| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of Osteoporosis in Postmenopausal Women |
|
| 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 |
To assess the effect of switching alendronate therapy to 5, 7.5, 10, or
15 mg MK-5442 daily compared to continued alendronate therapy on lumbar spine
areal BMD over 12 months. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the effect of switching alendronate therapy to 5, 7.5, or 10
mg MK-5442 daily:
1, 2 & 3) on lumbar spine areal BMD compared to placebo over 12 months or continued alendronate therapy over 12 months.
5, 6 & 7)on total hip, femoral neck, trochanter, total body, and 1/3 distal
forearm areal BMD, volumetric trabecular and cortical BMD at the lumbar spine
and hip (assessed by [QCT]), biochemical indices of bone turnover [urinary N-telopeptides of type I collagen (u-NTx), serum C-telopeptides of type I collagen (s-CTx), serum bone specific alkaline phosphatase (s-BSAP), serum N-terminal propeptide of type 1 collagen (s-P1NP)], and osteocalcin compared to continued alendronate therapy or switching to placebo over 12 months.
4) To assess the safety and tolerability of MK-5442 compared to placebo over 12 months.
8) To measure relevant pharmacokinetic parameters and conduct
pharmacokinetics/pharmacodynamic modeling in patients treated with MK-5442. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The patient is a woman 45 to 85 years of age, inclusive and has been postmenopausal for 5 years, defined as no menses for at least 5 years, OR at least 5 years status post bilateral oophorectomy.
3. The patient is currently taking alendronate for treatment of osteoporosis (either 70 mg once weekly with or without vitamin D3, or 10 mg daily), and has taken alendronate during the 12 consecutive months prior to Visit 1 (and no other bisphosphonate). In addition, the patient has taken bisphosphonates for treatment of osteoporosis for at least 3 years within the 4 years prior to screening (i.e. while in the 1st year prior to screening the bisphosphonate must be alendronate, for the 2nd, 3rd, and 4th years prior to screening the patient could have taken any one or combination of oral bisphosphonates for at least 2 of those 3 years).
4. Patients must have been approximately 80% compliant with either once-weekly or
daily alendronate during the 12 consecutive months prior to Visit 1, and therefore, to
the best of their recollection, may not have missed a total of more than 12 weekly
doses during the past year, or a total of more than 73 daily doses during that time.
5. The patient has, at screening either: (1) an areal BMD T-score -2.5 at one or more
of the lumbar spine, femoral neck, trochanter, or total hip, and a BMD T-score at all
of these sites that is -4.0, with or without a history of a prior vertebral or nonvertebral fragility fracture; OR (2) an areal BMD T-score -1.5 at one or more of
these 4 sites, and a BMD T-score at all of these sites that is -4.0, and at least one
prior vertebral or non-vertebral fragility fracture documented by medical record, or
detected on the screening spine radiographs by the local radiologist. Only the Tscores provided by the central imaging vendor can be used to determine eligibility.
Hip BMD measurements should be performed on the left hip only, unless the left hip
is not evaluable.
6. Patient has no increased risk of bone cancer due to any reason, such as a history of skeletal malignancy at any time, or a history of therapeutic irradiation.
7. Patient’s weight or body mass index (BMI) at screening does not preclude the
acquisition of DXA and CT images of good quality.
8. The patient has a 25-hydroxyvitamin D level as measured by the central laboratory of 15 ng/mL. Note: If the 25-hydroxyvitamin D level is 9 and <15 ng/mL, she may enter if her alkaline phosphatase and PTH levels, as measured by the central laboratory, are normal. Note: Patients with a serum 25-hydroxyvitamin D level (as measured by the central laboratory) that does not qualify for this study may have it retested once during the screening period.
9. The patient has a serum PTH value at screening that does not exceed the upper limit of normal (as measured by the central laboratory). Note: Patients with a serum PTH value above the upper limit of normal as measured by the central laboratory may have their serum PTH retested once during the screening period if the investigator believes the elevation is due to a low 25-hydroxyvitamin D. In that case, the patient should be supplemented with vitamin D before the PTH retest.
10. During the run-in period, patient took the placebo for MK-5442, and the calcium
supplement (if dispensed during the run-in period), on at least 11 of the 14 days (i.e., approximately 80% of the time) . Patients who fail this entrance criterion may not have the run-in period repeated unless specifically approved by the SPONSOR.
11. During the run-in period, patient took both tablets of alendronate 70 mg (one tablet each week), and took all 4 tablets of the vitamin D3 supplement (two tablets each week) following the dosing instructions described in Section 3.2.5. Patients who fail this entrance criterion may not have the run-in period repeated unless specifically approved by the SPONSOR.
12. The patient understands the procedures of the study, has been informed of potential alternative treatments for osteoporosis, and is willing to give written informed consent for participation.
