Steroid Withdrawal and Donor-specific Anti-HLA Antibodies in Renal Transplant Patients

NCT02284464 | Completed Phase 4 Results DMC

• 1 other identifier: EVITAESTEROIDE-12
• Study Type: interventional
• Target: 230
• Locations: 1 country
• Sites: 5

Brief Summary

Steroids are one of the pillars of immunosuppression for kidney transplant patients but their use is associated with a high rate of complications. Withdrawal of steroids reduces some metabolic and cardiovascular complications, but it may increase the risk of acute rejection. However, little is known about whether steroid withdrawal is associated with the generation of anti-HLA donor-specific antibodies (DSA) and the relation between DSA and clinical and histological data. The aim of this study is to compare the incidence of de novo anti-HLA DSA in stable kidney transplant patients after withdrawing the steroids 3 months after the transplantation as compared with patients who continue with steroids. The hypothesis is that steroid withdrawal will increase the presence of de novo anti-HLA DSA in stable kidney transplant patients

Conditions

Other Complication of Kidney Transplant; Renal Transplant Rejection

Keywords

Kidney transplant; Immunosuppression; Steroid withdrawal; Donor specific antibodies

Outcome Measures

Primary Outcomes (1)

• Cases of Kidney Transplant Patients With DSA

  Measurements of DSA at baseline, and at 3, 6, 12, 18 and 24 months

  24 months

Secondary Outcomes (10)

• Mean Score on the Protocol Biopsies in the Two Treatment Groups

  24 months

• Number of Participants With Acute Rejection Lesions

  24 months

• Incidence of Diabetes Mellitus

  24 months

• Lipid Profile

  24 months

• Blood Pressure

  24 months

Study Arms (2)

Steroids, tacrolimus and mycophenolate

ACTIVE COMPARATOR

Normal treatment arm

Drug: Prednisone continuation

Tacrolimus and mycophenolate

EXPERIMENTAL

Normal treatment for first 90 days, then steroid withdrawal carrying on with the other drugs

Drug: Prednisone withdrawal

Interventions

Prednisone withdrawal DRUG

Withdrawal of steroids

Tacrolimus and mycophenolate

Prednisone continuation DRUG

Continuation of steroids

Steroids, tacrolimus and mycophenolate

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female patients aged over 18 years with no immunological risk (PRA \<25% and no DSA) who are receiving their first cadaveric or living kidney transplant.
• Patients who, three months after the transplantation, are receiving tacrolimus in combination with mycophenolic acid (MPA) or mycophenolate mofetil (MMF) plus steroids, with stable plasma levels of tacrolimus.
• No clinical or histological immunological dysfunction before randomization
• No de novo anti-HLA DSA at the time of randomization.
• Patients who wish to and are able to give written informed consent to participate in the study.
• For women, agreeing to use efficient contraception during the study.

You may not qualify if:

• Patients who receive a multiorgan transplant.
• Retransplants.
• Presence of DSA before the transplant or at the time of randomization.
• Cold ischemia time \>30 hours
• Patients with serum creatinine \>2 mg/dL or proteinuria \>1g/day at the time of randomization
• Prior episode of severe rejection (II-B-III in the Banff/13 classification) prior to randomization.
• Presence of subclinical rejection on the protocol biopsy prior to randomization
• Patients with BK-polyomavirus nephropathy at the time of randomization.
• Patients with recurrent or de novo glomerulonephritis.
• Patients who are being treated with immunosuppressive drugs other than those in the randomized clinical trial in question.
• Patients who are positive for the human immunodeficiency virus (HIV) or those who have a severe systemic infection that, in the investigator's judgment, will require continued treatment.
• Patients with any present or prior (during the previous 5 years) malignant disease, except basal or squamous cell carcinoma that has been excised.

