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

NCT00996801 | Completed Phase 2 Results DMC

• 3 other identifiers: 5442-0122009-014729-18CTRI/2010/091/000258
• Study Type: interventional
• Target: 526
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Osteoporosis; Postmenopausal Osteoporosis

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (14)

• Least Squares Mean Percent Change From Baseline to Month 12 in Total Hip Areal BMD

  Baseline and Month 12

• Least Squares Mean Percent Change From Baseline to Month 12 in Femoral Neck Areal BMD

  Baseline and Month 12

• Least Squares Mean Percent Change From Baseline to Month 12 in Trochanter Areal BMD

  Baseline and Month 12

• Least Squares Mean Percent Change From Baseline to Month 12 in Total Body Areal BMD

  Baseline and Month 12

• Least Squares Mean Percent Change From Baseline to Month 12 in 1/3 Distal Forearm Areal BMD

  Baseline and Month 12

Study Arms (6)

Placebo

PLACEBO COMPARATOR

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; Drug: Vitamin D3; Drug: Calcium carbonate; Drug: Placebo to Alendronate

MK-5442 5 mg

EXPERIMENTAL

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; Drug: Vitamin D3; Drug: Calcium carbonate; Drug: Placebo to Alendronate

MK-5442 7.5 mg

EXPERIMENTAL

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; Drug: Vitamin D3; Drug: Calcium carbonate; Drug: Placebo to Alendronate

MK-5442 10 mg

EXPERIMENTAL

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; Drug: Vitamin D3; Drug: Calcium carbonate; Drug: Placebo to Alendronate

MK-5442 15 mg

EXPERIMENTAL

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; Drug: Vitamin D3; Drug: Calcium carbonate; Drug: Placebo to Alendronate

Alendronate 70 mg

ACTIVE COMPARATOR

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; Drug: Alendronate Sodium; Drug: Vitamin D3; Drug: Calcium carbonate

Interventions

MK-5442 DRUG

MK-5442 tablets (randomized to a dose of 5, 7.5, 10 or 15 mg) taken orally, once-daily, for 12 months

MK-5442 10 mg; MK-5442 15 mg; MK-5442 5 mg; MK-5442 7.5 mg

Placebo to MK-5442 DRUG

Matching placebo to MK-5442 taken orally, once-daily, for 12 months

Alendronate 70 mg; Placebo

Alendronate Sodium DRUG

Alendronate tablets 70 mg, taken orally, once-weekly, for 12 months

Also known as: FOSAMAX®

Alendronate 70 mg

Vitamin D3 DRUG

Vitamin D3 (cholecalciferol) administered orally, at a dose of 5600 IU (two tablets, 2800 IU each), once-weekly for 12 months

Also known as: Cholecalciferol

Alendronate 70 mg; MK-5442 10 mg; MK-5442 15 mg; MK-5442 5 mg; MK-5442 7.5 mg; Placebo

Calcium carbonate DRUG

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 70 mg; MK-5442 10 mg; MK-5442 15 mg; MK-5442 5 mg; MK-5442 7.5 mg; Placebo

Placebo to Alendronate DRUG

Placebo to alendronate once-weekly for 12 months

MK-5442 10 mg; MK-5442 15 mg; MK-5442 5 mg; MK-5442 7.5 mg; Placebo

Eligibility Criteria

• Age: 45 Years - 85 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (2)

• Cosman F, Gilchrist N, McClung M, Foldes J, de Villiers T, Santora A, Leung A, Samanta S, Heyden N, McGinnis JP 2nd, Rosenberg E, Denker AE. A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates. Osteoporos Int. 2016 Jan;27(1):377-86. doi: 10.1007/s00198-015-3392-7. Epub 2015 Nov 10.

  PMID: 26556736 RESULT

• Saag K, Cosman F, De Villiers T, Langdahl B, Scott BB, Denker AE, Pong A, Santora AC. Early changes in bone turnover and bone mineral density after discontinuation of long-term oral bisphosphonates: a post hoc analysis. Osteoporos Int. 2021 Sep;32(9):1879-1888. doi: 10.1007/s00198-020-05785-3. Epub 2021 Feb 19.

  PMID: 33606045 DERIVED

MeSH Terms

Conditions

Osteoporosis; Osteoporosis, Postmenopausal

Interventions

JTT 305; Alendronate; Cholecalciferol; Calcium Carbonate

Condition Hierarchy (Ancestors)

Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Cholestenes; Cholestanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Lipids; Calcium Compounds; Inorganic Chemicals; Carbonates; Carbonic Acid; Carbon Compounds, Inorganic; Minerals

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

clincaltrialsdisclosure@merck.com

1-800-672-6372

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 15, 2009
• First Posted: October 16, 2009
• Study Start: November 1, 2009
• Primary Completion: June 1, 2011
• Study Completion: June 1, 2011
• Last Updated: January 22, 2016
• Results First Posted: November 16, 2012

Record last verified: 2016-01