A Dose-Ranging Study of MK-5442 in Postmenopausal Women With Osteoporosis (MK-5442-001 AM4) - Full Text View

Purpose

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.

Condition	Intervention	Phase
Osteoporosis	Drug: MK-5442 Drug: Placebo Dietary Supplement: Vitamin D3 Dietary Supplement: Calcium carbonate	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	A Phase IIb, Randomized, Placebo-Controlled, Dose-Ranging Study of MK-5442 in the Treatment of Postmenopausal Women With Osteoporosis

Resource links provided by NLM:

MedlinePlus related topics: Calcium Osteoporosis Vitamin D

Drug Information available for: Cholecalciferol Calcium Gluconate Calcium carbonate Vitamin D

U.S. FDA Resources

Further study details as provided by Merck:

Primary Outcome Measures:

Least Squares (LS) Mean Percent Change From Baseline to Month 6 in Lumbar Spine Areal Bone Mineral Density (aBMD) [ Time Frame: Baseline (BL) and Month 6 ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline through Month 6 ] [ 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 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 [ Time Frame: Baseline through Month 6 ] [ 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 albumin-corrected calcium levels ≥10.6 mg/dL were considered as having a "Tier 1" safety event.
Percentage of Participants With Kidney Stones [ Time Frame: Baseline through Month 6 ] [ Designated as safety issue: Yes ]
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 [ Time Frame: Baseline through Month 6 ] [ Designated as safety issue: Yes ]
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 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
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) [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
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) [ Time Frame: Baseline to Month 6 ] [ Designated as safety issue: No ]
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) [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
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) [ Time Frame: Baseline to Month 6 ] [ Designated as safety issue: No ]
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 [ Time Frame: Baseline and Month 6 ] [ Designated as safety issue: No ]
Serum osteocalcin is a biomarker of bone formation and is measured using units of nanograms (ng) / milliliter (mL).

Enrollment:	383
Study Start Date:	October 2009
Study Completion Date:	December 2010
Primary Completion Date:	December 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.

Detailed Description:

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

Eligibility

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

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

Contacts and Locations

No Contacts or Locations Provided

More Information

No publications provided

Responsible Party:	Merck
ClinicalTrials.gov Identifier:	NCT00960934 History of Changes
Other Study ID Numbers:	5442-001, 2009-012926-35
Study First Received:	August 17, 2009
Results First Received:	August 14, 2012
Last Updated:	October 2, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Merck:

Osteoporosis
Postmenopausal
MK-5442

Additional relevant MeSH terms:

Osteoporosis
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Calcium Carbonate
Cholecalciferol
Vitamin D
Ergocalciferols

Vitamins
Antacids
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Micronutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents

ClinicalTrials.gov processed this record on May 19, 2013