Day 0) and 12 Months | 
| Number of Participants With Hypercalcemia | Participants with albumin-adjusted serum calcium pre-dose values of >11.0 mg/ deciliter (dL) or post-dose values of >12.0 mg/dL were recorded as participants with hypercalcemia. Number of participant with hypercalcemia were reported. | Up to Month 12 | 
| Number of Participants Withdrew Due to Hypercalcemia | A confirmed albumin-adjusted serum calcium pre-dose value of >11.0 mg/dL or post-dose value of >12.0 mg/dL was set as a withdrawal criteria for the study. Number of participants who met this pre-defined stopping criteria were reported. | Up to Month 12 | 
| Number of Participant With Laboratory Abnormalities of Potential Clinical Concern at Any Post-baseline Visit | The hematology parameters analyzed were white blood cells (WBC) count with differential WBC count, red blood cells, haemoglobin, haematocrit, mean corpuscular volume and platelet count. The clinical chemistry parameters analyzed were sodium, potassium, calcium, calcium (albumin adjusted), phosphate, bicarbonate, creatinine, bilirubin (total), alanine amino transferase, aspartate amino transferase, glucose, albumin, alkaline phosphatase, creatine phosphokinase, urea, uric acid, total protein, 25-OH vitamin D, 1,25-2(OH) vitamin D, whole parathyroid hormone (PTH 1-84)) and intact PTH (1-84 and 7-84). Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important laboratory findings at any visit were reported. | Up to Month 12 | 
| Number of Participant With Vital Signs of Potential Clinical Concern at Any Post-baseline Visit | The potential clinical importance ranges (low and high) of the vital sign parameters-systolic blood pressure (> 30 millimeter of mercury [mmHg] decrease from Baseline, > 30 mmHg increase from Baseline), diastolic blood pressure (> 20 mmHg decrease from Baseline and > 20 mmHg increase from Baseline) and heart rate (<45 and >120 beats per minute). Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important vital parameter findings at any visit were reported. | Up to 12 Months | 
| Number of Participant With Electrocardiogram (ECG) Findings Reported as Adverse Event | Full 12-lead ECGs pre-dose at screening and visits 6, 8, 11, 12 and 14 were recorded. Participants rested supine or seated for at least 10 minutes before each reading. All ECGs were transmitted to a central reviewer for blinded assessment. The central reviewer measured the following parameters and provide a clinical interpretation: heart rate, RR interval, PR interval, QRS interval, QT (uncorrected) interval, QTcB (Bazett's correction) interval, QTcF (Fridericia's correction) interval. The central reviewer was provided the investigator or designated qualified site physician with a central ECG report or confirmatory report to assist them in identifying any clinically significant abnormalities that would preclude the participant from further participation in the study. | Up to 12 months | 
| Mean Change From Baseline in Height | Assessments performed on Day 0 were considered as Baseline. Change from Baseline was computed as values at post baseline visit minus Baseline value. Mean change from baseline in height at Month 6 and 12 and early withdrawal were reported. | Baseline (Day 0), Month 6, 12 and early withdrawal | 
| Mean Change From Baseline in Weight | Baseline values were assessed on Day 0. Change from Baseline was computed as values at post baseline visit minus Baseline value. Mean change from baseline in weight at Month 6, 12 and early withdrawal were reported. | Baseline (Day 0), Month 6, 12 and early withdrawal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Month 6 in BMD Measured by DXA Scans of the Lumbar Spine (L1-L4) | DXA scanners from Hologic and GE Lunar was used to measure BMD by a DXA scan. At least two vertebrae (L1-L4) that were suitable for measurement of BMD were evaluated. The same scanner was used throughout the study for all measurements for a given participant. DXA scans were sent to a central reading facility for quality control and central analysis. Baseline values were assessed on Day 0. Percent Change from Baseline was computed as (change from baseline / baseline value) * 100%. Percent change from baseline to month 6 in aBMD was reported. | Baseline (Day 0) and Month 6 | 
| Percent Change From Baseline to Months 6 and 12 in BMD Measured by DXA Scans of the Hip (Total Hip, Femoral Neck and Trochanter). | DXA scanners from Hologic and GE Lunar was used to measure BMD by a DXA scan. At least two vertebrae (L1-L4) that were suitable for measurement of BMD were evaluated. The same scanner was used throughout the study for all measurements for a given participant. DXA scans were sent to a central reading facility for quality control and central analysis. Baseline values were assessed on Day 0. Percent Change from Baseline was computed as (change from baseline / baseline value) * 100%. Percent change from baseline to month 6 and 12 in aBMD of hip (total hip, femoral neck and trochanter) were reported. | Baseline (Day 0), Month 6 and Month 12 | 
| Number of Participants Who Remained the Same or Had Any Improvement in DXA BMD (> Baseline) | Responder rate of participants who remained the same or had any improvement as compared to baseline in DXA BMD of vertebra, femur and vertebra plus femur were reported. Baseline values were assessed on Day 0. Percent change (improvement) from Baseline was computed as (change from baseline / baseline value) * 100%. | Baseline (Day 0), Month 5, 6 and 12 | 
