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

January 21, 2016 updated by: Merck Sharp & Dohme LLC

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

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.

Study Overview

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

526

Phase

  • Phase 2

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
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.
Matching placebo to MK-5442 taken orally, once-daily, for 12 months
Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months
Other Names:
  • Cholecalciferol
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
Placebo to alendronate once-weekly for 12 months
Experimental: MK-5442 5 mg
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.
Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months
Other Names:
  • Cholecalciferol
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
Placebo to alendronate once-weekly for 12 months
MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months
Experimental: MK-5442 7.5 mg
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.
Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months
Other Names:
  • Cholecalciferol
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
Placebo to alendronate once-weekly for 12 months
MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months
Experimental: MK-5442 10 mg
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.
Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months
Other Names:
  • Cholecalciferol
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
Placebo to alendronate once-weekly for 12 months
MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months
Experimental: MK-5442 15 mg
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.
Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months
Other Names:
  • Cholecalciferol
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
Placebo to alendronate once-weekly for 12 months
MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months
Active Comparator: Alendronate 70 mg
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.
Matching placebo to MK-5442 taken orally, once-daily, for 12 months
Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months
Other Names:
  • Cholecalciferol
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
Alendronate tablets 70 mg, taken orally, once-weekly, for 12 months
Other Names:
  • FOSAMAX®

What is the study measuring?

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)
Time Frame: Baseline and Month 12

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
Time Frame: Baseline through Month 12

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
Time Frame: Baseline through Month 12

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
Time Frame: Baseline through Month 12
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
Time Frame: Baseline and Month 12

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
Time Frame: Baseline and Month 12

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
Time Frame: Baseline and Month 12

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
Time Frame: Baseline and Month 12

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
Time Frame: Baseline and Month 12

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
Time Frame: Baseline and Month 12
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
Time Frame: Baseline and Month 12
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
Time Frame: Baseline and Month 12
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
Time Frame: Baseline and Month 12
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)
Time Frame: Baseline and Month 12

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)
Time Frame: Baseline and Month 12
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)
Time Frame: Baseline and Month 12
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)
Time Frame: Baseline and Month 12
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
Time Frame: Baseline and Month 12

Serum osteocalcin is a biomarker of bone formation and is measured using units of nanograms (ng) / milliliter

(mL).

Baseline and Month 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2009

Primary Completion (Actual)

June 1, 2011

Study Completion (Actual)

June 1, 2011

Study Registration Dates

First Submitted

October 15, 2009

First Submitted That Met QC Criteria

October 15, 2009

First Posted (Estimate)

October 16, 2009

Study Record Updates

Last Update Posted (Estimate)

January 22, 2016

Last Update Submitted That Met QC Criteria

January 21, 2016

Last Verified

January 1, 2016

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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