Study to Evaluate Efficacy of Odanacatib (MK-0822) on Bone Mineral Density (BMD) and Bone Micro-architecture and Overall Safety in Postmenopausal Women (MK-0822-031)

Study Overview
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Brief Summary
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This study will evaluate the safety and treatment effect of 50 mg odanacatib (MK-0822) with Vitamin D versus placebo with Vitamin D in postmenopausal women with low bone density. The primary efficacy hypothesis is that odanacatib will increase aBMD at the lumbar spine compared to placebo at 12 months.

Official Title
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A Phase III Randomized, Placebo-Controlled Study to Evaluate the Effect of Odanacatib (MK-0822) on Bone Mineral Density (BMD) and Overall Safety, and to Estimate the Effect of Odanacatib (MK-0822) on Bone Micro-architecture in Postmenopausal Women Treated With Vitamin D

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: Odanacatib
* Drug: Placebo
* Drug: Vitamin D3
* Drug: Calcium supplement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has been postmenopausal for 3 years Participant has BMD t-score at the total hip, hip trochanter, femoral neck, or lumbar spine ≥ -1.5 but > -3.5 Participant has 2 hips that are evaluable by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT), e.g. contain no hardware from orthopedic procedures Participant is ambulatory Exclusion Criteria: Participant has had a previous hip fracture Participant has had >1 prior clinical vertebral fracture AND is a candidate for osteoporosis therapy Participant has been treated with oral bisphosphonates, strontium, parathyroid hormone (PTH) or other agents with an effect on bone Participant has had metabolic bone disorder other than osteoporosis Participant has renal stones, Parkinson's disease, multiple sclerosis (MS) or active parathyroid disease.

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: Odanacatib 50 mg<br>Participants receive 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also receive 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg. | Drug: Odanacatib<br>* Odanacatib 50 mg tablets, taken orally once weekly for 24 months.<br>* Other names: MK-0822;Drug: Vitamin D3<br>* Vitamin D3 tablets (5600 IU) taken orally once weekly for 24 months.<br>Drug: Calcium supplement<br>* Calcium supplement 500 mg tablet taken orally once daily (up to  1200 mg total) for 24 months.<br>* Other names: calcium citrate;|
| Placebo Comparator: Placebo<br>Participants receive matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also receive 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg. | Drug: Placebo<br>* Matching placebo tablets to odanacatib taken orally once weekly for 24 months.<br>Drug: Vitamin D3<br>* Vitamin D3 tablets (5600 IU) taken orally once weekly for 24 months.<br>Drug: Calcium supplement<br>* Calcium supplement 500 mg tablet taken orally once daily (up to  1200 mg total) for 24 months.<br>* Other names: calcium citrate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Month 12 in Lumbar Spine Areal Bone Mineral Density (aBMD) | aBMD (g/cm^2) was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and mean BMD measurements from at least 3 evaluable lumbar spine vertebrae (L1-L4) were used. If a vertebra was fractured at baseline or became fractured during the study, its BMD measurement was excluded from the analysis and the lumbar spine BMD was recalculated based on the three remaining vertebrae. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the lumbar spine was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal Analysis of Covariates (ANCOVA) model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as primary and secondary outcome measures, respectively. | Baseline, 12 months | 
| Percentage of Participants That Experienced an Adverse Event (AE) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that experienced at least one AE was reported for each treatment arm. | Up to  14 days post study end (up to  24 months) | 
| Percentage of Participants That Discontinued Study Treatment Due to an AE | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that discontinued study treatment (different from discontinuation of the study) due to an AE was reported for each treatment arm. | Up to  14 days post study end (up to  24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Month 24 in Lumbar Spine aBMD | aBMD (g/cm^2) was measured by DXA at the lumbar spine and mean BMD measurements from at least 3 evaluable vertebrae from L1 through L4 were used. If a vertebra was fractured at baseline or became fractured during the study, its BMD measurement was excluded from the analysis and the lumbar spine BMD was recalculated based on the three remaining vertebrae. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the lumbar spine was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as primary and secondary outcome measures, respectively. | Baseline, 24 months | 
| Percent Change From Baseline in Total Hip aBMD | aBMD (g/cm^2) data was measured by DXA at the total hip. All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the total hip was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. | Baseline, 12 months, 24 months | 
| Percent Change From Baseline in Femoral Neck aBMD | aBMD (g/cm^2) data was measured by DXA at the femoral neck (hip). All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the femoral neck was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. | Baseline, 12 months, 24 months | 
| Percent Change From Baseline in Hip Trochanter aBMD | aBMD (g/cm^2) data was measured by DXA at the hip trochanter. All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the hip trochanter was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. | Baseline, 12 months, 24 months | 
| Percent Change From Baseline in Total Radius aBMD | aBMD (g/cm^2) data was measured by DXA at the total radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the total radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. | Baseline, 12 months, 24 months | 
| Percent Change From Baseline in Ultradistal Radius aBMD | aBMD (g/cm^2) data was measured by DXA at the ultradistal radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the ultradistal radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. | Baseline, 12 months, 24 months | 
| Percent Change From Baseline in Distal Radius aBMD | aBMD (g/cm^2) data was measured by DXA at the one-third distal radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the distal radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. | Baseline, 12 months, 24 months | 
| Percent Change From Baseline in Trabecular Volumetric Bone Mineral Density (vBMD) at Central Section of Spine (L1) | Trabecular vBMD at the lumbar spine (L1) was measured by quantitative computed tomography (QCT). All QCT-derived vBMD measurements were evaluated centrally (and possibly locally) for bone and soft tissue abnormalities. Trabecular vBMD at the lumbar spine (L1) was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. | Baseline, 12 months, 24 months | 
| Percent Change From Baseline in Trabecular vBMD at Central Section of Spine (L2) | Trabecular vBMD at the lumbar spine (L2) was measured by quantitative computed tomography (QCT). All QCT-derived vBMD measurements were evaluated centrally (and possibly locally) for bone and soft tissue abnormalities. Trabecular vBMD at the lumbar spine (L2) was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. | Baseline, 12 months, 24 months | 
| Percent Change From Baseline in Serum C-Terminal Telopeptides of Type 1 Collagen (s-CTx) Level | s-CTx is a biochemical marker index of bone resorption. s-CTx was measured via fasting blood draws at Baseline (Randomization), Month 6, Month 12, Month 18, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. S-CTx was analyzed using the log-transformed fraction from baseline using the per-protocol approach. Data were back-transformed for presentation and geometric LS mean percent change from baseline was reported with 95% CI. | Baseline, 12 months, 24 months | 
| Percent Change From Baseline in Serum N-Terminal Propeptides of Type 1 Collagen (s-P1NP) Level | s-P1NP is a biochemical marker index of bone formation. s-P1NP was measured via fasting blood draws at Baseline (Randomization), Month 6, Month 12, Month 18, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. s-P1NP was analyzed using the log-transformed fraction from baseline using the per-protocol approach. Data were back-transformed for presentation and geometric LS mean percent change from baseline was reported with 95% CI. | Baseline, 12 months, 24 months |