MK-5442 in the Treatment of Osteoporosis in Postmenopausal Women Previously Treated With an Oral Bisphosphonate (MK-5442-012)

Study Overview
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Brief Summary
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This study seeks to demonstrate that additional gain in bone mineral density (BMD) can be achieved by switching to MK-5442 from an oral bisphosphonate in participants who have been receiving oral bisphosphonate therapy for at least 3 years.

Detailed Description
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The study was originally planned for a duration of 2 years and included efficacy analysis of a 15 mg MK-5442 treatment arm. Amendment 1 of the protocol eliminated the 2nd year of the study as well the 15-mg arm. Enrollment into the 15-mg MK-5442 arm was stopped as a result of the amendment and all participants who had been randomly assigned to the MK-5442 15-mg treatment arm were discontinued from the study.

Official Title
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A Phase IIb, Randomized, Double-Blind, Placebo- and Active-Controlled, Dose-Range-Finding Study to Evaluate the Effects of MK-5442 on Bone Mineral Density (BMD) in the Treatment of Osteoporosis in Postmenopausal Women Previously Treated With an Oral Bisphosphonate

Conditions
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Osteoporosis, Postmenopausal Osteoporosis

Intervention / Treatment
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* Drug: MK-5442
* Drug: Placebo to MK-5442
* Drug: Alendronate Sodium
* Drug: Vitamin D3
* Drug: Calcium carbonate
* Drug: Placebo to Alendronate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Taking oral bisphosphonate treatment for osteoporosis for at least 3 of the past 4 years. At present, and for the past 12 months, treated with alendronate Bone Mineral Density (BMD) T-score that is ≤ -1.5 at one or more of the following anatomic sites; lumbar spine, femoral neck, trochanter, and total hip, AND a BMD T-score at all of these sites that is ≥ -4.0, AND a history of at least one fragility fracture, OR, a BMD T-score that is ≤ -2.5 at one or more of the following anatomic sites; lumbar spine, femoral neck, trochanter, and total hip, AND a BMD T-score at all of these sites that is ≥ -4.0 Postmenopausal for at least 5 years Exclusion Criteria: Obesity (ie, weight greater than 250 pounds) that prohibits the use of dual-emission X-ray absorptiometry (DXA) Received intravenous (IV) bisphosphonates, fluoride treatment at a dose >1 mg/day for more than 2 weeks, strontium, growth hormone, a cathepsin K (CTSK) inhibitor, or a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor at any time in the past Use of oral bisphosphonates other than alendronate in the last 12 months, parathyroid hormone (PTH) in the last 24 months, cyclosporin for more than 2 weeks in the last 6 months, heparin in the last 2 weeks, or anabolic steroids or glucocorticoids for more than 2 weeks in the past 6 months Use of estrogen with or without progestin or a selective estrogen receptor modulator (SERM) in the last 6 months or calcitonin in the last 30 days Has used pioglitazone hydrochloride or rosiglitazone hydrochloride in the last 6 months Taking more than 10,000 International Units (IU) vitamin A daily or more than 5,000 IU vitamin D daily Has had a total thyroidectomy History of Paget's disease Has human immunodeficiency virus (HIV) History of cancer in the last 5 years, except certain skin or cervical cancers History of major upper gastrointestinal (GI) mucosal erosive disease Unable to adhere to dosing instructions for alendronate in regard to fasting and positioning Not ambulatory