| 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 | QCT is a three-dimensional non-projectional technique to quantify BMD with a number of advantages to other densitometric techniques. Cortical and trabecular bone can be separated, trabecular volume of interest (VOI) are largely independent of degenerative changes in the spine and 3 dimensional geometric parameters can be determined. BMD as measured by QCT is a true density measured in g/cm^3 in contrast to DXA Which determines an areal density measured in g/cm^2. Baseline values were assessed on Day 0. Percent change from Baseline was computed as (change from baseline / baseline value) * 100%. Percent change from Baseline to month 12 in the volumetric integral, cortical, and trabecular density (BMD) at the hip and lumbar spine measured by QCT were reported. | Baseline (Day 0) and Month 12 | 
| Percent Change From Baseline to Month 12 in the Total Vertebra Integral VOI at the Lumbar Spine as Measured by QCT Scans | QCT is a three-dimensional non-projectional technique to quantify BMD with a number of advantages to other densitometric techniques. Cortical and trabecular bone can be separated, trabecular VOI are largely independent of degenerative changes in the spine and 3 dimensional geometric parameters can be determined. BMD as measured by QCT is a true density measured in g/cm^3 in contrast to DXA Which determines an areal density measured in g/cm^2. Baseline values were assessed on Day 0. Percent change from Baseline was computed as (change from baseline / baseline value) * 100%. | Baseline (Day 0) and Month 12 | 
| Percent Change From Baseline to Month 12 in the Volumetric Integral, Cortical, and Trabecular Density (BMD) at the Hip as Measured by QCT Scans | QCT is a three-dimensional non-projectional technique to quantify BMD with a number of advantages to other densitometric techniques. Cortical and trabecular bone can be separated, trabecular VOI are largely independent of degenerative changes in the spine and 3 dimensional geometric parameters can be determined. BMD as measured by QCT is a true density measured in mg/cm^3 in contrast to DXA Which determines an areal density measured in g/cm^2. Baseline values were assessed on Day 0. Percent change from Baseline was computed as (change from baseline / baseline value) * 100%. | Baseline (Day 0) and Month 12 | 
| Percent Change From Baseline to Month 12 in Cortical Thickness at the Hip as Measured by QCT Scans | Percent change in thickness of femur neck cortical VOI thickness and trochanter cortical VOI thickness were at Month 12 measured by QCT were reported. Assessments performed on Day 0 were considered as Baseline. Percent change from Baseline was computed as (change from baseline / baseline value) * 100%. | Baseline (Day 0) and Month 12 | 
| Biochemical Markers of Bone Turnover: Levels of C-terminal Telopeptide α1 Chain of Type 1 Collagen (CTX1) | Blood samples were collected at Baseline (Day 0), Week 4, Month 3, 6, and 12 for measurement of CTX1. | Baseline (Day 0), Week 4, Month 3, 6, and 12 | 
| Biochemical Markers of Bone Turnover: Procollagen Type 1 N-terminal Propeptide (P1NP) | Blood samples were collected at Baseline (Day 0), Week 4, Month 3, 6, and 12 for measurement of P1NP. | Baseline (Day 0), Week 4, Month 3, 6, and 12 | 
| Biochemical Markers of Bone Turnover: Bone Specific Alkaline Phosphatase (BALP) | Blood samples were collected at Baseline (Day 0), Week 4, Month 3, 6, and 12 for measurement of BALP. | Baseline (Day 0), Week 4, Month 3, 6, and 12 | 
| Blood Concentrations of Ronacaleret | Blood samples were collected and analyzed for concentrations of ronacaleret. The individual blood concentration-time data from the intensive PK-PD subgroup of participants were analyzed by standard noncompartmental methods. Blood concentrations of ronacaleret were reported. | 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 | 
| 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 | Blood samples were collected and analyzed for concentrations of ronacaleret. The individual blood concentration-time data from the intensive pharmacokinetic and pharmacodynamics subgroup of participants were analyzed by standard noncompartmental methods. Blood samples were collected and analyzed for concentrations of ronacaleret. The individual blood concentration-time data from the intensive PK-PD subgroup of participants were analyzed by standard noncompartmental methods. Following log transformation, AUC(0-t) and AUC(0-τ) of ronacaleret were separately analyzed by ANOVA using mixed effects model, fitting treatment and country/region as fixed effects. | 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 | 
| Maximum Blood Concentration (Cmax) of Ronacaleret | Blood samples were collected and analyzed for concentrations of ronacaleret. The individual blood concentration-time data from the intensive pharmacokinetic and pharmacodynamics subgroup of participants were analyzed by standard noncompartmental methods. Blood samples were collected and analyzed for concentrations of ronacaleret. The individual blood concentration-time data from the intensive PK-PD subgroup of participants were analyzed by standard noncompartmental methods. Following log transformation, Cmax of ronacaleret were separately analyzed by ANOVA using mixed effects model, fitting treatment and country/region as fixed effects. | 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 | 
| Time Required to Achieve Maximum Concentration of Ronacaleret in Blood (Tmax) | Blood samples were collected and analyzed for concentrations of ronacaleret. The individual blood concentration-time data from the intensive pharmacokinetic and pharmacodynamics subgroup of participants were analyzed by standard noncompartmental methods. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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osteoporosis,, bone mineral density,, Ronacaleret, teriparatide, alendronate,, Post-menopausal women,, SB-751689