Sponsors & Collaborators

• Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud: lead
• Sociedad Andaluza de Trasplantes de Organos y Tejidos: collaborator

Study Sites (5)

Vall d Hebron Hospital

Barcelona, 08035, Spain

Location

Bellvitge Hospital

Barcelona, 08907, Spain

Location

Carlos Haya Hospital

Málaga, 29010, Spain

Location

Canarias University Hospital

Santa Cruz de Tenerife, 38200, Spain

Location

Dr. Peset Hospital

Valencia, 46017, Spain

Location

Related Publications (21)

• Miller LW. Cardiovascular toxicities of immunosuppressive agents. Am J Transplant. 2002 Oct;2(9):807-18. doi: 10.1034/j.1600-6143.2002.20902.x.

  PMID: 12392286 BACKGROUND

• Marcen R. Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs. 2009 Nov 12;69(16):2227-43. doi: 10.2165/11319260-000000000-00000.

  PMID: 19852526 BACKGROUND

• Vincenti F, Schena FP, Paraskevas S, Hauser IA, Walker RG, Grinyo J; FREEDOM Study Group. A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients. Am J Transplant. 2008 Feb;8(2):307-16. doi: 10.1111/j.1600-6143.2007.02057.x.

  PMID: 18211506 BACKGROUND

• Arnol M, de Mattos AM, Chung JS, Prather JC, Mittalhenkle A, Norman DJ. Late steroid withdrawal and cardiovascular events in kidney transplant recipients. Transplantation. 2008 Dec 27;86(12):1844-8. doi: 10.1097/TP.0b013e31818ffec0.

  PMID: 19104432 BACKGROUND

• Opelz G, Dohler B. Association between steroid dosage and death with a functioning graft after kidney transplantation. Am J Transplant. 2013 Aug;13(8):2096-105. doi: 10.1111/ajt.12313. Epub 2013 Jun 10.

  PMID: 23750878 BACKGROUND

• Opelz G, Dohler B, Laux G; Collaborative Transplant Study. Long-term prospective study of steroid withdrawal in kidney and heart transplant recipients. Am J Transplant. 2005 Apr;5(4 Pt 1):720-8. doi: 10.1111/j.1600-6143.2004.00765.x.

  PMID: 15760395 BACKGROUND

• Gonzalez-Molina M, Gentil MA, Burgos D, Cabello M, Cobelo C, Bustamante J, Errasti P, Franco A, Hernandez D. Effect of long-term steroid withdrawal in renal transplant recipients: a retrospective cohort study. NDT Plus. 2010 Jun;3(Suppl_2):ii32-ii36. doi: 10.1093/ndtplus/sfq064.

  PMID: 20508858 BACKGROUND

• Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol. 2000 Oct;11(10):1910-1917. doi: 10.1681/ASN.V11101910.

  PMID: 11004223 BACKGROUND

• Pascual J, Quereda C, Zamora J, Hernandez D; Spanish Group for Evidence-Based Medicine in Renal Transplantation. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation. 2004 Nov 27;78(10):1548-56. doi: 10.1097/01.tp.0000140969.43761.1f.

  PMID: 15599321 BACKGROUND

• Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P; Astellas Corticosteroid Withdrawal Study Group. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg. 2008 Oct;248(4):564-77. doi: 10.1097/SLA.0b013e318187d1da.

  PMID: 18936569 BACKGROUND

• Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant. 2004 Mar;4(3):438-43. doi: 10.1111/j.1600-6143.2004.00360.x.

  PMID: 14961999 BACKGROUND

• Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ, Goldberg A, Birk PE, Rush DN, Nickerson PW. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012 May;12(5):1157-67. doi: 10.1111/j.1600-6143.2012.04013.x. Epub 2012 Mar 19.

  PMID: 22429309 BACKGROUND

• Gill JS, Landsberg D, Johnston O, Shapiro RJ, Magil AB, Wu V, Tinckam K, Keown P. Screening for de novo anti-human leukocyte antigen antibodies in nonsensitized kidney transplant recipients does not predict acute rejection. Transplantation. 2010 Jan 27;89(2):178-84. doi: 10.1097/TP.0b013e3181c3503e.

  PMID: 20098280 BACKGROUND

• Cantarovich D, De Amicis S, Akl A, Devys A, Vistoli F, Karam G, Soulillou JP. Posttransplant donor-specific anti-HLA antibodies negatively impact pancreas transplantation outcome. Am J Transplant. 2011 Dec;11(12):2737-46. doi: 10.1111/j.1600-6143.2011.03729.x. Epub 2011 Sep 11.