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received either matching placebo to alendronate (administered orally, once-weekly) or matching placebo to MK-5442 (administered orally, once-daily) for 12 months. Participants also received supplemental vitamin D3 and calcium (as needed) during treatment. | Drug: Placebo to MK-5442<br>* Matching placebo to MK-5442 taken orally, once-daily, for 12 months<br>Drug: Vitamin D3<br>* Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months<br>* Other names: Cholecalciferol;Drug: Calcium carbonate<br>* Participants who qualify (those who have a calcium intake of less than 1200 mg/day) will receive oral supplemental calcium carbonate, at a dose of either 400 mg or 500 mg, once-daily, for 12 months<br>Drug: Placebo to Alendronate<br>* Placebo to alendronate once-weekly for 12 months<br>|
| Experimental: MK-5442 5 mg<br>Participants received 5 mg of MK-5442 (orally, once-daily) plus matching placebo to alendronate (administered orally, once-weekly) for 12 months. Participants also received supplemental vitamin D3 and calcium (as needed) during treatment. | Drug: MK-5442<br>* MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months<br>Drug: Vitamin D3<br>* Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months<br>* Other names: Cholecalciferol;Drug: Calcium carbonate<br>* Participants who qualify (those who have a calcium intake of less than 1200 mg/day) will receive oral supplemental calcium carbonate, at a dose of either 400 mg or 500 mg, once-daily, for 12 months<br>Drug: Placebo to Alendronate<br>* Placebo to alendronate once-weekly for 12 months<br>|
| Experimental: MK-5442 7.5 mg<br>Participants received 7.5 mg of MK-5442 (orally, once-daily) plus matching placebo to alendronate (administered orally, once-weekly) for 12 months. Participants also received supplemental vitamin D3 and calcium (as needed) during treatment. | Drug: MK-5442<br>* MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months<br>Drug: Vitamin D3<br>* Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months<br>* Other names: Cholecalciferol;Drug: Calcium carbonate<br>* Participants who qualify (those who have a calcium intake of less than 1200 mg/day) will receive oral supplemental calcium carbonate, at a dose of either 400 mg or 500 mg, once-daily, for 12 months<br>Drug: Placebo to Alendronate<br>* Placebo to alendronate once-weekly for 12 months<br>|
| Experimental: MK-5442 10 mg<br>Participants received 10 mg of MK-5442 (orally, once-daily) plus matching placebo to alendronate (administered orally, once-weekly) for 12 months. Participants also received supplemental vitamin D3 and calcium (as needed) during treatment. | Drug: MK-5442<br>* MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months<br>Drug: Vitamin D3<br>* Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months<br>* Other names: Cholecalciferol;Drug: Calcium carbonate<br>* Participants who qualify (those who have a calcium intake of less than 1200 mg/day) will receive oral supplemental calcium carbonate, at a dose of either 400 mg or 500 mg, once-daily, for 12 months<br>Drug: Placebo to Alendronate<br>* Placebo to alendronate once-weekly for 12 months<br>|
| Experimental: MK-5442 15 mg<br>Participants received 15 mg of MK-5442 (orally, once-daily) plus matching placebo to alendronate (administered orally, once-weekly) for 12 months. Participants also received supplemental vitamin D3 and calcium (as needed) during treatment. | Drug: MK-5442<br>* MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months<br>Drug: Vitamin D3<br>* Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months<br>* Other names: Cholecalciferol;Drug: Calcium carbonate<br>* Participants who qualify (those who have a calcium intake of less than 1200 mg/day) will receive oral supplemental calcium carbonate, at a dose of either 400 mg or 500 mg, once-daily, for 12 months<br>Drug: Placebo to Alendronate<br>* Placebo to alendronate once-weekly for 12 months<br>|
| Active Comparator: Alendronate 70 mg<br>Participants received 70 mg alendronate (orally, once-weekly) plus matching placebo to MK-5442 (administered orally, once-daily) for 12 months. Participants also received supplemental vitamin D3 and calcium (as needed) during treatment. | Drug: Placebo to MK-5442<br>* Matching placebo to MK-5442 taken orally, once-daily, for 12 months<br>Drug: Alendronate Sodium<br>* Alendronate tablets 70 mg, taken orally, once-weekly, for 12 months<br>* Other names: FOSAMAX®;Drug: Vitamin D3<br>* Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months<br>* Other names: Cholecalciferol;Drug: Calcium carbonate<br>* Participants who qualify (those who have a calcium intake of less than 1200 mg/day) will receive oral supplemental calcium carbonate, at a dose of either 400 mg or 500 mg, once-daily, for 12 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Squares Mean Percent Change From Baseline To Month 12 in Lumbar Spine Areal Bone Mineral Density (BMD) | Areal bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DXA) scanning technology. Scanning is performed with two X-ray beams with different energy levels which are aimed at the participant's bones. When soft tissue absorption is subtracted out, the BMD is determined from the absorption of each beam by bone. BMD = BMC / W, where BMD = bone mineral density in g/cm^2, BMC = bone mineral content in g/cm, and W = width at the scanned line in cm | Baseline and Month 12 | 
| Number of Participants With Trough Serum Calcium Level Exceeding Predefined Limits At Least Once | Normal serum calcium level is 8-10 mg/dL (2-2.5 mmol/L) with some interlaboratory variation in the reference range, and hypercalcemia is defined as a serum calcium level greater than 10.5 mg/dL (>2.5 mmol/L). Based on these references, ≥10.6 mg/dL was predefined in this study as the cut-off for the normal limits of change. Participants with at least a one calcium level value ≥10.6 mg/dL were considered as having a Tier 1 adverse event (AE). A Tier 1 AE was an AE of special interest identified a priori that could be used for inferential testing for statistical significance for between-group comparisons. | Baseline through Month 12 | 
