| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Postmenopausal Osteoporosis |
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| E.1.1.1 | Medical condition in easily understood language |
| Postmenopausal Osteoporosis |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10031282 |
| E.1.2 | Term | Osteoporosis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 |
1. To assess the effect of switching alendronate therapy to 5, 7.5 or 10mg MK-5442 daily compared to continued alendronate therapy on lumbar spine areal BMD over 12 months.
2. To assess the safety and tolerability of 5, 7.5, and 10 mg MK 5442 daily compared to placebo over 12 months.
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| E.2.2 | Secondary objectives of the trial |
Effect of switching ALN to MK-5442 daily regime:
1. compared to pbo on LS aBMD over 12 months
2. on LS and BMD compared to continued ALN over 12 months
3. on total hip, femoral neck, trochanter, total body, and 1/3 distal forearm aBMD compared to continued ALN or switching to pbo over 12
Safety and tolerability of MK 5442 daily regime compared to pbo over 12 months
Effect of switching ALN to an MK-5442 daily regime, compared to continued ALN or switching to pbo in a subset of patients over 12 months:
1. on volumetric trabecular and cortical BMD at the LS and hip (assessed by QCT)
2. on biochemical indices of bone turnover (NTx, CTx, BSAP, P1NP), and osteocalcin
PK parameters and conduct PK/PD modeling in patients treated with MK-5442
Effect of 5, 7.5, and 10 mg MK-5442 daily on indices of calcium and mineral homeostasis (Ca, P, PTH, 1,25-dihydroxyvitamin D, 24-hour urine Ca) compared to pbo over 12 months
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| 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.
2. The patient 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 non-vertebral 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 T-scores 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. 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.
8. 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.
Additional inclusion criteria appear in the study protocol.
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| E.4 | Principal exclusion criteria |
1. Has received the following agents with action on bone (all time periods are relative to V1):
(a) IV bisphosphonates at any time in the past
(b) fluoride treatment at a dose greater than 1 mg/day for more than 2 weeks at any time in the past,
(c) strontium at any time in the past,
(d) growth hormone at any time in the past,
(e) any cathepsin K inhibitor, such as MK-0822/odanacatib, at any time in the past,
(f) use of denosumab or any other RANK-L inhibitor at any time in the past,
(g) oral bisphosphonates other than alendronate within the past 12 months
(h) PTH (1-34, or 1-84) at any time within the prior 24 months,
(i) cyclosporin for more than 2 weeks within the prior 6 months,
(j) heparin within the prior 2 weeks,
(k) anabolic steroids or glucocorticoids (≥5 mg/day prednisone or equivalent) for more than 2 weeks in the prior 6 months,
(l) 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 V1, or calcitonin within the prior 30 days.
3. Has used either pioglitazone hydrochloride, or rosiglitazone maleate, within the 6 months prior to V1.
4. 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:
Inhibitors
(a) grapefruit juice
(b) systemically administered azole antifungals such as ketoconazole, fluconazole, itraconazole, miconazole, posaconozole, ravuconazole, and voriconazole,
(c) nefazodone,
(d) the macrolide antibiotics clarithromycin, dirithromycin, erythromycin, and troleandomycin. Azithromycin use is permitted,
(e) protease inhibitors
Inducers
(f) rifampin,
(g) rifabutin,
(h) orally administered dexamethasone,
(i) phenytoin,
(j) any barbiturate, e.g., phenobarbital or primidone,
(k) St. John's Wort.
6. Primary parathyroid disease, or secondary hyperparathyroidism with an elevated PTH.
7. Prior total thyroidectomy.
8. History of Paget's disease of bone.
9. HIV positive or is known to have an AIDS-related illness.
10. History of malignancy ≤ 5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.
11. Evidence of a metabolic bone disorder other than osteopenia or osteoporosis.
12. History of recent major upper gastrointestinal (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) esophageal stricture, achalasia, or severe esophageal motor dysfunction.
13. Myocardial infarction, unstable angina, stroke or revascularization condition within the 3 months prior to V1.
14. The patient has had untreated malabsorption syndrome within the 4 years prior to the V1.
15. History of nephrolithiasis at any time in the past.
16. New-onset diabetes, or poorly controlled hyperglycemia.
17. History of ONJ, or is contemplating or planning a dental extraction, or implantation of a dental prosthetic anchor during the study.
18. Total sCa value outside the normal range.
19. Abnormal TSH.
20. Unexplained elevation in alkaline phosphatase above the upper limit of normal for the central laboratory at V1.
21. AST or an ALT ≥1.5 times the upper limit of normal.
22. Serum creatinine > 1.6 mg/dL.
Additional exclusion criteria appear in the study protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be the change from baselinein lumbar spine areal BMD at 12 months of treatment, with a 6 month interim analysis for safety. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 12 months of treatment, with a 6 month interim analysis for safety. |
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| E.5.2 | Secondary end point(s) |
To assess the effect of switching alendronate therapy to 5, 7.5, or 10 mg MK-5442 daily compared to placebo on lumbar spine areal BMD, on total hip, femoral neck, trochanter, total body, and 1/3 distal
forearm areal BMD, on volumetric trabecular and cortical BMD at the lumbar spine and hip, on biochemical indices of bone turnover (assessed by quantitative computed tomography [QCT]) over 12 months. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
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| 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.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 | No |
| 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 | No |
| 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
| |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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