Selection of Immunosuppression in Kidney Transplant Recipients Depending on Pre-transplant Donor-specific T-cell Reactivity. (SIRES)

This study has been completed.
Sponsor:
Collaborator:
Carlos III Health Institute
Information provided by (Responsible Party):
Josep M Grinyo, Hospital Universitari de Bellvitge
ClinicalTrials.gov Identifier:
NCT01195194
First received: April 19, 2010
Last updated: February 24, 2014
Last verified: February 2014
  Purpose

The objective is to assess if low pre-transplantation donor specific T-cell reactive patients measured by Enzyme-linked immunosorbent spot (ELISPOT)assay can be safely managed with Calcineurin inhibitor(CNI)-free Sirolimus(SRL)-based immunosuppression.


Condition Intervention Phase
Disorder Related to Renal Transplantation
Drug: PRE-TRANSPLANT (PRE=before)
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pilot Study of Selection of Either Calcineurin Inhibitor(CNI)-Based or CNI-free Immunosuppressive Regimen Depending on the Result of Pre-transplantation Donor-specific T-cell Reactivity Measured by Enzyme-linked Immunosorbent Spot(ELISPOT) in Standard-risk Kidney Recipients.

Resource links provided by NLM:


Further study details as provided by Hospital Universitari de Bellvitge:

Primary Outcome Measures:
  • Percentage of biopsy-confirmed acute rejection episodes [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To describe cumulative biopsy-confirmed acute rejection in both groups by intention to treat analysis.


Secondary Outcome Measures:
  • Percentage of steroid-sensitive acute rejection episodes [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To describe the percentage of steroid-sensitive acute rejections rejection in both groups by intention to treat analysis.

  • Percentage of acute rejection episodes requiring treatment with antilymphocyte antibodies. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To describe the need for antibody treatment in acute rejection episodes in both groups by intention to treat analysis.

  • Renal function estimated by Modification of Diet in Renal Disease (MDRD) formula. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    To describe renal function measured by MDRD in both groups by intention to treat and "on therapy" analysis.

  • Proteinuria measured in g/day [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To describe proteinuria in g/day in both groups by intention to treat analysis.

  • Histology at month 6 protocol kidney allograft biopsy [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To describe histology at month 6 in both groups by intention to treat and "on therapy" analysis.

  • Percentage of patients with negative ELISPOT [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To describe percentage of patients with negative ELISPOT in both groups by intention to treat and "on therapy" analysis.

  • Percentage of patients in group A requiring CNI introduction. [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    To describe the percentage of patients in group A requiring CNI introduction.

  • Percentage of patients presenting adverse events requiring study withdrawal [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
    To describe adverse events in the whole group ("screening failure" plus "intention to treat") in both treatments groups.

  • Percentage of biopsy-confirmed acute rejection episodes [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    To describe cumulative biopsy-confirmed acute rejection in both groups by intention to treat analysis.

  • Percentage of steroid-sensitive acute rejections rejection episodes [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    To describe the percentage of steroid-sensitive acute rejections rejection in both groups by intention to treat analysis.

  • Percentage of acute rejection episodes requiring treatment with antilymphocyte antibodies [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    To describe the need for antibody treatment in acute rejection episodes in both groups by intention to treat analysis.

  • Proteinuria measured in g/day [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    To describe proteinuria in g/day in both groups by intention to treat analysis.

  • Percentage of patients with negative ELISPOT [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    To describe percentage of patients with negative ELISPOT in both groups by intention to treat and "on therapy" analysis.


Enrollment: 61
Study Start Date: March 2008
Study Completion Date: June 2013
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A- negative pre-transplant ELISPOT
Sirolimus: Start at 5 mg/day as soon as treatment allocation arrives to obtain targeting levels to 8 -15 ng/ml (immunoassay) in the first 3 months, followed by trough levels of 5-10 ng/ml.
Drug: PRE-TRANSPLANT (PRE=before)

All patients will start with Thymoglobulin 1 mg/kg before transplant followed by 0,5 mg/kg/d during the next 5 days (total accumulated 3,5 mg/kg).

Steroids will be administered at 0,25 mg/kg/d until month 3rd, followed by 0,1 mg/kg/d thereafter.

Mycophenolate Mofetil: Pre-transplant 2 grams iv. After transplantation 1g/12 hours, starting iv and changing to oral formulation as soon as patient starts with oral intake (targeting mycophenolic acid (MPA) C0h levels 2-5 µg/mL).

