| 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 |
| To assess the effects of daily oral doses of MK-5442 (2.5, 5, 7.5, 10 or 15 mg) versus placebo for one and two years on areal bone mineral density (aBMD) of the spine, and general safety in postmenopausal women with low-normal BMD or osteoporosis. |
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| E.2.2 | Secondary objectives of the trial |
| To measure relevant pharmacokinetic parameters and conduct pharmacokinetics/pharmacodynamic modeling in patients treated with MK-5442. To assess the treatment effect of MK-5442 daily on non-Japanese post-menopausal women relative to a similar patient population studied in Japanese women in Protocol ABA3-1.To assess the effects of daily oral doses of MK-5442 (2.5, 5, 7.5, 10 or 15 mg) versus placebo for one and two years on areal bone mineral density (aBMD) of the hip, volumetric bone mineral density of the spine and hip, biochemical markers of bone turnover, and indices of calcium metabolism in postmenopausal women with low-normal BMD or osteoporosis. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| The patient is a woman 45 to 85 years of age, inclusive. Has been postmenopausal for 5 years, defined as no menses for at least 5 years, OR at least 5 years status post bilateral oophorectomy. The patient has no fragility fracture (including any vertebral fracture), documented by medical record, or detected on the screening spine radiographs read locally, unless the patient is unwilling to take, or is not a candidate for marketed osteoporosis therapy. Patient has a BMD T-score <-2.5 at one or more of the following anatomic sites, lumbar spine, femoral neck, trochanter, and total hip, measured at screening by the central imaging vendor, and BMD T-scores ≥ -3.5 at all of these 4 BMD sites, with or without a prior vertebral or non-vertebral fragility fracture. 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. Patient is not having QCT conducted in this study, or if patient is having QCT conducted in this study she has a body mass index (BMI) that permits CT images of good quality to be obtained (defined as BMI ≤ 35 kg/m2). The patient has a 25-hydroxyvitamin D level 15 ng/mL. During the placebo run-in period, patient took the placebo, calcium supplement (if dispensed during the placebo run-in), and the vitamin D3 supplement, and followed the method of dosing instructions on at least 11 of the 14 days. Patients may also receive vitamin D supplementation prior to alkaline phosphatase and PTH retesting during the screening period (alkaline phosphatase and PTH may be retested once during the screening period)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 and agrees not to use medications for the treatment of osteoporosis |
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| E.4 | Principal exclusion criteria |
Patient is unable to have DXA performed due to obesity, defined as weight >250 lbs or >113 Kg. Has received any agents with action on bone including, but not limited to the following (all time periods are relative to Visit 1): IV bisphosphonates (e.g., zoledronic acid), fluoride treatment at a dose greater than 1 mg/day for more than 2 weeks, strontium , growth hormone, any cathepsin K inhibitor, such as MK-0822/odanacatib, use of denosumab or any other RANK-L inhibitor , oral bisphosphonates (use of any oral bisphosphonate in the 6 months prior to screening, use of any oral bisphosphonate for more than 3 months in the prior 2 years, or lifetime use of more than 6 months total), PTH (1-34, or 1-84) at any time within the prior 24 months, cyclosporin for more than 2 weeks within the prior 6 months, heparin within the prior 2 weeks, anabolic steroids or glucocorticoids ( 5 mg/day prednisone or equivalent) for more than 2 weeks in the prior 6 months. 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. Used either pioglitazone hydrochloride, or rosiglitazone maleate, within the 6 months prior to Visit 1. Currently taking vitamin A (excluding beta carotene) >10,000 IU daily, or vitamin D >5,000 IU daily, and is not willing to reduce their vitamin A dose to 10,000 IU daily, and their vitamin D dose to 2000 IU daily. Has primary parathyroid disease, or secondary hyperparathyroidism with an elevated PTH in conjunction with total serum calcium greater than the upper limit of normal (as measured by the central laboratory). Has had prior total thyroidectomy (patient with a hemithyroidectomy may be included. The patient has an abnormal TSH (as measured by the central laboratory). The TSH may be repeated once by the central laboratory during the screening period. Enrollment will be based on the repeat TSH value. If the repeat TSH is <lower limit of normal (as measured by the central laboratory), the patient is not eligible. If the repeat TSH is >upper limit of normal in a subject with known hypothyroidism, she is eligible provided that no change in thyroxine replacement is required. Patients with abnormal TSH who are on thyroid medication (anti-thyroid medication or thyroxine replacement), may be rescreened after the treatment has been adjusted and the patient’s condition has stabilized (defined by a normal TSH at least 6 weeks after the change in medication). Patients with newly diagnosed thyroid conditions are not eligible. Has any history of Paget’s disease of bone. Has an unexplained elevation in alkaline phosphatase or a total serum calcium value or serum PTH value above the upper limit of normal, or an AST (aspartate aminotransferase) or an ALT (alanine aminotransferase) 1.5 times the upper limit of normal. Has hypocalcemia as defined as a total serum calcium <8.5 mg/dL
Patient anticipates the use of any of the following potent inhibitors or potent inducers of CYP3A4 within 2 weeks prior to starting blinded study medication: 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); protease inhibitors.
Patients who discontinue these medications, and/or grapefruit juice, at least two weeks prior to starting blinded study medication eligible: rifampin; rifabutin; orally administered dexamethasone; phenytoin; any barbiturate, e.g., phenobarbital or primidone; St. John’s wort.
Patients who discontinue these medications at least two weeks prior to starting blinded study medication and do not plan their use during the study are eligible.
The patient has significant clinical or laboratory abnormalities at the screening visit that, in the opinion of the investigator, or SPONSOR, could complicate interpretation of the study results. Has a serum creatinine > 1.6 mg/dL. Is known to be HIV positive or is known to have an AIDS-related illness. Has a history of malignancy 5 years prior to signing the informed consent, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer. Has evidence of a metabolic bone disorder other than osteopenia or osteoporosis (e.g., rickets, osteomalacia). In the opinion of the investigator, unable to provide informed consent due to mental incapacitation. Has participated in an investigational drug study within the past 30 days. Is currently a user of any illicit drug and/or has a history of alcohol abuse. Patient has a history of nephrolithiasis at any time in the past.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Lumbar spine areal BMD – Percent Change from baseline at Month 12 and 24. |
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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 | Yes |
| 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 | 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 | Yes |
| 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) | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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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| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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