Denosumab for Prevention of Osteoporosis in Renal Transplant Recipients (POSTOP)

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

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

Study Overview

• Status: Completed
• Conditions: Chronic Kidney Disease; Osteoporosis
• Intervention / Treatment: Drug: Denosumab (Prolia)

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.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 3

Contacts and Locations

Study Locations

• Switzerland
  • Zurich, Switzerland, 8091
    • Division of Nephrology, University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; No treatment
Experimental: Denosumab; 60 mg denosumab s.c. at baseline and after 6 months	Drug: Denosumab (Prolia); 60 mg s.c. injection at baseline and after 6 months; Other Names: Prolia

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Levels of Calcium (mmol/L) at Baseline and Months 0.5, 1, 2, 3, 6, 12	Blood levels of calcium (mmol/L) were measured at baseline and at months 0.5, 1, 2, 3, 6, and 12	baseline, months 0.5, 1, 2, 3, 6, 12
Blood Levels of Phosphate (mmol/L) at Baseline and Months 0.5, 1, 2, 3, 6, 12	Blood levels of phosphate (mmol/L) were measured at baseline and at months 0.5, 1, 2, 3, 6, 12	baseline, months 0.5, 1, 2, 3, 6, 12
Blood Levels of PTH (ng/L) at Baseline and Months 3, 6, and 12	Blood levels of PTH (ng/L) were measured at baseline and at months 3, 6, and 12	baseline and months 3, 6, and 12
25-OH-vitamin D3	Blood levels of 25-OH-vitamin D3 were measured as microgramm/L	baseline, months 3, 6, and 12
1,25-(OH)2 Vitamin D3	Blood levels of 1,25-(OH)2 vitamin D3 were measured as ng/L	baseline, months 3, 6, and 12
Percent Change From Baseline in Total Volumetric Bone Mineral Densitiy (Tot.vBMD) at the Distal Tibia	Volumetric BMD (vBMD) was measured via HR-pQCT (Xtreme CT) at the distal tibia and was expressed as mg HA/cm3.	Baseline and month 12
Percent Change From Baseline in Cortical Volumetric Bone Mineral Densitiy (Ct.vBMD) at the Distal Tibia	Volumetric BMD (vBMD) was measured via HR-pQCT (Xtreme CT) at the distal tibia and was expressed as mg HA/cm3.	Baseline and month 12
Percent Change From Baseline in Trabecular Volumetric Bone Mineral Densitiy (Tb.vBMD) at the Distal Tibia	Volumetric BMD (vBMD) was measured via HR-pQCT (Xtreme CT) at the distal tibia and was expressed as mg HA/cm3.	Baseline and month 12
Percent Change From Baseline in Cortical Thickness (Ct.Th) at the Distal Tibia	Cortical thickness was measured via HR-pQCT (Xtreme CT) at the distal tibia and was expressed as mm.	Baseline and month 12
Percent Change From Baseline in Total Volumetric Bone Mineral Densitiy (Tot.vBMD) at the Distal Radius	Volumetric BMD (vBMD) was measured via HR-pQCT (Xtreme CT) at the distal radius and was expressed as mg HA/cm3.	Baseline and month 12
Percent Change From Baseline in Cortical Volumetric Bone Mineral Densitiy (Ct.vBMD) at the Distal Radius	Volumetric BMD (vBMD) was measured via HR-pQCT (Xtreme CT) at the distal radius and was expressed as mg HA/cm3.	Baseline and month 12
Percent Change From Baseline in Trabecular Volumetric Bone Mineral Densitiy (Tb.vBMD) at the Distal Radius	Volumetric BMD (vBMD) was measured via HR-pQCT (Xtreme CT) at the distal radius and was expressed as mg HA/cm3.	Baseline and month 12
Percent Change From Baseline in Cortical Thickness (Ct.Th) at the Distal Radius	Cortical thickness was measured via HR-pQCT (Xtreme CT) at the distal radius and was expressed as mm.	Baseline and month 12

Collaborators and Investigators

• Sponsor: Rudolf Wuethrich
• Investigators: Principal Investigator: Rudolf P Wuthrich, MD, Division of Nephrology, University Hospital, Zurich

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: June 20, 2011
• First Submitted That Met QC Criteria: June 20, 2011
• First Posted (Estimate): June 21, 2011

Study Record Updates

• Last Update Posted (Estimate): May 26, 2016
• Last Update Submitted That Met QC Criteria: April 26, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: Transplantation; Osteoporosis; Kidney; Osteopenia; Denosumab
• Additional Relevant MeSH Terms: Metabolic Diseases; Urologic Diseases; Renal Insufficiency; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Kidney Diseases; Renal Insufficiency, Chronic; Osteoporosis; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: UZH-NEP 2.1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No