| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| 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 |
| The primary objective is to demonstrate significant improvement in areal lumbar spine BMD in at least one SB-462795 treatment group compared to placebo. |
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| E.2.2 | Secondary objectives of the trial |
• Determine an effective dose range for SB-462795 to enable dose selection for subsequent efficacy studies
• Assess the safety & tolerability of SB-462795.
• Estimate effects of SB-462795 on volumetric density of cortical and trabecular bone and cortical width and volume at the lumbar spine and hip.
• Assess effects of SB-462795 on areal hip BMD.
• Evaluate the effects of SB-462795 on bone resorption and formation markers.
• Assess effects of SB-462795 on parameters of cortical and trabecular bone quality based on the bone biopsies using histomorphometry and micro computed tomography (µCT).
• Assess pharmacokinetic (PK) effects of SB-462795 through population PK.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Subjects who have signed informed consent.
2. Ambulatory postmenopausal women <80 years of age at screening. (Postmenopausal is defined as 3 years of spontaneous amenorrhea or 1 year post surgical bilateral oophorectomy at baseline. In those cases where bilateral oophorectomy status is uncertain, follicle stimulating hormone [FSH] levels >40 mIU/ml can be used to confirm surgical postmenopausal status).
3. Subjects who, in the opinion of the investigator, are willing and able to comply with the protocol requirements.
4. BMD T-Score ≤-2.0 at the femoral neck, total hip, or lumbar spine at the Screening visit. All subjects must have BMD T-scores > -3.5 at all three sites at the Screening visit.
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| E.4 | Principal exclusion criteria |
1. Any previous osteoporotic fracture or previously documented Grade 2 or worse prevalent vertebral fracture or one or more Grade 2 or 3 vertebral fracture(s) identified by baseline vertebral fracture assessment (VFA) of the spine.
2. Less than three vertebra in the range of L1 to L4 that are suitable for BMD measurement by DXA.
3. Significant spine deformity which would preclude VFA assessment.
4. History of hip surgery resulting in a metal implant which would cause artifact on a CT scan.
5. Subjects with a history of, or ongoing diffuse collagen related diseases or autoimmune related diseases
6. Subjects with localized morphea or Raynaud’s phenomenon.
7. A marked baseline prolongation of QT/QTc interval
8. A history of additional risk factors for Torsades de Pointes
9. Any clinically relevant biological abnormality found 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
10. Malignant disease diagnosed within the previous 5 years (except resected basal cell cancer).
11. History of major upper gastrointestinal disease defined by:
• Significant upper gastrointestinal bleeding within the last year requiring hospitalization or transfusion;
• Recurrent peptic ulcer disease documented by radiographic or endoscopic means;
• Dyspepsia or gastroesophageal reflux that is uncontrolled by medication;
• Abnormalities of the esophagus that delay esophageal emptying, such as stricture, achalasia, or dysmotility;
• Active gastric/duodenal ulcers;
• Subjects are not excluded because of previous or active gastrointestinal disease , except as outlined above.
12. Malabsorption syndrome
13. Inability to swallow a tablet whole.
14. Contraindications to therapy with calcium, vitamin D or alendronate.
15. Administration of any investigational drug within 90 days preceding the first dose of the study drug.
16. History or current evidence of drug or alcohol abuse within the previous 12 months.
17. Other than osteoporosis, history or concurrent diseases affecting bone metabolism. Subjects receiving thyroid hormone replacement therapy must be on a stable dosing regimen for at least 3 months prior to screening.
18. 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
19. Any previous treatment with intravenous bisphosphonate.
20. Treatment with strontium ranelate within the past year.
21. Treatment with fluoride for osteoporosis (dose greater than 10mg/day) within the last 12 months, or past treatment for more than a total of two years.
22. Treatment with PTH or similar anabolic agent for osteoporosis within the last two years.
23. Treatment with other drugs affecting bone metabolism within the last six months prior to screening:
• chronic systemic corticosteroid treatment (oral, parenteral, intra-articular, or long-term, high-dose inhaled) except for topical treatment at a frequency of up to twice per week
• hormones [e.g., estrogens/"natural estrogen preparations"(except for topical treatment at a frequency of up to twice per week), 19-norprogestins, SERM 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 or methotrexate
24. Vitamin A in excess of 10,000 IU per day, calcitonin, phenytoin, heparin, or lithium
25. Vitamin D deficiency (serum 25-hydroxy vitamin D < 20 ng/mL, equivalent to 50nmol/L) at screening.
26. Liver chemistries exceeding 2-fold the upper limit of the laboratory-specified reference range, at screening.
27. Past or current history of liver disease or known hepatic or biliary abnormalities, (with the exception of previously documented diagnosis of Gilbert's syndrome).
28. Serum total calcium outside the central laboratory reference range.
29. Glomerular filtration rate (GFR) <30 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation as follows:
• GFR (mL/min/1.73 m2) = 186 x (screening visit)-1.154 x (Age) - 0.203 x (0.742 if female) x (1.210 if African American) (conventional units).
30. Subjects with the following conditions within six months prior to screening: myocardial infarction, coronary bypass surgery, unstable angina, cardiac arrhythmia, clinically evident congestive heart failure, or cerebrovascular accident.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from Baseline BMD at Month 12, as measured by DXA scans of the lumbar spine (L1-L4). |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | Information not present in EudraCT |
| 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 | No |
| 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 | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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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| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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