| Number of Participants With Trough Albumin-Corrected Calcium Level Exceeding Predefined Limits At Least Once | Albumin-Corrected Calcium = ([4 - plasma albumin in g/dL] × 0.8 + serum calcium). ≥10.6 mg/dL was predefined in this study as the cut-off for the normal limits of change. Participants with at least one albumin-corrected calcium level value ≥10.6 mg/dL were considered as having a Tier 1 AE (an AE of special interest identified a priori that could be used for inferential testing for statistical significance for between-group comparisons). | Baseline through Month 12 | 
| Number of Participants With Predefined Tier 1 Adverse Events | Osteonecrosis of the jaw (ONJ), kidney stones, and bone neoplasms were predefined Tier-1 AEs in the study (an AE of special interest identified a priori that could be used for inferential testing for statistical significance for between-group comparisons). | Baseline through Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Squares Mean Percent Change From Baseline to Month 12 in Total Hip Areal BMD | Areal bone mineral density (BMD) was measured using DXA scanning technology. Scanning is performed with two X-ray beams with different energy levels which are aimed at the participant's bones. When soft tissue absorption is subtracted out, the BMD is determined from the absorption of each beam by bone. BMD = BMC / W, where BMD = bone mineral density in g/cm^2, BMC = bone mineral content in g/cm, and W = width at the scanned line in cm | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in Femoral Neck Areal BMD | Areal bone mineral density (BMD) was measured using DXA scanning technology. Scanning is performed with two X-ray beams with different energy levels which are aimed at the participant's bones. When soft tissue absorption is subtracted out, the BMD is determined from the absorption of each beam by bone. BMD = BMC / W, where BMD = bone mineral density in g/cm^2, BMC = bone mineral content in g/cm, and W = width at the scanned line in cm | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in Trochanter Areal BMD | Areal bone mineral density (BMD) was measured using DXA scanning technology. Scanning is performed with two X-ray beams with different energy levels which are aimed at the participant's bones. When soft tissue absorption is subtracted out, the BMD is determined from the absorption of each beam by bone. BMD = BMC / W, where BMD = bone mineral density in g/cm^2, BMC = bone mineral content in g/cm, and W = width at the scanned line in cm | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in Total Body Areal BMD | Areal bone mineral density (BMD) was measured using DXA scanning technology. Scanning is performed with two X-ray beams with different energy levels which are aimed at the participant's bones. When soft tissue absorption is subtracted out, the BMD is determined from the absorption of each beam by bone. BMD = BMC / W, where BMD = bone mineral density in g/cm^2, BMC = bone mineral content in g/cm, and W = width at the scanned line in cm | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in 1/3 Distal Forearm Areal BMD | Areal bone mineral density (BMD) was measured using DXA scanning technology. Scanning is performed with two X-ray beams with different energy levels which are aimed at the participant's bones. When soft tissue absorption is subtracted out, the BMD is determined from the absorption of each beam by bone. BMD = BMC / W, where BMD = bone mineral density in g/cm^2, BMC = bone mineral content in g/cm, and W = width at the scanned line in cm | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in Trabecular Volumetric BMD (vBMD) of the Lumbar Spine | vBMD was measured using quantitative computed tomography (QCT) in order to assess bone strength. Quantitative computed tomography is a three-dimensional non-projectional technique that quantifies trabecular and cortical BMD in the lumbar spine and hip as a true volumetric mineral density in g/cm^3. | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in Trabecular Volumetric BMD of the Hip | vBMD was measured using QCT in order to assess bone strength. QCT is a three-dimensional non-projectional technique that quantifies trabecular and cortical BMD in the lumbar spine and hip as a true volumetric mineral density in g/cm^3. | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in Cortical Volumetric BMD of the Lumbar Spine | vBMD was measured using QCT in order to assess bone strength. QCT is a three-dimensional non-projectional technique that quantifies trabecular and cortical BMD in the lumbar spine and hip as a true volumetric mineral density in g/cm^3. | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in Cortical Volumetric BMD of the Hip | vBMD was measured using QCT in order to assess bone strength. QCT is a three-dimensional non-projectional technique that quantifies trabecular and cortical BMD in the lumbar spine and hip as a true volumetric mineral density in g/cm^3. | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in Urinary-N Telopeptides of Type 1 Collagen (u-NTx) | Urinary, type I collagen, crosslinked N-telopeptide (uNTx) is a biomarker used to measure the rate of bone turnover found in urine. uNTx was expressed in units of nanomoles (nM) per bone collagen equivalents (BCE) per millimoles of creatinine (Cr) or nM/BCE/mM Cr | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in Serum C-Terminal Propeptide of Type 1 Collagen (s-CTx) | C-Terminal Telopeptide Collagen I is used as a serum-marker of bone resorption in the assessment of osteoporosis and in measured in units of nanograms (n)/milliliter (ml). | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in Serum N-Terminal Propeptide (s-P1NP) | s-P1NP is a sensitive marker of bone formation rate in the assessment of osteoporosis and is measured in units of ng/ml. | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in Serum Bone-Specific Alkaline Phosphatase (s-BSAP) | Bone Specific Alkaline Phosphatase is a biomarker of bone formation and is measured in units of μg/L. | Baseline and Month 12 | 
| Least Squares Mean Percent Change From Baseline to Month 12 in Serum Osteocalcin | Serum osteocalcin is a biomarker of bone formation and is measured using units of nanograms (ng) / milliliter (mL). | Baseline and Month 12 |