Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Paricalcitol Versus Calcitriol for the Management of Renocardiac Syndrome in Renal Transplant Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01265615
Recruitment Status : Completed
First Posted : December 23, 2010
Results First Posted : June 21, 2011
Last Update Posted : June 9, 2015
Sponsor:
Collaborators:
Ural Institute of Cardiology
De Haar Research Foundation
Information provided by (Responsible Party):
Alexander Kharlamov, Ural Medical University

Tracking Information
First Submitted Date  ICMJE December 22, 2010
First Posted Date  ICMJE December 23, 2010
Results First Submitted Date  ICMJE December 27, 2010
Results First Posted Date  ICMJE June 21, 2011
Last Update Posted Date June 9, 2015
Study Start Date  ICMJE October 2009
Actual Primary Completion Date April 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 23, 2011)
CAD (Chronic Allograft Dysfunction) Degree [ Time Frame: day 180 after Tx (transplantation) ]
Beyond 180 days, chronic allograft dysfunction (CAD) was characterized by mean Banff degree (revised 2005/2007 criteria) with the data of renal biopsy material. Renal tissue was recovered during routined biopsy. We assessed antibody-mediated rejection, borderline changes, T-cell-mediated rejection, interstitial fibrosis and tubular atropthy, and other changes. Grades: Grade I. Mild interstitial fibrosis and tubular atrophy (<25% of cortical area) II. Moderate (26-50%) III. Severe (>50%) (may include non-specific vascular and glomerular sclerosis)
Original Primary Outcome Measures  ICMJE
 (submitted: December 22, 2010)
CAN degree on day 180 after Tx [ Time Frame: day 180 ]
CAN degree assessed by routine kidney biopsy
Change History Complete list of historical versions of study NCT01265615 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 23, 2011)
  • Heart Failure (HF) [ Time Frame: on day 180 after Tx (transplantation) ]
    NYHA (New York Heart Association) functional class verified with veloergometry probe and by NYHA clinical classification NYHA Class Symptoms I No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, climbing stairs etc. II Mild symptoms and slight limitation during ordinary activity. III Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m). Comfortable only at rest. IV Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.
  • GFR (Glomerular Filtration Rate) [ Time Frame: on day 180 ]
    Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated form of the Modification of Diet in Renal Disease (MDRD) study equation: eGFR = exp (5.228 − 1.154 × ln (serum creatinine) − 0.203 × ln (age). Concerning of GFR with Tc99m DTPA renography was used for the complex analysis of renal function. Camera based GFR estimated from Tc99m DTPA renography was named Gates GFR.
  • CAD (Chronic Allograft Dysfunction) Degree [ Time Frame: on day 90 ]
    CAD degree measured by Banff score after routine renal biopsy (revised 2005/2007 criteria). We assessed antibody-mediated rejection, borderline changes, T-cell-mediated rejection, interstitial fibrosis and tubular atropthy, and other changes. Grades: Grade I. Mild interstitial fibrosis and tubular atrophy (<25% of cortical area) II. Moderate (26-50%) III. Severe (>50%) (may include non-specific vascular and glomerular sclerosis)
  • Serum Creatinine [ Time Frame: on day 180 after Tx ]
    After an overnight fast, plasma concentrations of hemoglobin, creatinine, cholesterol, glucose, total calcium, and phosphate were measured using an autoanalyzer as described by Adorini L. (2005)
  • Number of Circulating SP (Side Population) Stem-Progenitor Cells [ Time Frame: on day 180 ]
    Renal cells and solid tissue were obtained from the normal portion of cortex obtained from surgically removed kidneys or by standart biopsy on day 180. Cytofluorimetric analysis and immunofluorescence were performed as described by Oliver J.A. (2004). Sorting and analysis of different cells was done on a FACS (fluorescent activated cell sorting) and by flow cytometry. Cells were analyzed with EPICS systems (Beckman Coulter). Quantification of mRNA expression was achieved using Assays-on-Demand gene expression kits and the ABI PRISM 7000 Sequence Detection System (Applied Biosystem).
  • VDR (Vitamin D Receptor) Expression in Myocardium [ Time Frame: on day 180 ]
    VDR content was determined by using an ELISA developed in this laboratory. The protein concentration of the homogenates was determined by the method of Bradford (1976), using BSA as a standard.
  • VDR (Vitamin D Receptor) Expression in Kidney [ Time Frame: on day 180 ]
    VDR content was determined by using an ELISA developed in this laboratory. The protein concentration of the homogenates was determined by the method of Bradford (1976), using BSA as a standard.
  • Systolic Blood Pressure [ Time Frame: on day 180 ]
    SBP measured by routine method
  • Coronary Calcium Score [ Time Frame: on day 180 ]
    Bone mineral density assessed by dual-energy X-ray absorptiometry (DXA) of the whole body, lumbar spine and hip was performed using Hologic scanners (QDR 1000W or QDR 2000). The total Agatston coronary calcium score (CCS) was measured as the sum of calcified plaque scores of all the coronary arteries. The amount of calcium present in the coronary arteries is scored according to the Agatson scale, as follows: 0 - no identifiable disease; 1 to 99 - mild disease; 100 to 399 - moderate disease; 400 or higher - severe disease.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 22, 2010)
Combined outcome [ Time Frame: day 180 ]
CAN degree on day 90; glomerular filtration rate (GFR), and creatinine before and on day 180; distribution of SPCs (SP+ circulating, and 'incorporated' cells), and CD133, CD34, CD73, CD105-positive cells in blood, and in the renal tissue on day 180; CD-phenotype of SP-positive cells on day 180; VDR expression in SPCs and renal tissue on day 180; hypercalcemia rate; blood pressure (BP), NYHA functional class of heart failure (HF), ejection fraction (Ef), and brain-natriuretic peptide (BNP) on day 180; coronary calcium score (CCS) before Tx and on day 180
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Paricalcitol Versus Calcitriol for the Management of Renocardiac Syndrome in Renal Transplant Patients
Official Title  ICMJE Phase 4 Study of Paricalcitol and Calcitriol for Reparative Management of Chronic Allograft Dysfunction and Renocardiac Syndrome in Vitamin D Insufficient Renal Transplant Recipients
Brief Summary We hypothesize that paricalcitol and calcitriol in dose-dependent manner are effective for the management of chronic allograft dysfunction (CAD), protection and repair of kidney and heart, management of chronic renocardiac syndrome (CRS). We assume that paricalcitol can have some advantages if compare with calcitriol or cholecalciferol due to absence of calcemic and phosphatemic complications alongside with great beneficial potential.
Detailed Description

