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

Primary Purpose

Osteoporosis

Status

Terminated

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

MK-5442

Placebo

Vitamin D3

Calcium carbonate

About this trial

This is an interventional treatment trial for Osteoporosis focused on measuring Osteoporosis, Postmenopausal, MK-5442

Eligibility Criteria

45 Years - 85 Years (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Placebo Comparator

Arm Label

MK-5442 2.5 mg

MK-5442 5 mg

MK-5442 7.5 mg

MK-5442 10 mg

MK-5442 15 mg

Placebo

Arm Description

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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).

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.

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.

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.

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.

Secondary Outcome Measures

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).

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).

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).

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).

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).

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).

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).

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).

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.

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).

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.

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).

Full Information

NCT ID

NCT00960934

First Posted

August 17, 2009

Last Updated

February 1, 2015

Sponsor

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT00960934

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2015

Overall Recruitment Status

Terminated

Study Start Date

October 2009 (undefined)

Primary Completion Date

December 2010 (Actual)

Study Completion Date

December 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Merck Sharp & Dohme LLC

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Osteoporosis

Keywords

Osteoporosis, Postmenopausal, MK-5442

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

383 (Actual)

8. Arms, Groups, and Interventions

Arm Title

MK-5442 2.5 mg

Arm Type

Experimental

Arm Description

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.

Arm Title

MK-5442 5 mg

Arm Type

Experimental

Arm Description

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.

Arm Title

MK-5442 7.5 mg

Arm Type

Experimental

Arm Description

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.

Arm Title

MK-5442 10 mg

Arm Type

Experimental

Arm Description

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.

Arm Title

MK-5442 15 mg

Arm Type

Experimental

Arm Description

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.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

MK-5442

Intervention Description

MK-5442 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg tablet once daily for at least 6 months.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Dose-matched oral placebo to MK-5442

Intervention Type

Dietary Supplement

Intervention Name(s)

Vitamin D3

Intervention Description

Vitamin D3, two 400 IU tablets daily throughout the study.

Intervention Type

Dietary Supplement

Intervention Name(s)

Calcium carbonate

Intervention Description

Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.

Primary Outcome Measure Information:

Title

Least Squares (LS) Mean Percent Change From Baseline to Month 6 in Lumbar Spine Areal Bone Mineral Density (aBMD)

Description

Time Frame

Baseline (BL) and Month 6

Title

Percentage of Participants With Total Serum Calcium Levels Outside the Pre-defined Limits of Change

Description

Time Frame

Baseline through Month 6

Title

Percentage of Participants With Albumin-Corrected Calcium Levels Outside the Pre-defined Limits of Change

Description

Time Frame

Baseline through Month 6

Title

Percentage of Participants With Kidney Stones

Description

Evidence of kidney stone(s) was considered an event of interest and was prespecified as a "Tier 1" safety event.

Time Frame

Baseline through Month 6

Title

Percentage of Participants With Bone Neoplasms

Description

Evidence of bone neoplasm(s) was considered an event of interest and was prespecified as a "Tier 1" safety event.

Time Frame

Baseline through Month 6

Secondary Outcome Measure Information:

Title

LS Mean Percent Change From Baseline to Month 6 in Total Hip aBMD

Description

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).

Time Frame

Baseline and Month 6

Title

LS Mean Percent Change From Baseline to Month 6 in Femoral Neck aBMD

Description

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).

Time Frame

Baseline and Month 6

Title

LS Mean Percent Change From Baseline to Month 6 in Trochanter aBMD

Description

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).

Time Frame

Baseline and Month 6

Title

LS Mean Percent Change From Baseline to Month 6 in Total Body aBMD

Description

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).

Time Frame

Baseline and Month 6

Title

LS Mean Percent Change From Baseline to Month 6 in Distal One-third Forearm Areal BMD

Description

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).

Time Frame

Baseline and Month 6

Title

LS Mean Percent Change From Baseline to Month 6 in Trabecular Volumetric BMD of the Hip

Description

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).

Time Frame

Baseline and Month 6

Title

LS Mean Percent Change From Baseline to Month 6 in Trabecular Volumetric BMD of the Lumbar Spine

Description

Time Frame

Baseline and Month 6

Title

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)

Description

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).

Time Frame

Baseline and Month 6

Title

LS Mean Percent Change From Baseline to Month 6 in Serum C-Terminal Telopeptide Collagen I (s-CTx)

Description

C-Terminal Telopeptide Collagen I is used as a serum-marker of bone resorption in the assessment of osteoporosis.

Time Frame

Baseline to Month 6

Title

LS Mean Percent Change From Baseline to Month 6 in Serum Bone-Specific Alkaline Phosphatase (s-BSAP)

Description

Bone Specific Alkaline Phosphatase is a biomarker of bone formation and is measured in units of microgram (μg)/liter (L).

Time Frame

Baseline and Month 6

Title

LS Mean Percent Change From Baseline to Month 6 in Serum Procollagen Type I N-Terminal Propeptide (P1NP)

Description

Measurement of P1NP appears to be a sensitive marker of bone formation rate in the assessment of osteoporosis.

Time Frame

Baseline to Month 6

Title

LS Mean Percent Change From Baseline to Month 6 in Serum Osteocalcin

Description

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

Time Frame

Baseline and Month 6

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

45 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

12. IPD Sharing Statement

Citations:

PubMed Identifier

25166719

Citation

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.

Results Reference

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

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