The Effects of 12-months of Denosumab on Bone Density in Prevalent Kidney Transplant Recipients

Study Overview
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Brief Summary
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This is a Phase 2 Multi-Center Clinical Trial (safety and effectiveness trial) in 60 patients (40 denosumab; 20 placebo) who have had a kidney transplant for 12-months or longer with more than 30% of kidney function. The investigators will test whether denosumab safely improves bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) and improves bone strength by high resolution peripheral quantitative computed tomography (HR-pQCT) in the subset of patients recruited at Columbia University Irving Medical Center. These data will inform the development and execution of a larger trial to test if denosumab prevents fractures in kidney transplant recipients.

Detailed Description
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Bone fractures are 3-times more common in kidney transplant recipients than in the general population and risk of dying after a hip fracture is 60% higher compared to kidney transplant recipients without a fracture. Unfortunately, there are no anti-fracture strategies that have been proven to be effective in double blinded randomized clinical trials for kidney transplant recipients. This is because some anti-fracture medications that are commonly used to treat osteoporosis and prevent fractures in the general population (i.e., bisphosphonates), may be harmful to the skeleton when kidney function is less than 30% of normal. In addition, intravenous bisphosphonates may be toxic to the kidneys, which further limits their utility in patients with a kidney transplant. Denosumab, a monoclonal antibody against RANKL, inhibits osteoclast function and is not harmful to the kidney. Denosumab prevents fractures in men and women with age-related and glucocorticoid-induced osteoporosis. Recently, a non-blinded randomized trial of denosumab versus usual care during the first year of kidney transplantation in 90 patients reported the bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA) increased at the spine and hip and that bone strength measured by high resolution peripheral quantitative computed tomography (HR-pQCT) increased in patients treated with denosumab. Adverse events in denosumab-treated patients included greater risk of urinary tract infections, diarrhea, and transient levels of low serum calcium that were asymptomatic. This study demonstrated that denosumab safely increased BMD at the spine and hip in new kidney transplant recipients. However, long-term kidney recipients, who comprise the vast majority of patients living with a transplanted kidney and who are also at increased risk of fracture, were not included.

Official Title
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The Effects of 12-months of Denosumab on Bone Density, Quality and Strength in Prevalent Kidney Transplant Recipients

Conditions
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Osteoporosis, Renal Osteodystrophy, Kidney Transplant; Complications

Intervention / Treatment
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* Drug: Denosumab Inj 60 mg/ml
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Men and women All race-ethnicities Age ≥ 18 years ≥ 12-months after kidney transplantation (living or deceased donor recipient) Stable allograft function over the previous year defined as: No rejections No more than a 15% decline in Glomerular filtration rate (GFR) over the prior year Allograft GFR ≥ 30 mL/minute/1.73 m2 (MDRD or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) per local lab reporting) 25OHD ≥ 30 ng/mL (determined at screening visit) Serum calcium ≥ 9.0 mg/dL (determined at screening visit) T-Score at the spine including and between -1.0 and -3.5 (determined at screening visit) Must have had a routine dental exam within 6-months of study recruitment Must agree to continue with routine dental exams over the course of the study Has not undergone an invasive dental procedure (i.e., tooth extraction, dental implants, oral surgery) within ≤ 3-months of recruitment Must agree to referral to metabolic bone disease specialist at the end of the study Women of child bearing potential must be willing to use one form of effective contraception over the course of the study Exclusion Criteria Allograft GFR < 30 mL/minute/1.73 m2 (MDRD or CKD-EPI per local lab reporting) Within 24-months of starting renal replacement therapy Prevalent or occult vertebral fractures History of post-transplantation non-basal cell carcinoma cancers Non-ambulatory Malignancy requiring chemotherapy or metastatic to bone Non-transplant related metabolic bone diseases that alter bone mineral density, including but not limited to Primary hyperparathyroidism, Paget's, Osteogenesis Imperfecta Within one-year of parathyroidectomy Untreated hyperthyroidism for 6-months or longer Untreated hypothyroidism for 6-months of longer Medical diseases (end stage liver, lung or heart, intestinal malabsorption) Use within the prior year of bisphosphonates, teriparatide, selective estrogen receptor modulators, testosterone, estrogen, denosumab, abaloparatide, calcitonin, and romosozumab Allergy to components within the denosumab preparation or to denosumab Weight > 300 pounds Parathyroid hormone (PTH) > 450 pg /mL Will undergo an invasive dental procedure (i.e., tooth extraction, dental implants, oral surgery) within the next 12-months Pregnant Planned pregnancy during the course of the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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 |
| --- | --- |
| Active Comparator: Active drug<br>Denosumab 60 mg subcutaneous injection every 6 months for 12 months (i.e., 2 injections) | Drug: Denosumab Inj 60 mg/ml<br>* Treatment will be administered by study personnel as a subcutaneous injection every 6-months for one year.<br>* Other names: Prolia;|
| Placebo Comparator: Placebo<br>Placebo subcutaneous injection every 6 months for 12 months (i.e., 2 injections) | Other: Placebo<br>* Placebo will be administered by study personnel as a subcutaneous injection every 6-months for one year.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA) | BMD will be measured to determine if 1-year of treatment with denosumab changes BMD as measured by DXA. | 12 months | 
| Estimated bone strength measured by high resolution peripheral quantitative computed tomography (HR-pQCT) Imaging | Estimated bone mechanical competence will be measured by HR-pQCT. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Denosumab, Bone density, Kidney transplant, Prolia