Paricalcitol and calcitriol are identically effective for the management of chronic allograft dysfunction (CAD), protection and repair of kidney and heart, management of chronic renocardiac syndrome (CRS). Vitamin D can reduce progression of CAD. Activation of VDR in proximal part of nephron leads to rapid non-genomic beneficial effects with urgent multilevel protection of the most functionally important portion of kidney. Rising expression of VDR in distal portions of nephron stimulates slows genomic effects with some local repair responses.

Hormone D may stimulate recruitment and activity of the different origin stem-progenitor cells (SPCs) with beneficial effects on different stages of regeneration by force of para- and autocrine activity. SPCs are revealing mostly in interstitium and among fibroblast-like cells. Vitamin D did not confirm efficacy as a tool for management of mesenchymal stem cells (MSCs) in human however it needs more research experimental evidences due to multifactorial influence on SPCs in human being including immunosuppressive and bone-marrow-related effects of cyclosporine in kidney transplant (Tx) patients. Paricalcitol and calcitriol can slow down migration and infiltration of MSC into interstitium and vessel wall. The side population of mature and SPCs (first of all, with bone-marrow and mesenchymal phenotype) is the most metabolically and functionally active portion of cells with high sensitivity to vitamin D receptor (VDR) activation that responsible for repair of tissue.

