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

Study Overview
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Brief Summary
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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
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Amendment 4 of the protocol changed the duration of the study from 2 years to 6 months.

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

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: MK-5442
* Drug: Placebo
* Dietary Supplement: Vitamin D3
* Dietary Supplement: Calcium carbonate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-5442 2.5 mg<br>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<br>* MK-5442 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg tablet once daily for at least 6 months.<br>Drug: Placebo<br>* Dose-matched oral placebo to MK-5442<br>Dietary Supplement: Vitamin D3<br>* Vitamin D3, two 400 IU tablets daily throughout the study.<br>Dietary Supplement: Calcium carbonate<br>* Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.<br>|
| Experimental: MK-5442 5 mg<br>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<br>* MK-5442 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg tablet once daily for at least 6 months.<br>Drug: Placebo<br>* Dose-matched oral placebo to MK-5442<br>Dietary Supplement: Vitamin D3<br>* Vitamin D3, two 400 IU tablets daily throughout the study.<br>Dietary Supplement: Calcium carbonate<br>* Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.<br>|
| Experimental: MK-5442 7.5 mg<br>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<br>* MK-5442 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg tablet once daily for at least 6 months.<br>Drug: Placebo<br>* Dose-matched oral placebo to MK-5442<br>Dietary Supplement: Vitamin D3<br>* Vitamin D3, two 400 IU tablets daily throughout the study.<br>Dietary Supplement: Calcium carbonate<br>* Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.<br>|
| Experimental: MK-5442 10 mg<br>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<br>* MK-5442 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg tablet once daily for at least 6 months.<br>Drug: Placebo<br>* Dose-matched oral placebo to MK-5442<br>Dietary Supplement: Vitamin D3<br>* Vitamin D3, two 400 IU tablets daily throughout the study.<br>Dietary Supplement: Calcium carbonate<br>* Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.<br>|
| Experimental: MK-5442 15 mg<br>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<br>* MK-5442 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 15 mg tablet once daily for at least 6 months.<br>Drug: Placebo<br>* Dose-matched oral placebo to MK-5442<br>Dietary Supplement: Vitamin D3<br>* Vitamin D3, two 400 IU tablets daily throughout the study.<br>Dietary Supplement: Calcium carbonate<br>* Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.<br>|
| Placebo Comparator: Placebo<br>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<br>* Dose-matched oral placebo to MK-5442<br>Dietary Supplement: Vitamin D3<br>* Vitamin D3, two 400 IU tablets daily throughout the study.<br>Dietary Supplement: Calcium carbonate<br>* Participants who had a calcium intake of less than 1200 mg/day at baseline received a daily 500 mg calcium supplement throughout the study.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoporosis, Postmenopausal, MK-5442