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

• ClinicalTrials.gov Identifier: NCT01377467
• Recruitment Status: Completed
• First Posted: June 21, 2011
• Results First Posted: April 26, 2016
• Last Update Posted: May 26, 2016
• Sponsor: Rudolf Wuethrich
• Information provided by (Responsible Party): Rudolf Wuethrich, University of Zurich

Study Description

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

Condition or disease	Intervention/treatment	Phase
Osteoporosis; Chronic Kidney Disease	Drug: Denosumab (Prolia)	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: June 2011
• Actual Primary Completion Date: May 2015
• Actual Study Completion Date: October 2015

Arms and Interventions

Arm	Intervention/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 Name: Prolia
No Intervention: Control; No treatment

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Other Outcome Measures:

1. Blood Levels of Calcium (mmol/L) at Baseline and Months 0.5, 1, 2, 3, 6, 12 [ Time Frame: baseline, 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
2. Blood Levels of Phosphate (mmol/L) at Baseline and Months 0.5, 1, 2, 3, 6, 12 [ Time Frame: baseline, 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
3. Blood Levels of PTH (ng/L) at Baseline and Months 3, 6, and 12 [ Time Frame: baseline and months 3, 6, and 12 ]
   Blood levels of PTH (ng/L) were measured at baseline and at months 3, 6, and 12
4. 25-OH-vitamin D3 [ Time Frame: baseline, months 3, 6, and 12 ]
   Blood levels of 25-OH-vitamin D3 were measured as microgramm/L
5. 1,25-(OH)2 Vitamin D3 [ Time Frame: baseline, months 3, 6, and 12 ]
   Blood levels of 1,25-(OH)2 vitamin D3 were measured as ng/L
6. Percent Change From Baseline in Total Volumetric Bone Mineral Densitiy (Tot.vBMD) at the Distal Tibia [ Time Frame: Baseline and month 12 ]
   Volumetric BMD (vBMD) was measured via HR-pQCT (Xtreme CT) at the distal tibia and was expressed as mg HA/cm3.
7. Percent Change From Baseline in Cortical Volumetric Bone Mineral Densitiy (Ct.vBMD) at the Distal Tibia [ Time Frame: Baseline and month 12 ]
   Volumetric BMD (vBMD) was measured via HR-pQCT (Xtreme CT) at the distal tibia and was expressed as mg HA/cm3.
8. Percent Change From Baseline in Trabecular Volumetric Bone Mineral Densitiy (Tb.vBMD) at the Distal Tibia [ Time Frame: Baseline and month 12 ]
   Volumetric BMD (vBMD) was measured via HR-pQCT (Xtreme CT) at the distal tibia and was expressed as mg HA/cm3.
9. Percent Change From Baseline in Cortical Thickness (Ct.Th) at the Distal Tibia [ Time Frame: Baseline and month 12 ]
   Cortical thickness was measured via HR-pQCT (Xtreme CT) at the distal tibia and was expressed as mm.
10. Percent Change From Baseline in Total Volumetric Bone Mineral Densitiy (Tot.vBMD) at the Distal Radius [ Time Frame: Baseline and month 12 ]
    Volumetric BMD (vBMD) was measured via HR-pQCT (Xtreme CT) at the distal radius and was expressed as mg HA/cm3.
11. Percent Change From Baseline in Cortical Volumetric Bone Mineral Densitiy (Ct.vBMD) at the Distal Radius [ Time Frame: Baseline and month 12 ]
    Volumetric BMD (vBMD) was measured via HR-pQCT (Xtreme CT) at the distal radius and was expressed as mg HA/cm3.
12. Percent Change From Baseline in Trabecular Volumetric Bone Mineral Densitiy (Tb.vBMD) at the Distal Radius [ Time Frame: Baseline and month 12 ]
    Volumetric BMD (vBMD) was measured via HR-pQCT (Xtreme CT) at the distal radius and was expressed as mg HA/cm3.
13. Percent Change From Baseline in Cortical Thickness (Ct.Th) at the Distal Radius [ Time Frame: Baseline and month 12 ]
    Cortical thickness was measured via HR-pQCT (Xtreme CT) at the distal radius and was expressed as mm.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Switzerland

Division of Nephrology, University Hospital

Zurich, Switzerland, 8091

Sponsors and Collaborators

Rudolf Wuethrich

Investigators

• Principal Investigator: Rudolf P Wuthrich, MD; Division of Nephrology, University Hospital, Zurich

More Information

Publications of Results:

Bonani M, Frey D, Brockmann J, Fehr T, Mueller TF, Saleh L, von Eckardstein A, Graf N, Wüthrich 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.

• Responsible Party: Rudolf Wuethrich, Professor and Director, University of Zurich
• ClinicalTrials.gov Identifier: NCT01377467
• Other Study ID Numbers: UZH-NEP 2.1
• First Posted: June 21, 2011
• Results First Posted: April 26, 2016
• Last Update Posted: May 26, 2016
• Last Verified: April 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Rudolf Wuethrich, University of Zurich:

Osteoporosis; Osteopenia; Denosumab; Transplantation; Kidney

Additional relevant MeSH terms:

Osteoporosis; Kidney Diseases; Renal Insufficiency, Chronic; Urologic Diseases; Renal Insufficiency; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Denosumab; Bone Density Conservation Agents; Physiological Effects of Drugs