Experimental: B- Positive pre-transplant ELISPOT
Tacrolimus 0.1 mg/kg/12h starting as soon as treatment allocation arrives to obtain targeting troughs levels of 8-15 ng/ml the first 3 months, followed by trough levels of 5-10 ng/ml until the end of the study.
Drug: PRE-TRANSPLANT (PRE=before)

All patients will start with Thymoglobulin 1 mg/kg before transplant followed by 0,5 mg/kg/d during the next 5 days (total accumulated 3,5 mg/kg).

Steroids will be administered at 0,25 mg/kg/d until month 3rd, followed by 0,1 mg/kg/d thereafter.

Mycophenolate Mofetil: Pre-transplant 2 grams iv. After transplantation 1g/12 hours, starting iv and changing to oral formulation as soon as patient starts with oral intake (targeting mycophenolic acid (MPA) C0h levels 2-5 µg/mL).


Detailed Description:

Non randomized, pilot, prospective, open-label trial.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age of donor and recipient between 18 and 65 years.
  2. End-stage renal disease and scheduled to receive a primary or secondary renal allograft from a cadaveric, a living-unrelated, or a living-related donor. Patients scheduled for a second transplant must have maintained their primary graft for at least 6 months after transplantation, with the exception of graft failure due to technical reasons.
  3. Panel reactive antibody (PRA) ≤ 20%, with negative standard cross-match.
  4. Women of childbearing potential must have a negative serum pregnancy test before randomization.
  5. Women of childbearing potential must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months following discontinuation of assigned treatment.
  6. Signed and dated informed consent prior to transplantation.

Exclusion Criteria:

  1. Multiple organ transplants
  2. Recipients of adult or pediatric en bloc kidney transplants or dual transplantation or non-heart beating donors.
  3. Evidence of active systemic or localized major infection.
  4. Evidence of infiltrate, cavitation, or consolidation on chest x-ray obtained during the screening/baseline evaluation.
  5. Use of any investigational drug or treatment up to 4 weeks prior to transplantation.
  6. Treatment with voriconazole, ketoconazole, itraconazole, fluconazole, clotrimazole, astemizole, pimozide, terfenadine, erythromycin, clarithromycin, telithromycin, troleandomycin, rifampin, rifabutin, or St. John's Wort that is not discontinued prior to randomization.
  7. Treatment with aminoglycosides, amphotericin B, cisplatin, cisapride, metoclopramide, cimetidine, bromocriptine, danazol, or other drugs associated with renal dysfunction that are not discontinued prior to randomization.
  8. Subjects with a screening/baseline total white blood cell count < 2,000/mm3 or absolute neutrophil count (ANC) < 500, platelet count < 100,000/mm3.
  9. Fasting triglycerides > 400 mg/dL (> 4.6 mmol/L) or fasting total cholesterol > 300 mg/dL (> 7.8 mmol/L) despite optimal lipid-lowering therapy.
  10. History of malignancy within 2 years of enrollment (except for adequately treated basal cell or squamous cell carcinoma of the skin).
  11. Auto-immune diseases inactive immunosuppressive treatment ( 3 months prior to inclusion).
  12. Patient with psychiatric disorders that could be non-compliance for the treatment.
  13. Non Caucasian patients.
  14. Active peptic ulcers that could produce intestinal absorption disorders.
  15. Subjects who are known to be human immunodeficiency virus(HIV) or hepatitis B virus (HBV) positive. Patients with hepatitis C virus (HCV) positive should be excluded if polymerase chain reaction (PCR) positive or transaminates values are ≥2 upper normal value (UNV).
  16. Diabetic patients.
  17. Body mass index higher than 30 Kg/m2.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01195194

Locations
Spain
Nephrology Department. Hospital de Bellvitge
L'Hospitalet de Llobregat, Barcelone, Spain, 08907
Nephrology Department. Hospital Vall d'Hebró
Barcelona, Spain, 08035
Sponsors and Collaborators
Josep M Grinyo
Carlos III Health Institute
Investigators
Principal Investigator: Josep M Grinyó, PhD MD Nephrology Department. Hospital de Bellvitge. Spain
  More Information

Additional Information:
Publications:
Responsible Party: Josep M Grinyo, Chief of the Nephrology Department- Hospital Universitari de Bellvitge, Hospital Universitari de Bellvitge
ClinicalTrials.gov Identifier: NCT01195194     History of Changes
Other Study ID Numbers: SIRES, 2007-002378-68
Study First Received: April 19, 2010
Last Updated: February 24, 2014
Health Authority: Spain: Spanish Agency of Medicines

Keywords provided by Hospital Universitari de Bellvitge:
T-cell lymphocyte allo-recognition
CNI-free immunosuppressive regimen
Enzyme-linked immunospot (ELISPOT)

Additional relevant MeSH terms:
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 20, 2014