Denosumab for Prevention of Osteoporosis in Renal Transplant Recipients

Study Overview
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Brief Summary
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The primary objective of the study is to examine the effect of denosumab on lumbar spine bone mineral density (BMD) after one year of treatment in newly transplanted renal allograft recipients. Secondary endpoints include BMD changes at the total hip and the femoral neck, changes in body height, changes in bone mineral metabolism parameters, incidence of fractures, and allograft function at one year. Safety measurements include the occurrence of rejection episodes, infectious complications, graft loss and mortality. Trial with medicinal product

Detailed Description
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Renal allograft recipients are at high risk to suffer a substantial loss of bone mineral density (BMD) within the first year after kidney transplantation. This loss of BMD correlates with an increased risk for the development of osteoporosis or worsening of pre-existing osteopenia/osteoporosis, heightening the risk for the subsequent occurrence of fractures. Renal allograft recipients are often treated with calcium and vitamin D preparations to prevent BMD loss. The addition of bisphosphonates can further improve BMD. However, bisphosphonates are potentially nephrotoxic and promote adynamic bone disease, and are therefore not regularly prescribed. Receptor Activator of Nuclear factor- Kappa-B Ligand (RANKL) is a key molecule mediating development, activity, and survival of osteoclasts. Osteoporosis results in part from increased osteoclastic bone resorption, and therefore the inhibition of RANKL activity has become an obvious therapeutic strategy to prevent bone mineral density (BMD) loss and the development of osteoporosis. The novel anti-osteoporotic drug denosumab (trade name Prolia®) is a fully human monoclonal antibody against RANKL. By inhibiting the development and the activity as well as reducing the survival of osteoclasts it decreases bone resorption and increases bone density. The hypothesis of the present study is that denosumab has a beneficial effect on the loss of BMD in the first year after renal transplantation. The preservation of BMD is a surrogate parameter, generally predicting subsequent improvements in the occurrence rate of fractures. The hypothesis will be tested by studying the effect of denosumab on BMD in newly transplanted renal allograft recipients. The purpose of the present trial is to study the effect of denosumab on BMD in kidney allograft recipients. The study participants will be treated for 1 year, receiving a total of 2 injections of the standard 60 mg dose at baseline and at 6 months. Ninety sequential renal allograft recipients will be randomized 1:1 to receive two subcutaneous 60 mg denosumab injections within 14 days and 6 months following renal transplantation, or no treatment. All patients will also receive oral standard treatment with 1000 mg calcium plus 800 IU vitamin D.

Official Title
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A Phase 3, Investigator-initiated, Randomized, Open-label Single-center Study of the Effect of Denosumab on the Prevention of Bone Mineral Density Loss After Renal Transplantation

Conditions
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Osteoporosis, Chronic Kidney Disease

Intervention / Treatment
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* Drug: Denosumab (Prolia)


Participation Criteria
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Eligibility Criteria
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The key inclusion criteria are: Male or female adult de novo kidney, kidney-pancreas or kidney-islet, or kidney-liver transplant recipients Functioning graft within 28 days after transplantation (creatinine having decreased to <200 micromol/l without the need for dialysis) Being on standard triple immunosuppression including a calcineurin antagonist (cyclosporine or tacrolimus), mycophenolate (MMF or MPA) and steroids, with or without induction treatment with basiliximab or anti-thymocyte globulin Key exclusion criteria are: Age <18 years Rising creatinine after initial drop <200 micromol/l or creatinine >200 micromol/l at baseline Evidence of early acute rejection, either suspected clinically and/or proven by biopsy Presence of severe osteoporosis as evidenced by a T score <-4 at the hip, femoral neck or any of the 4 vertebrae L1 to L4 Evidence of severe hyper- or hypoparathyroidism (iPTH >800 ng/l or <10 ng/l) Hypocalcemia (total calcium <1.8 mmol/l) or hypercalcemia (total calcium >2.7 mmol/l) Steroid-free de novo immunosuppression scheme

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Denosumab<br>60 mg denosumab s.c. at baseline and after 6 months | Drug: Denosumab (Prolia)<br>* 60 mg s.c. injection at baseline and after 6 months<br>* Other names: Prolia;|
| No Intervention: Control<br>No treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in BMD at the Total Lumbar Spine From Baseline to Month 12 | The total lumbar spine BMD was measured via Dual Energy X-ray Absorptiometry (DXA) and was expressed in g/cm2 hydroxylapatite | Baseline and month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in BMD at the Total Hip From Baseline to Month 12 | The total hip BMD was measured via Dual Energy X-ray Absorptiometry (DXA) and was expressed in g/cm2 hydroxylapatite | Baseline and month 12 | 
| Percent Change in BMD at the Femoral Neck From Baseline to Month 12 | The total femoral neck BMD was measured via Dual Energy X-ray Absorptiometry (DXA) and was expressed in g/cm2 hydroxylapatite | Baseline and month 12 | 
| Percent Change in BMD at the Total Lumbar Spine From Baseline to Month 6 | The total lumbar spine BMD was measured via DXA and was expressed in g/cm2 hydroxylapatite. | Baseline and month 6 | 
| Percent Change in BMD at the Total Hip From Baseline to Month 6 | The total hip BMD was measured via DXA and was expressed in g/cm2 hydroxylapatite | Baseline and month 6 | 
| Percent Change in BMD at the Femoral Neck From Baseline to Month 6 | The femoral neck BMD was measured via DXA and was expressed in g/cm2 hydroxylapatite | Baseline and month 6 | 
| Beta-CTX at Baseline and Months 3, 6 and 12 | Blood concentrations of beta-CTX (microgram/L) | baseline, month 3, month 6, and month 12 | 
| P1NP at Baseline and Months 3, 6 and 12 | Blood concentrations of P1NP were measured in microgram/L | baseline, month 3, month 6, and month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoporosis, Osteopenia, Denosumab, Transplantation, Kidney