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Efficacy and Safety of Paricalcitol for Reduction of Proteinuria in Kidney Transplant Recipients

Primary Purpose

Disorder of Transplanted Kidney, Proteinuria, Albuminuria

Status
Completed
Phase
Phase 3
Locations
Slovenia
Study Type
Interventional
Intervention
Paricalcitol
Placebo
Sponsored by
University Medical Centre Ljubljana
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Disorder of Transplanted Kidney focused on measuring Kidney transplantation, Proteinuria, Albuminuria, Vitamin D, Paricalcitol

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Recipients of a deceased donor kidney transplant at least 3 months after transplantation
  • Urinary protein to creatinine ratio (UPCR) > 200 mg/g (20 mg/mmol) as determined by the the mean of three second morning void urine specimens
  • Subject is on stable immunosuppression for at least 3 months
  • Subject is on stable doses of antihypertensive medications for at least 3 months
  • Subject is not expected to begin dialysis for at least 6 months
  • Estimated glomerular filtration rate > 15 ml/min/1.73 m2
  • Corrected serum calcium level < 2.6 mmol/l
  • Intact parathormone value > 30 pg/ml

Exclusion Criteria:

  • Subjects on vitamin D receptor activation therapy within 3 months prior to the first study visit
  • Acute kidney injury within 3 months of the first study visit
  • Subjects with poorly controlled hypertension

Sites / Locations

  • University Medical Centre Ljubljana

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Paricalcitol

Matching placebo

Arm Description

Outcomes

Primary Outcome Measures

The percentage change in urinary protein to creatinine ratio (UPCR) from baseline to the last measurement during treatment.

Secondary Outcome Measures

The percentage change in urinary albumin to creatinine ratio (UACR) from baseline to the last measurement during treatment.
Change in 24-hour urinary protein excretion form baseline to the last measurement during treatment.
The proportion of patients achieving at least a 15 mg/mmol reduction in the last on-treatment UPCR level from the baseline.
Change in estimated glomerular filtration rate, blood pressure and biomarkers, including (but not limited to) C-reactive protein, plasma renin activity, aldosterone.

Full Information

First Posted
September 14, 2011
Last Updated
December 22, 2017
Sponsor
University Medical Centre Ljubljana
Collaborators
Abbott
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1. Study Identification

Unique Protocol Identification Number
NCT01436747
Brief Title
Efficacy and Safety of Paricalcitol for Reduction of Proteinuria in Kidney Transplant Recipients
Official Title
Efficacy and Safety of Selective Vitamin D Receptor Activation With Paricalcitol for Reduction of Proteinuria in Kidney Transplant Recipients: a Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
December 2017
Overall Recruitment Status
Completed
Study Start Date
July 2012 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
July 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Medical Centre Ljubljana
Collaborators
Abbott

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The study 'Safety and Efficacy of Paricalcitol for Reduction of Proteinuria in Kidney Transplant Recipients' is designed to assess the effects of paricalcitol in kidney transplant recipients with proteinuria. It is a single centre, randomized, placebo-controlled, double-blind clinical trial that tests the hypothesis that 24 weeks' treatment with paricalcitol compared to placebo will result in a decrease in urinary protein excretion in recipients of a kidney transplant at least three months after transplantation. Additionally, the effects of paricalcitol on albuminuria, estimated glomerular filtration rate, and blood pressure will be investigated.
Detailed Description
Kidney transplantation is the treatment of choice for end-stage renal disease patients. In comparison to dialysis it offers longer survival and better quality of life to certain patients with end stage renal disease. In the last two decades, short-term (i.e. 1- and 3-year) kidney transplant survival has increased significantly and is currently exceeding 90% in state-of-the-art transplant centers. This is considered to be due to the safe and effective immunosuppressive therapy in the early post-transplant period, and to the careful management of patients with chronic renal disease (CRD) before and after the transplantation. In spite of the progress described above, long-term (i.e. 5- and 10-year) transplant survival has not significantly improved over the recent decades. Two main causes for long-term loss of transplanted kidneys are the development of the transplant chronic kidney disease (CKD) (i.e. chronic allograft nephropathy) and patient death with a functioning transplant due to cardiovascular events. Proteinuria (> 150 mg of proteins in urine per day) is a manifestation of kidney disease and is an important risk factor for CKD progression. This applies also to kidney transplant recipients. Studies have shown that proteinuria is present in 20-40% of transplanted patients. According to observational studies, proteinuria is an independent predictor for CKD progression and transplant failure, as well as of increased risk for cardiovascular events. In CKD patients, treatment with renin-angiotensin-aldosterone system inhibitors (RAAS - angiotensin converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor blockers) reduces proteinuria and thus slows the renal disease progression. In spite of the demonstrated renoprotective effect of RAAS inhibitors, the risk for CKD progression remains high. Furthermore, large epidemiological studies have not shown clinically significant effect of RAAS inhibitor therapy on the reduction of cardiovascular risk. In spite of an optimal RAAS inhibitor therapy, renal and cardiovascular diseases continue to progress, which is also associated with persistent proteinuria. Therefore, new treatment modalities to reduce proteinuria with consequent delay in the progression of CKD and cardiovascular disease are being sought. Calcitriol is an active form of vitamin D produced in the kidneys. It is important for calcium and phosphate metabolism, as well as for bone mineralization. Decreasing blood calcitriol levels are associated with declining renal function. Decreased calcitriol levels in patients with CKD contribute to the development of secondary hyperparathyroidism. Furthermore, calcitriol deficiency is associated with increased proteinuria and further progression of renal impairment. Vitamin D deficiency in patients with end stage renal disease is also related to higher cardiovascular mortality. The pleiotropic effects of calcitriol probably reflect the presence of vitamin D receptors in different tissues; it is via these receptors that calcitriol exerts its pharmacological effects. Vitamin D receptors have been found not only in kidneys and bones, but also in the cells of the myocardium, in the vascular endothelium, the endocrine part of the pancreas, the intestine and the prostate. Treatment with an analogue of the active vitamin D form, paricalcitol, significantly reduced proteinuria and slowed progression of renal disease in animal models as well as in patients with CKD, particularly in patients diabetes and diabetic nephropathy. This is considered to be due to the positive effect of paricalcitol on RAAS inhibition in the kidneys, which is independent of calcium and parathormone metabolism. Reduced proteinuria leads to a reduced inflammatory response, preservation of the glomerular basement membrane structure and slowing of glomerulosclerosis. The positive effects of paricalcitol on the reduction of proteinuria observed in patients with CKD may also be important for kidney transplant recipients: by reducing the proteinuria, progression of CKD in the transplanted kidney might be delayed and the risk for cardiovascular events reduced. This might contribute to the improvement of long-term kidney transplant survival, which has not changed significantly in the last two decades. This study tests the hypothesis whether paricalcitol persistently reduces proteinuria in kidney transplant recipients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Disorder of Transplanted Kidney, Proteinuria, Albuminuria
Keywords
Kidney transplantation, Proteinuria, Albuminuria, Vitamin D, Paricalcitol

