A Dose-Ranging Study of MK-5442 in Postmenopausal Women With Osteoporosis (MK-5442-001)

A Phase IIb, Randomized, Placebo-Controlled, Dose-Ranging Study of MK-5442 in the Treatment of Postmenopausal Women With Osteoporosis

The purpose of this study was to identify an appropriate dose of

MK-5442 that produced an osteoanabolic effect without causing hypercalcemia in postmenopausal women with osteoporosis.

Study Overview

• Status: Terminated
• Conditions: Osteoporosis
• Intervention / Treatment: Drug: MK-5442; Drug: Placebo; Dietary supplement: Vitamin D3; Dietary supplement: Calcium carbonate

Detailed Description

Amendment 4 of the protocol changed the duration of the study from 2 years to 6 months.

• Study Type: Interventional
• Enrollment (Actual): 383
• Phase: Phase 2

Participation Criteria

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:

• Postmenopausal for at least 5 years
• No history of fragility fracture, unless participant is not willing to take marketed osteoporosis therapy or is not a candidate for marketed osteoporosis therapy
• Agrees not to use medications for osteoporosis except medications associated with the study
• Areal bone mineral density (BMD) T-score <-2.5 at one or more of the following 4 BMD sites: total hip, femoral neck, trochanter, or lumbar spine and is ≥ -3.5 at all 4 BMD sites. Participants unwilling to take or ineligible for marketed osteoporosis therapy may have one or more areal BMD T-scores of < -3.5

Exclusion Criteria:

• Unable to undergo dual-energy X-ray absorptiometry (DXA) scan due to obesity (ie, weight >250 lbs)
• Use of oral bisphosphonates in the 6 months prior to study screening, for more than 3 months in the past 2 years, or lifetime use of more than 6 months
• Use of intravenous bisphosphonates, strontium, or growth hormone at any time
• Use of phenytoin or heparin within 2 weeks prior to Visit 1; use of raloxifene within 6 months prior to Visit 1
• Use of pioglitazone or rosiglitazone at study screening
• Use of estrogen ± progestin, in any form other than vaginal or topical application, for 6 months prior to Study Visit 1
• Prior total thyroidectomy
• Human immunodeficiency virus (HIV)- positive or acquired immune deficiency syndrome (AIDS)-related illness
• History of malignant cancer within 5 years of study screening, except for certain skin or cervical cancers
• History of Paget's disease and/or kidney stones
• An active user of any illicit drug
• History of or active alcohol abuse
• Participated in an investigational drug study within the past 30 days

