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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00996801
First received: October 15, 2009
Last updated: November 7, 2014
Last verified: November 2014
  Purpose

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.


Condition Intervention Phase
Osteoporosis
Postmenopausal Osteoporosis
Drug: MK-5442
Drug: Placebo to MK-5442
Drug: Alendronate Sodium
Drug: Vitamin D3
Drug: Calcium carbonate
Drug: Placebo to Alendronate
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Least Squares Mean Percent Change From Baseline To Month 12 in Lumbar Spine Areal Bone Mineral Density (BMD) [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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


  • Number of Participants With Trough Serum Calcium Level Exceeding Predefined Limits At Least Once [ Time Frame: Baseline through Month 12 ] [ Designated as safety issue: Yes ]

    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.


  • Number of Participants With Trough Albumin-Corrected Calcium Level Exceeding Predefined Limits At Least Once [ Time Frame: Baseline through Month 12 ] [ Designated as safety issue: Yes ]

    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).


  • Number of Participants With Predefined Tier 1 Adverse Events [ Time Frame: Baseline through Month 12 ] [ Designated as safety issue: Yes ]
    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).


Secondary Outcome Measures:
  • Least Squares Mean Percent Change From Baseline to Month 12 in Total Hip Areal BMD [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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


  • Least Squares Mean Percent Change From Baseline to Month 12 in Femoral Neck Areal BMD [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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


  • Least Squares Mean Percent Change From Baseline to Month 12 in Trochanter Areal BMD [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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


  • Least Squares Mean Percent Change From Baseline to Month 12 in Total Body Areal BMD [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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


  • Least Squares Mean Percent Change From Baseline to Month 12 in 1/3 Distal Forearm Areal BMD [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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


  • 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 ] [ Designated as safety issue: No ]
    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.

  • Least Squares Mean Percent Change From Baseline to Month 12 in Trabecular Volumetric BMD of the Hip [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
    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.

  • Least Squares Mean Percent Change From Baseline to Month 12 in Cortical Volumetric BMD of the Lumbar Spine [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
    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.

  • Least Squares Mean Percent Change From Baseline to Month 12 in Cortical Volumetric BMD of the Hip [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]

    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


  • 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 ] [ Designated as safety issue: No ]
    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).

  • Least Squares Mean Percent Change From Baseline to Month 12 in Serum N-Terminal Propeptide (s-P1NP) [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
    s-P1NP is a sensitive marker of bone formation rate in the assessment of osteoporosis and is measured in units of ng/ml.

  • Least Squares Mean Percent Change From Baseline to Month 12 in Serum Bone-Specific Alkaline Phosphatase (s-BSAP) [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
    Bone Specific Alkaline Phosphatase is a biomarker of bone formation and is measured in units of μg/L.

  • Least Squares Mean Percent Change From Baseline to Month 12 in Serum Osteocalcin [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

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

    (mL).



Enrollment: 526
Study Start Date: November 2009
Study Completion Date: June 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Placebo to MK-5442
Matching placebo to MK-5442 taken orally, once-daily, for 12 months
Drug: Vitamin D3
Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months
Other Name: Cholecalciferol
Drug: Calcium carbonate
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
Drug: Placebo to Alendronate
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.
Drug: MK-5442
MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months
Drug: Vitamin D3
Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months
Other Name: Cholecalciferol
Drug: Calcium carbonate
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
Drug: Placebo to Alendronate
Placebo to alendronate once-weekly 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.
Drug: MK-5442
MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months
Drug: Vitamin D3
Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months
Other Name: Cholecalciferol
Drug: Calcium carbonate
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
Drug: Placebo to Alendronate
Placebo to alendronate once-weekly 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.
Drug: MK-5442
MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months
Drug: Vitamin D3
Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months
Other Name: Cholecalciferol
Drug: Calcium carbonate
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
Drug: Placebo to Alendronate
Placebo to alendronate once-weekly 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.
Drug: MK-5442
MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months
Drug: Vitamin D3
Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months
Other Name: Cholecalciferol
Drug: Calcium carbonate
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
Drug: Placebo to Alendronate
Placebo to alendronate once-weekly 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.
Drug: Placebo to MK-5442
Matching placebo to MK-5442 taken orally, once-daily, for 12 months
Drug: Alendronate Sodium
Alendronate tablets 70 mg, taken orally, once-weekly, for 12 months
Other Name: FOSAMAX®
Drug: Vitamin D3
Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months
Other Name: Cholecalciferol
Drug: Calcium carbonate
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

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.

  Eligibility

Ages Eligible for Study:   45 Years to 85 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

No Contacts or Locations Provided
  More Information

No publications provided

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00996801     History of Changes
Other Study ID Numbers: 5442-012, 2009-014729-18, CTRI/2010/091/000258
Study First Received: October 15, 2009
Results First Received: August 31, 2012
Last Updated: November 7, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Osteoporosis
Osteoporosis, Postmenopausal
Bone Diseases
Bone Diseases, Metabolic
Musculoskeletal Diseases
Alendronate
Calcium Carbonate
Cholecalciferol
Diphosphonates
Ergocalciferols
Vitamin D
Vitamins
Antacids
Bone Density Conservation Agents
Growth Substances
Micronutrients
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 23, 2014