  PMID: 21906255 BACKGROUND

• Hoshino J, Kaneku H, Everly MJ, Greenland S, Terasaki PI. Using donor-specific antibodies to monitor the need for immunosuppression. Transplantation. 2012 Jun 15;93(11):1173-8. doi: 10.1097/TP.0b013e31824f3d7c.

  PMID: 22592887 BACKGROUND

• Worthington JE, Martin S, Al-Husseini DM, Dyer PA, Johnson RW. Posttransplantation production of donor HLA-specific antibodies as a predictor of renal transplant outcome. Transplantation. 2003 Apr 15;75(7):1034-40. doi: 10.1097/01.TP.0000055833.65192.3B.

  PMID: 12698094 BACKGROUND

• Mao Q, Terasaki PI, Cai J, Briley K, Catrou P, Haisch C, Rebellato L. Extremely high association between appearance of HLA antibodies and failure of kidney grafts in a five-year longitudinal study. Am J Transplant. 2007 Apr;7(4):864-71. doi: 10.1111/j.1600-6143.2006.01711.x.

  PMID: 17391129 BACKGROUND

• Moreso F, Ibernon M, Goma M, Carrera M, Fulladosa X, Hueso M, Gil-Vernet S, Cruzado JM, Torras J, Grinyo JM, Seron D. Subclinical rejection associated with chronic allograft nephropathy in protocol biopsies as a risk factor for late graft loss. Am J Transplant. 2006 Apr;6(4):747-52. doi: 10.1111/j.1600-6143.2005.01230.x.

  PMID: 16539631 BACKGROUND

• Anil Kumar MS, Irfan Saeed M, Ranganna K, Malat G, Sustento-Reodica N, Kumar AM, Meyers WC. Comparison of four different immunosuppression protocols without long-term steroid therapy in kidney recipients monitored by surveillance biopsy: five-year outcomes. Transpl Immunol. 2008 Nov;20(1-2):32-42. doi: 10.1016/j.trim.2008.08.005. Epub 2008 Sep 4.

  PMID: 18773960 BACKGROUND

• Hernandez D, Alonso-Titos J, Vazquez T, Leon M, Caballero A, Cobo MA, Sola E, Lopez V, Ruiz-Esteban P, Cruzado JM, Sellares J, Moreso F, Manonelles A, Torio A, Cabello M, Delgado-Burgos J, Casas C, Gutierrez E, Jironda C, Kanter J, Seron D, Torres A. Clinical Relevance of Corticosteroid Withdrawal on Graft Histological Lesions in Low-Immunological-Risk Kidney Transplant Patients. J Clin Med. 2021 May 7;10(9):2005. doi: 10.3390/jcm10092005.

  PMID: 34067039 DERIVED

• Hernandez D, Vazquez T, Alonso-Titos J, Leon M, Caballero A, Cobo MA, Sola E, Lopez V, Ruiz-Esteban P, Cruzado JM, Sellares J, Moreso F, Manonelles A, Torio A, Cabello M, Delgado-Burgos J, Casas C, Gutierrez E, Jironda C, Kanter J, Seron D, Torres A. Impact of HLA Mismatching on Early Subclinical Inflammation in Low-Immunological-Risk Kidney Transplant Recipients. J Clin Med. 2021 Apr 29;10(9):1934. doi: 10.3390/jcm10091934.

  PMID: 33947168 DERIVED

Results Point of Contact

• Title: Dr. Domingo Hernandez
• Organization: Hospital Regional Universitario de Málaga

domingohernandez@gmail.com

951291174

Study Officials

• Domingo Hernandez, PhD

  Carlos Haya Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 16, 2014
• First Posted: November 6, 2014
• Study Start: February 1, 2015
• Primary Completion: July 1, 2019
• Study Completion: December 1, 2019
• Last Updated: April 14, 2020
• Results First Posted: April 14, 2020

Record last verified: 2019-12

Locations

ES (5)