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

Phase 2

Terminated

• Conditions: Osteoporosis
• Interventions: Drug: MK-5442; Drug: Placebo; Dietary Supplement: Vitamin D3; Dietary Supplement: Calcium carbonate

• Registration Number: NCT00960934
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

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.

Detailed Description

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

Study Timeline

• Study First Submitted: 2009-08-17
• Study First Submitted QC: 2009-08-17
• Study First Posted: 2009-08-18
• Study Start: 2009-10
• Primary Completion: 2010-12
• Study Completion: 2010-12
• Results First Submitted: 2012-08-14
• Results First Submitted QC: 2012-10-02
• Results First Posted: 2012-10-10
• Status Verified: 2015-02
• Last Update Submitted: 2015-02-01
• Last Update Posted: 2015-02-18

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Female
• Target Recruitment: 383

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MK-5442 15 mg	Vitamin D3	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.
MK-5442 2.5 mg	MK-5442	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.
MK-5442 7.5 mg	Placebo	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.
MK-5442 2.5 mg	Placebo	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.
MK-5442 7.5 mg	Vitamin D3	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.
MK-5442 7.5 mg	Calcium carbonate	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.
MK-5442 15 mg	MK-5442	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.
MK-5442 15 mg	Calcium carbonate	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.
MK-5442 5 mg	Placebo	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.
MK-5442 5 mg	Vitamin D3	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.
MK-5442 7.5 mg	MK-5442	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.
MK-5442 10 mg	Placebo	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.
MK-5442 2.5 mg	Calcium carbonate	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.
MK-5442 5 mg	MK-5442	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.
MK-5442 5 mg	Calcium carbonate	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.
MK-5442 10 mg	MK-5442	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.
MK-5442 10 mg	Vitamin D3	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.
MK-5442 15 mg	Placebo	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.
MK-5442 2.5 mg	Vitamin D3	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.
Placebo	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.
Placebo	Vitamin D3	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.
MK-5442 10 mg	Calcium carbonate	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.
Placebo	Calcium carbonate	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.

Primary Outcome Measures

Name	Time	Method
Least Squares (LS) Mean Percent Change From Baseline to Month 6 in Lumbar Spine Areal Bone Mineral Density (aBMD)	Baseline (BL) and Month 6	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).
Percentage of Participants With Total Serum Calcium Levels Outside the Pre-defined Limits of Change	Baseline through Month 6	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.
Percentage of Participants With Albumin-Corrected Calcium Levels Outside the Pre-defined Limits of Change	Baseline through Month 6	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.
Percentage of Participants With Kidney Stones	Baseline through Month 6	Evidence of kidney stone(s) was considered an event of interest and was prespecified as a "Tier 1" safety event.
Percentage of Participants With Bone Neoplasms	Baseline through Month 6	Evidence of bone neoplasm(s) was considered an event of interest and was prespecified as a "Tier 1" safety event.

Secondary Outcome Measures

Name	Time	Method
LS Mean Percent Change From Baseline to Month 6 in Distal One-third Forearm Areal BMD	Baseline and Month 6	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).
LS Mean Percent Change From Baseline to Month 6 in Trabecular Volumetric BMD of the Hip	Baseline and Month 6	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).
LS Mean Percent Change From Baseline to Month 6 in Trochanter aBMD	Baseline and Month 6	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).
LS Mean Percent Change From Baseline to Month 6 in Trabecular Volumetric BMD of the Lumbar Spine	Baseline and Month 6	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).
LS Mean Percent Change From Baseline to Month 6 in Total Hip aBMD	Baseline and Month 6	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).
LS Mean Percent Change From Baseline to Month 6 in Femoral Neck aBMD	Baseline and Month 6	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).
LS Mean Percent Change From Baseline to Month 6 in Total Body aBMD	Baseline and Month 6	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).
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)	Baseline and Month 6	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).
LS Mean Percent Change From Baseline to Month 6 in Serum C-Terminal Telopeptide Collagen I (s-CTx)	Baseline to Month 6	C-Terminal Telopeptide Collagen I is used as a serum-marker of bone resorption in the assessment of osteoporosis.
LS Mean Percent Change From Baseline to Month 6 in Serum Bone-Specific Alkaline Phosphatase (s-BSAP)	Baseline and Month 6	Bone Specific Alkaline Phosphatase is a biomarker of bone formation and is measured in units of microgram (μg)/liter (L).
LS Mean Percent Change From Baseline to Month 6 in Serum Procollagen Type I N-Terminal Propeptide (P1NP)	Baseline to Month 6	Measurement of P1NP appears to be a sensitive marker of bone formation rate in the assessment of osteoporosis.
LS Mean Percent Change From Baseline to Month 6 in Serum Osteocalcin	Baseline and Month 6	Serum osteocalcin is a biomarker of bone formation and is measured using units of nanograms (ng) / milliliter (mL).