| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Post-menopausal Osteoporosis |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10031285 |
| E.1.2 | Term | Osteoporosis postmenopausal |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To characterise the dose-response for SB-751689 with respect to safety and efficacy based on BMD and biomarkers of bone turnover to enable dose selection for subsequent studies |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to evaluate safety and tolerability of SB-751689 administered for 12 months in post-menopausal women compared to placebo, alendronate and teriparatide, to demonstrate a statistically significant increase in BMD as measured by DXA at the lumbar spine following 6 and 12 months treatment with SB-751689 compared to placebo and a significant increase in BMD as measured by DXA at the total hip, femoral neck and trochanter following 6 and 12 months treatment with SB-751689.
To investigate the effect of SB-751689 on biomarkers of bone turnover, on volumetric integral, cortical and trabecular density, cortical width and other parameters at the lumbar spine and hip as measured by QCT in a subset of study subjects, the effects on parameters of vertebral and hip strength as measured by QCT-derived finite element analysis, the effects on parameters of hip structural analysis as measured by DXA-derived data and the PK/PD relationship of SB-751689 in this study population. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Informed consent: Subject is willing and able to provide written informed consent.
2. Menopausal status: Ambulatory female aged < 80 years at screening and >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.
3. 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.
Fracture is defined as having a 20% reduction in anterior, middle or posterior vertebral height determined by semi-quantitative DXA examination at the site.
4. Suitable vertebra: Two or more vertebra in the range of L1 to L4 that are suitable for BMD measurement by DXA.
5. Protocol compliance: Subject who, in the opinion of the investigator, is willing and able to comply with the requirements of the protocol.
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. 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.
2. Vertebral fractures: Has >1 prevalent vertebral fracture at the screening visit (where fracture is defined as having a 20% reduction in anterior, middle or posterior vertebral height determined by semi-quantitative DXA examination at the site).
3. Non-vertebral fractures: Any previous non-vertebral osteoporosis related/fragility fracture after age 40.
4. 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 [e.g., human immunodeficiency virus (HIV) infection, chronic hepatitis B and C (as evidenced by positive Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody), significant mental illness].
5. 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.
6. 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).
7. QT/QTc prolongation: A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of QTc interval ≥450 msec on the Screening ECG).
8. Torsades de Pointes: A history of risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
9. Liver chemistries: Liver chemistries [aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase or total bilirubin] exceeding 2-fold the upper limit of the laboratory-specified reference range, at screening.
10. Abnormal serum calcium: Serum calcium (total or albumin-adjusted) outside the central laboratory reference range at the screening visit.
11. Abnormal PTH: PTH (intact and whole) outside the normal range.
12. 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.
13. 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.
14. Previous anabolic agents: Treatment with PTH, PTH analogues or similar anabolic agent for osteoporosis within the last two years.
15. Contraindications: Contraindications to therapy with calcium, vitamin D, or alendronate.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is percent change from baseline in BMD at Month 12 measured by DXA scans of the lumbar spine (L1-L4). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Investigation of toleribility of SB-751689 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| End of trial is last subject last visit |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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