The most optimal scheme of treatment with vitamin D in patients with CAD and CRS is an administration of paricalcitol with dose 2-4 μg daily and supplemental intake of vitamin D including special diet, multivitamins, and others with optimal dose until 1800 international units (IU) but excluding insolation as a factor of skin carcinoma. High-dose medicinal intake of calcitriol (until 6 mcg and higher) showed relatively high efficacy but rather excessive level of complications mediated with mineral metabolism.

Paricalcitol and calcitriol may significantly improve contractility of myocardium and reduce cardiovascular risk, heart failure (HF) and hypertension with some beneficial effects on cardiorenal axis and renin-angiotensin-aldosterone system.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Cardiorenal Syndrome
  • Chronic Allograft Nephropathy
Intervention  ICMJE
  • Drug: Paricalcitol
    paricalcitol group (6-8 μg daily per os - orally - without special diet)
    Other Name: Zemplar
  • Drug: Calcitriol
    calcitriol group (2-4 μg daily orally under with dietary restrictions of vitamin D)
    Other Name: Rocaltrol
  • Drug: Cholecalciferol
    cholecalciferol group (intake of cholecalciferol with recommended daily allowance equals 1200-2400 IU per day)
    Other Name: Fosamax
  • Dietary Supplement: Supplemental
    intake of cholecalciferol in food and multivitamins, less than 400-900 IU per day
    Other Name: Diet, sun, multivitamin drugs, food
Study Arms  ICMJE
  • Active Comparator: Paricalcitol treatment
    6-8 μg daily per os (orally) without special diet
    Intervention: Drug: Paricalcitol
  • Active Comparator: Calcitriol treatment
    2-4 μg daily orally under with dietary restrictions of vitamin D
    Intervention: Drug: Calcitriol
  • Active Comparator: Cholecalciferol
    alendronate sodium/ cholecalciferol capsules with recommended daily allowance equals 1200-2400 IU per day
    Intervention: Drug: Cholecalciferol
  • Supplemental
    intake of cholecalciferol in food and multivitamins, less than 400-900 IU per day
    Intervention: Dietary Supplement: Supplemental
Publications * Kharlamov AN, Perrish AN, Gabiskiĭ IaL, Ronne Kh, Ivanova EIu. [Vitamin D in the treatment of cardiorenal syndrome in patients with chronic nephropathy]. Kardiologiia. 2012;52(3):33-44. Russian.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 23, 2011)
109
Original Actual Enrollment  ICMJE
 (submitted: December 22, 2010)
120
Actual Study Completion Date  ICMJE September 2010
Actual Primary Completion Date April 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age 40-75
  • Male
  • History of chronic kidney disease and cardiorenal syndrome
  • Written informed consent

Exclusion Criteria:

  • Female
  • Acute illness
  • Life-threat competitive illness
  • Mental disorders
  • Endocrinologic diseases (including diabetes mellitus, hyperparathyroidism, and other thyroid disorders)
  • Need for dialyses
  • Hypercalcemia
  • Concomitant use of hormone or cytokine medication
  • Participation to any drug-investigation during the previous 60 days as checked with VIP check
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 40 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands,   Russian Federation
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01265615
Other Study ID Numbers  ICMJE VDCRS03
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Alexander Kharlamov, Ural Medical University
Study Sponsor  ICMJE Ural Medical University
Collaborators  ICMJE
  • Ural Institute of Cardiology
  • De Haar Research Foundation
Investigators  ICMJE
Principal Investigator: Alexander Kharlamov, M.D. Ural Institute of Cardiology
Principal Investigator: Alexander Perrish, M.D. Ural Medical University
PRS Account Ural Medical University
Verification Date May 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP