Efficacy and Safety of Odanacatib in Postmenopausal Women Previously Treated With Oral Bisphosphonate (MK-0822-076)

Study Overview
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Brief Summary
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The purpose of this study is to assess to what extent sequential treatment with odanacatib results in incremental gains in bone mineral density (BMD) over time in female participants who have received at least 3 years of bisphosphonate therapy. It was hypothesized that odanacatib treatment would increase femoral neck BMD relative to placebo after 24 months.

Official Title
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A Phase III Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effects of Odanacatib (MK-0822) on Bone Mineral Density (BMD) and Overall Safety in the Treatment of Osteoporosis in Postmenopausal Women Previously Treated With an Oral Bisphosphonate

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: odanacatib
* Other: placebo to odanacatib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal for ≥5 years (defined as no menses for at least 5 years or at least 5 years post bilateral oophorectomy). Prior or current treatment with oral bisphosphonate therapy (i.e., alendronate, risedronate, ibandronate) for postmenopausal osteoporosis for ≥3 years. BMD T-score at any hip site (femoral neck, trochanter, or total hip) ≤-2.5 and >-3.5 as assessed by dual-energy X-ray absorptiometry (DXA) without a history of a prior fragility fracture. For participants with a history of a prior fragility fracture (except hip fracture), BMD T-score can be ≤-1.5 and >-3.5 at any hip site. Serum 25-hydroxyvitamin D level of ≥20 and ≤60 ng/mL within 90 days of the time of randomization. Exclusion Criteria: Evidence of a metabolic bone disorder other than osteopenia or osteoporosis History or current evidence of hip fracture. History of malignancy ≤5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Active parathyroid disease. Participant with a documented history of parathyroid disease can be considered for inclusion if she has normal parathyroid hormone (PTH) at screening. History of thyroid disease not adequately controlled by medication. Current treatment with anti-seizure medication, with indices of calcium metabolism not within normal limits. Prior treatment with strontium-containing products; intravenous bisphosphonates; cathepsin K inhibitors; RANK ligand inhibitors; fluoride treatment at a dose greater than 1 mg/day for more than 2 weeks. Use of following medications within the 6 months prior to the screening visit: activated vitamin D; estrogen, with or without progestin, at a dose high enough to have systemic effects; raloxifene or other selective estrogen receptor modulator (SERM), tibolone or any aromatase inhibitor; sub-cutaneous calcitonin (Note: use of intranasal calcitonin is allowed at any time); anabolic steroid; PTH (1-34 or 1-84); growth hormone; systemic glucocorticoids (≥5 mg/day of prednisone or equivalent) for more than 2 weeks; cyclosporine for more than 2 weeks. Concurrent use of cancer chemotherapy or heparin; protease inhibitors for human immunodeficiency virus (HIV) treatment; and vitamin A (excluding beta carotene) >10,000 IU daily, unless willing to discontinue this dose during the study. Current treatment with cytochrome P450 3A4 (CYP3A4) inducers or treatment with CYP3A4 inducer within 4 weeks of screening.

Ages Eligible for Study
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Minimum Age: 60 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 will receive odanacatib 50 mg once weekly for 24 months. Additionally, all participants will receive weekly supplementation with 5600 international units (IU) of Vitamin D3 and, if required, will be provided with an open-label daily calcium supplement of 500 mg (sourced locally as calcium carbonate or calcium citrate) to ensure a total daily intake (from both dietary and supplemental sources) of approximately 1200 mg of elemental calcium. | Drug: odanacatib<br>* odanacatib 50 mg oral tablet<br>* Other names: MK-0822;|
| Placebo Comparator: Placebo<br>Participants will receive dose-matched placebo to odanacatib once weekly for 24 months. Additionally, all participants will receive weekly supplementation with 5600 IU Vitamin D3 and, if required, will be provided with an open-label daily calcium supplement of 500 mg (sourced locally as calcium carbonate or calcium citrate) to ensure a total daily intake (from both dietary and supplemental sources) of approximately 1200 mg of elemental calcium. | Other: placebo to odanacatib<br>* dose-matched placebo to odanacatib, oral tablet<br>|

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 Femoral BMD | Dual-energy X-ray absorptiometry (DXA) was used to determine the change from baseline in femoral neck BMD at Month 12. | Baseline and Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Month 24 in Femoral Neck BMD: Within-Group Comparison of Odanacatib | DXA was used to determine the within-group change from baseline in femoral neck BMD at Month 24. | Baseline and Month 24 | 
| Percent Change From Baseline to Month 12 in Trochanter, Total Hip, and Lumbar Spine BMD | DXA was used to determine the change from baseline in trochanter, total hip, and lumbar spine BMD at Month 12. | Baseline and Month 12 | 
| Change From Baseline in Serum C-telopeptides of Type 1 Collagen (s-CTx) | s-CTx is a biochemical marker of bone resorption. At baseline and Month 12, s-CTx was measured and expressed in ng/mL and results are expressed as percentage change from baseline. | Baseline and Month 12 | 
| Change From Baseline in Urine C-telopeptides of Type I Collagen (u-CTx) | u-CTx is a biochemical marker of bone resorption. At baseline and Month 12, u-CTx was measured and expressed in ug/mL and results are expressed as percentage change from baseline. | Baseline and Month 12 | 
| Change From Baseline in Urine N-telopeptides of Type 1 Collagen Corrected for Creatinine (u-NTx/Cr) | The u-NTx/Cr ratio is a biochemical marker of bone resorption. u-NTx/Cr was measured at baseline and Month 12 and expressed in nM:mM and results are expressed as percentage change from baseline. | Baseline and Month 12 | 
| Change From Baseline in Serum Bone Specific Alkaline Phosphatase (s-BSAP) | s-BSAP is a biochemical marker of bone resorption. s-BSAP was measured and expressed in ng/mL at Baseline and Month 12, and results are shown as percentage change from baseline. | Baseline and Month 12 | 
| Change From Baseline in Serum N-terminal Propeptide of Type 1 Collagen (s-P1NP) | s-P1NP is a biochemical marker of bone resorption. s-P1NP was measured and expressed as ng/mL at Baseline and Month 12, and results are expressed as percentage change from baseline. | Baseline and Month 12 |