13. The patient agrees not to use medications for the treatment of osteoporosis (except as provided through this study) for the duration of her participation in the trial. |
|
| E.4 | Principal exclusion criteria |
1. Has received the following agents with action on bone : IV bisphosphonates (e.g., zoledronic acid) ; strontium; growth hormone; any cathepsin K inhibitor, such as MK-0822/odanacatib; use of denosumab or any other RANK-L inhibitor; fluoride treatment at a dose greater than 1 mg/day for more than 2 weeks at any time in the past; oral bisphosphonates other than alendronate within the past 12 months; PTH (1-34, or 1-84) at any time within the prior 24 months; cyclosporin, anabolic steroids or glucocorticoids ( 5 mg/day prednisone or equivalent) for more than 2 weeks within the prior 6 months; heparin within the prior 2 weeks; prescription soy isoflavones (e.g., Genistein, Diadzein, IsofemTM) used to treat osteoporosis within the prior 6 months
2. Has used estrogen ± progestin, raloxifene, tamoxifen, tibolone or another selective estrogen receptor modulator (SERM) within the 6 months prior to Visit 1, or calcitonin within the prior 30 days. (Note: vaginal estrogen creams used topically once or twice weekly are permitted.)
3.Has used either pioglitazone hydrochloride, or rosiglitazone maleate,
within the 6 months prior to Visit 1.
4. Is currently taking vitamin A (excluding beta carotene) >10,000 IU daily, or vitamin D >5,000 IU daily, and is not willing to reduce her vitamin A dose to
10,000 IU daily, and her vitamin D dose to an equivalent of 2000 IU daily
(including the weekly vitamin D supplementation being provided for this study)
during the study.
5. Anticipates the use of any of the following potent inhibitors or potent inducers of CYP3A4 within 2 weeks prior to randomization or during the study:
grapefruit juice; systemically administered azole antifungals such as ketoconazole, fluconazole; itraconazole, miconazole, posaconozole, ravuconazole, and voriconazole; nefazodone; the macrolide antibiotics clarithromycin, dirithromycin, erythromycin, and troleandomycin; (Azithromycin use is permitted (the use of any other macrolide antibiotic requires approval by the SPONSOR); protease inhibitors; rifampin; rifabutin; orally administered dexamethasone; phenytoin; any barbiturate, e.g., phenobarbital or primidone; St. John’s Wort. Patients who discontinue these medications/grapefruit juice at least two weeks prior to randomization and do not plan their use during the study are eligible.
6. Has primary parathyroid disease, or secondary hyperparathyroidism with an elevated PTH. (Note: patients with a history of primary hyperparathyroidism and with curative partial parathyroidectomy 2 years prior to the screening visit are not excluded).
7. Has had prior total thyroidectomy (patient with a hemithyroidectomy may be included).
8. Has any history of Paget’s disease of bone or evidence of a metabolic bone disorder other than osteopenia or osteoporosis.
9. Is known to be HIV positive or is known to have an AIDS-related illness.
10. Has a history of malignancy 5 years prior except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.
11. Has a history of recent major upper GI mucosal erosive disease as defined by (a) significant upper GI bleeding within the previous year resulting in hospitalization and/or transfusion; (b) recurrent ulcer disease documented by radiographic or endoscopic means (2 episodes in the last 2 years, or any documented ulcer in the preceding 3 months); (c) uncontrolled dyspepsia being treated on a daily basis; (d) esophageal or gastric variceal disease; or (e) oesophageal stricture, achalasia, or severe esophageal motor dysfunction.
13.Has had a myocardial infarction, unstable angina, stroke or revascularization
condition within the 3 months prior to Visit 1.
14. Has had untreated malabsorption syndrome within the 4 years prior to Visit 1.
15. Has a history of nephrolithiasis at any time in the past.
16. Has new-onset diabetes (within 3 months prior to Visit 1), or poorly controlled hyperglycemia.
17. Has a history of osteonecrosis of the jaw, or is contemplating or planning a dental extraction, or implantation of a dental prosthetic anchor during the entire
duration of study.
18. Has a total serum calcium value outside the normal range (as measured by the central laboratory).
19. Has an abnormal TSH (as measured by the central laboratory).
20. Has an unexplained elevation in alkaline phosphatase above the upper limit of
normal for the central laboratory at the screening visit.
21. Has an AST (aspartate aminotransferase) or an ALT (alanine
aminotransferase) 1.5 times the upper limit of normal (as measured by the central
laboratory).
22. Has a serum creatinine > 1.6 mg/dL.
23. Has significant clinical or laboratory abnormalities at the screening visit
for the study that, in the opinion of the investigator, or SPONSOR, could complicate
interpretation of the study results or pose additional risk to the patient.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change from baseline in lumbar spine areal BMD |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
|
| 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
|
| Last visist of last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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