Clinical trial NCT01377467: Denosumab for Prevention of Osteoporosis in Renal Transplant Recipients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Osteoporosis
Chronic Kidney Disease
Keywords: Osteoporosis
Osteopenia
Denosumab
Transplantation
Kidney
Lead sponsor: University of Zurich
Sponsor class: OTHER
First posted: 2011-06-21
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: The key inclusion criteria are:

1. Male or female adult de novo kidney, kidney-pancreas or kidney-islet, or kidney-liver transplant recipients
2. Functioning graft within 28 days after transplantation (creatinine having decreased to \<200 micromol/l without the need for dialysis)
3. 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:

1. Age \<18 years
2. Rising creatinine after initial drop \<200 micromol/l or creatinine \>200 micromol/l at baseline
3. Evidence of early acute rejection, either suspected clinically and/or proven by biopsy
4. 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
5. Evidence of severe hyper- or hypoparathyroidism (iPTH \>800 ng/l or \<10 ng/l)
6. Hypocalcemia (total calcium \<1.8 mmol/l) or hypercalcemia (total calcium \>2.7 mmol/l)
7. Steroid-free de novo immunosuppression scheme

Primary outcomes:
measure: Percent Change in BMD at the Total Lumbar Spine From Baseline to Month 12
timeFrame: Baseline and month 12
Secondary outcomes:
measure: Percent Change in BMD at the Total Hip From Baseline to Month 12
timeFrame: Baseline and month 12
measure: Percent Change in BMD at the Femoral Neck From Baseline to Month 12
timeFrame: Baseline and month 12
measure: Percent Change in BMD at the Total Lumbar Spine From Baseline to Month 6
timeFrame: Baseline and month 6
measure: Percent Change in BMD at the Total Hip From Baseline to Month 6
timeFrame: Baseline and month 6
measure: Percent Change in BMD at the Femoral Neck From Baseline to Month 6
timeFrame: Baseline and month 6
measure: Beta-CTX at Baseline and Months 3, 6 and 12
timeFrame: baseline, month 3, month 6, and month 12
measure: P1NP at Baseline and Months 3, 6 and 12
timeFrame: baseline, month 3, month 6, and month 12
Other outcomes:
measure: Blood Levels of Calcium (mmol/L) at Baseline and Months 0.5, 1, 2, 3, 6, 12
timeFrame: baseline, months 0.5, 1, 2, 3, 6, 12
measure: Blood Levels of Phosphate (mmol/L) at Baseline and Months 0.5, 1, 2, 3, 6, 12
timeFrame: baseline, months 0.5, 1, 2, 3, 6, 12
measure: Blood Levels of PTH (ng/L) at Baseline and Months 3, 6, and 12
timeFrame: baseline and months 3, 6, and 12
measure: 25-OH-vitamin D3
timeFrame: baseline, months 3, 6, and 12
measure: 1,25-(OH)2 Vitamin D3
timeFrame: baseline, months 3, 6, and 12
measure: Percent Change From Baseline in Total Volumetric Bone Mineral Densitiy (Tot.vBMD) at the Distal Tibia
timeFrame: Baseline and month 12
measure: Percent Change From Baseline in Cortical Volumetric Bone Mineral Densitiy (Ct.vBMD) at the Distal Tibia
timeFrame: Baseline and month 12
measure: Percent Change From Baseline in Trabecular Volumetric Bone Mineral Densitiy (Tb.vBMD) at the Distal Tibia
timeFrame: Baseline and month 12
measure: Percent Change From Baseline in Cortical Thickness (Ct.Th) at the Distal Tibia
timeFrame: Baseline and month 12
measure: Percent Change From Baseline in Total Volumetric Bone Mineral Densitiy (Tot.vBMD) at the Distal Radius
timeFrame: Baseline and month 12
measure: Percent Change From Baseline in Cortical Volumetric Bone Mineral Densitiy (Ct.vBMD) at the Distal Radius
timeFrame: Baseline and month 12
measure: Percent Change From Baseline in Trabecular Volumetric Bone Mineral Densitiy (Tb.vBMD) at the Distal Radius
timeFrame: Baseline and month 12
measure: Percent Change From Baseline in Cortical Thickness (Ct.Th) at the Distal Radius
timeFrame: Baseline and month 12
Locations:
city: Zurich
country: Switzerland
facility: Division of Nephrology, University Hospital
Study officials:
affiliation: Division of Nephrology, University Hospital, Zurich
name: Rudolf P Wuthrich, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bonani M, Frey D, Brockmann J, Fehr T, Mueller TF, Saleh L, von Eckardstein A, Graf N, Wuthrich RP. Effect of Twice-Yearly Denosumab on Prevention of Bone Mineral Density Loss in De Novo Kidney Transplant Recipients: A Randomized Controlled Trial. Am J Transplant. 2016 Jun;16(6):1882-91. doi: 10.1111/ajt.13692. Epub 2016 Feb 29.