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MK-5442 2.5 mg; Following a 2-week open-label placebo run-in, participants received a daily oral dose of 2.5 mg of MK-5442 for a duration of at least 6 months.	Drug: MK-5442; MK-5442 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg tablet once daily for at least 6 months.; Drug: Placebo; Dose-matched oral placebo to MK-5442; Dietary supplement: Vitamin D3; Vitamin D3, two 400 IU tablets daily throughout the study.; Dietary supplement: Calcium carbonate; Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.
Experimental: MK-5442 5 mg; Following a 2-week open-label placebo run-in, participants received a daily oral dose of 5 mg of MK-5442 for a duration of at least 6 months.	Drug: MK-5442; MK-5442 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg tablet once daily for at least 6 months.; Drug: Placebo; Dose-matched oral placebo to MK-5442; Dietary supplement: Vitamin D3; Vitamin D3, two 400 IU tablets daily throughout the study.; Dietary supplement: Calcium carbonate; Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.
Experimental: MK-5442 7.5 mg; Following a 2-week open-label placebo run-in, participants received a daily oral dose of 7.5 mg of MK-5442 for a duration of at least 6 months.	Drug: MK-5442; MK-5442 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg tablet once daily for at least 6 months.; Drug: Placebo; Dose-matched oral placebo to MK-5442; Dietary supplement: Vitamin D3; Vitamin D3, two 400 IU tablets daily throughout the study.; Dietary supplement: Calcium carbonate; Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.
Experimental: MK-5442 10 mg; Following a 2-week open-label placebo run-in, participants received a daily oral dose of 10 mg of MK-5442 for a duration of at least 6 months.	Drug: MK-5442; MK-5442 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg tablet once daily for at least 6 months.; Drug: Placebo; Dose-matched oral placebo to MK-5442; Dietary supplement: Vitamin D3; Vitamin D3, two 400 IU tablets daily throughout the study.; Dietary supplement: Calcium carbonate; Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.
Experimental: MK-5442 15 mg; Following a 2-week open-label placebo run-in, participants received a daily oral dose of 15 mg of MK-5442 for a duration of at least 6 months.	Drug: MK-5442; MK-5442 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg tablet once daily for at least 6 months.; Drug: Placebo; Dose-matched oral placebo to MK-5442; Dietary supplement: Vitamin D3; Vitamin D3, two 400 IU tablets daily throughout the study.; Dietary supplement: Calcium carbonate; Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.
Placebo Comparator: Placebo; Following a 2-week open-label placebo run-in, participants received a daily oral dose of placebo dose-matched to MK-5442 for a duration of at least 6 months.	Drug: Placebo; Dose-matched oral placebo to MK-5442; Dietary supplement: Vitamin D3; Vitamin D3, two 400 IU tablets daily throughout the study.; Dietary supplement: Calcium carbonate; Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Least Squares (LS) Mean Percent Change From Baseline to Month 6 in Lumbar Spine Areal Bone Mineral Density (aBMD)	Dual Energy X-ray Absorptiometry (DXA) was used to assess and measure aBMD of the lumbar spine. Areal BMD was measured as "areal" density using units of gram (gm) of tissue /centimeter of tissue squared (cm^2).	Baseline (BL) and Month 6
Percentage of Participants With Total Serum Calcium Levels Outside the Pre-defined Limits of Change	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 calcium levels ≥10.6 mg/dL were considered as having a "Tier 1" safety event.	Baseline through Month 6
Percentage of Participants With Albumin-Corrected Calcium Levels Outside the Pre-defined Limits of Change	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 albumin-corrected calcium levels ≥10.6 mg/dL were considered as having a "Tier 1" safety event.	Baseline through Month 6
Percentage of Participants With Kidney Stones	Evidence of kidney stone(s) was considered an event of interest and was prespecified as a "Tier 1" safety event.	Baseline through Month 6
Percentage of Participants With Bone Neoplasms	Evidence of bone neoplasm(s) was considered an event of interest and was prespecified as a "Tier 1" safety event.	Baseline through Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LS Mean Percent Change From Baseline to Month 6 in Total Hip aBMD	DXA was used to assess and measure aBMD of the total hip. Areal BMD was measured as "areal" density using units of gram (gm) of tissue /centimeter of tissue squared (cm^2).	Baseline and Month 6
LS Mean Percent Change From Baseline to Month 6 in Femoral Neck aBMD	DXA was used to assess and measure aBMD of the femoral neck. Areal BMD was measured as "areal" density using units of gram (gm) of tissue /centimeter of tissue squared (cm^2).	Baseline and Month 6
LS Mean Percent Change From Baseline to Month 6 in Trochanter aBMD	DXA was used to assess and measure aBMD of the trochanter. Areal BMD was measured as "areal" density using units of gram (gm) of tissue /centimeter of tissue squared (cm^2).	Baseline and Month 6
LS Mean Percent Change From Baseline to Month 6 in Total Body aBMD	DXA was used to assess and measure aBMD of the total body. Areal BMD was measured as "areal" density using units of gram (gm) of tissue /centimeter of tissue squared (cm^2).	Baseline and Month 6
LS Mean Percent Change From Baseline to Month 6 in Distal One-third Forearm Areal BMD	DXA was used to assess and measure aBMD of the distal 1/3 forearm. Areal BMD was measured as "areal" density using units of gram (gm) of tissue /centimeter of tissue squared (cm^2).	Baseline and Month 6
LS Mean Percent Change From Baseline to Month 6 in Trabecular Volumetric BMD of the Hip	Quantitative computed tomography (QCT) technology was used to assess and measure bone mineral content volumetrically (ie, in grams of tissue per centimeter of tissue cubed).	Baseline and Month 6
LS Mean Percent Change From Baseline to Month 6 in Trabecular Volumetric BMD of the Lumbar Spine	Quantitative computed tomography (QCT) technology was used at baseline and periodically through out the study to assess and measure bone mineral content volumetrically (ie, in grams of tissue per centimeter of tissue cubed).	Baseline and Month 6
LS Mean Percent Change From Baseline to Month 6 in the Ratio of Urinary N-Telopeptides of Type I Collagen to Creatinine (u-NTx/Cr)	The ratio of u-NTx to Cr is a biomarker for bone resorption. It is measured in the serum in units of nanomoles (nm) of bone collagen equivalents (BCE)/millimoles of creatinine (Cr).	Baseline and Month 6
LS Mean Percent Change From Baseline to Month 6 in Serum C-Terminal Telopeptide Collagen I (s-CTx)	C-Terminal Telopeptide Collagen I is used as a serum-marker of bone resorption in the assessment of osteoporosis.	Baseline to Month 6
LS Mean Percent Change From Baseline to Month 6 in Serum Bone-Specific Alkaline Phosphatase (s-BSAP)	Bone Specific Alkaline Phosphatase is a biomarker of bone formation and is measured in units of microgram (μg)/liter (L).	Baseline and Month 6
LS Mean Percent Change From Baseline to Month 6 in Serum Procollagen Type I N-Terminal Propeptide (P1NP)	Measurement of P1NP appears to be a sensitive marker of bone formation rate in the assessment of osteoporosis.	Baseline to Month 6
LS Mean Percent Change From Baseline to Month 6 in Serum Osteocalcin	Serum osteocalcin is a biomarker of bone formation and is measured using units of nanograms (ng) / milliliter (mL).	Baseline and Month 6

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Halse J, Greenspan S, Cosman F, Ellis G, Santora A, Leung A, Heyden N, Samanta S, Doleckyj S, Rosenberg E, Denker AE. A phase 2, randomized, placebo-controlled, dose-ranging study of the calcium-sensing receptor antagonist MK-5442 in the treatment of postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2014 Nov;99(11):E2207-15. doi: 10.1210/jc.2013-4009. Epub 2014 Aug 28.

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: August 17, 2009
• First Submitted That Met QC Criteria: August 17, 2009
• First Posted (Estimate): August 18, 2009

Study Record Updates

• Last Update Posted (Estimate): February 18, 2015
• Last Update Submitted That Met QC Criteria: February 1, 2015
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Keywords: Osteoporosis; Postmenopausal; MK-5442
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antacids; Vitamin D; Cholecalciferol; Calcium; Calcium Carbonate
• Other Study ID Numbers: 5442-001; 2009-012926-35 (EudraCT Number)