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
168 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Paricalcitol
Arm Type
Active Comparator
Arm Title
Matching placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Paricalcitol
Other Intervention Name(s)
Zemplar
Intervention Description
2 micrograms daily, peroral, 24 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
2 micrograms daily, peroral, 24 weeks
Primary Outcome Measure Information:
Title
The percentage change in urinary protein to creatinine ratio (UPCR) from baseline to the last measurement during treatment.
Time Frame
baseline and 6 months
Secondary Outcome Measure Information:
Title
The percentage change in urinary albumin to creatinine ratio (UACR) from baseline to the last measurement during treatment.
Time Frame
baseline and 6 months
Title
Change in 24-hour urinary protein excretion form baseline to the last measurement during treatment.
Time Frame
baseline and 6 months
Title
The proportion of patients achieving at least a 15 mg/mmol reduction in the last on-treatment UPCR level from the baseline.
Time Frame
baseline and 6 months
Title
Change in estimated glomerular filtration rate, blood pressure and biomarkers, including (but not limited to) C-reactive protein, plasma renin activity, aldosterone.
Time Frame
baseline and 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Recipients of a deceased donor kidney transplant at least 3 months after transplantation Urinary protein to creatinine ratio (UPCR) > 200 mg/g (20 mg/mmol) as determined by the the mean of three second morning void urine specimens Subject is on stable immunosuppression for at least 3 months Subject is on stable doses of antihypertensive medications for at least 3 months Subject is not expected to begin dialysis for at least 6 months Estimated glomerular filtration rate > 15 ml/min/1.73 m2 Corrected serum calcium level < 2.6 mmol/l Intact parathormone value > 30 pg/ml Exclusion Criteria: Subjects on vitamin D receptor activation therapy within 3 months prior to the first study visit Acute kidney injury within 3 months of the first study visit Subjects with poorly controlled hypertension
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Miha Arnol, M.D., Ph.D.
Organizational Affiliation
University Medical Centre Ljubljana, Department of Nephrology
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Aljoša Kandus, M.D., Ph.D.
Organizational Affiliation
University Medical Centre Ljubljana, Department of Nephrology
Official's Role
Study Chair
Facility Information:
Facility Name
University Medical Centre Ljubljana
City
Ljubljana
ZIP/Postal Code
1000
Country
Slovenia

12. IPD Sharing Statement

Citations:
Citation
Arnol M, Oblak M, Mlinsek G, Bren AF, Buturović-Ponikvar J, Kandus A. Proteinuria in kidney transplant recipients: prevalence in a national cohort and study design of the effect of paricalcitol for reduction of proteinuria. Transplant International 2011; 24(2): 185(A204).
Results Reference
background
PubMed Identifier
30062716
Citation
Oblak M, Mlinsek G, Kandus A, Buturovic-Ponikvar J, Arnol M. Paricalcitol versus placebo for reduction of proteinuria in kidney transplant recipients: a double-blind, randomized controlled trial. Transpl Int. 2018 Dec;31(12):1391-1404. doi: 10.1111/tri.13323. Epub 2018 Aug 20.
Results Reference
derived

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Efficacy and Safety of Paricalcitol for Reduction of Proteinuria in Kidney Transplant Recipients

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