Simulect Versus ATG in Sensitized Renal Transplant Patient

Study Overview
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Brief Summary
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Induction therapy by either T-cell depleting polyclonal antibodies such as anti-thymocyte globulins (ATG) or non-depleting anti-interleukine 2 receptor monoclonal antibodies (anti-CD25 moAb: basiliximab or daclizumab) are used to prevent acute rejection, especially in highly sensitized patients. Both induction therapy regimens have a different tolerance profile. Infections and haematological side-effects are more frequently reported in patients receiving ATG. The aim of the pilot study is to evaluate ATG and basiliximab induction therapy in de novo sensitized kidney-transplant patients (incompatible grafts rate ≥ 50%) without donor specific antibodies (DSAs) detected by Luminex.

Detailed Description
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Acute rejection after kidney transplantation can lead to graft loss by irreversible acute rejection or to interstitial fibrosis/ tubular atrophy that can induce graft loss. Induction therapy by either T-cell depleting polyclonal antibodies such as Anti-Thymocyte Globulins (ATG) or non-depleting anti-interleukine 2 receptor monoclonal antibodies (anti-CD25 moAb: basiliximab or daclizumab) are used to prevent acute rejection, especially in highly sensitized patients. Both induction therapy regimens have a different tolerance profile. Infections and haematological side-effects are more frequently reported in patients receiving ATG. With respect to the efficacy, no comparison exists between both induction therapy regimens in high risk immunological patients as actually defined. Within the last few years, the development of new immunological screening tools, i.e. Luminex assay, had lead to a better evaluation of the immunological status of candidates for kidney transplantation, mainly those who were considered as highly sensitized. The aim of our pilot study is to evaluate ATG and basiliximab induction therapy in de novo sensitized kidney-transplant patients (incompatible grafts rate ≥ 50%) without Donor Specific Antibodies (DSAs) detected by Luminex. Maintenance immunosuppressive regimen will be based on the combination of tacrolimus, mycophenolate sodium and steroids. The primary endpoint is a composite of biopsy-proven acute rejection, graft loss, loss of follow up, or death at 6 months post-transplant. The secondary endpoints are the efficacy of the therapy at month 12 posttransplant, and safety parameters (CMV infection, BK virus nephropathy, haematological tolerance, Adverse Events (AE)and Serious Adverse Events (SAE)). Our hypothesis is that basiliximab induction therapy may be sufficiently effective to prevent acute rejection in sensitized patients without DSA. This may reduce the post-transplant immunosuppression-induced side-effects.

Official Title
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Prospective, Multicenter, Randomized, Evaluating Two Induction Therapies With Simulect® Versus ATG® Fresenius Associated With Tacrolimus and Myfortic® in the Prevention of Treatment Failure, in Sensitized Renal Transplant

Conditions
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Renal Transplant Rejection

Intervention / Treatment
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* Drug: Simulect
* Drug: ATG Fresenius


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged from 18 to 70 years Recipient of a deceased or living donor kidney transplant with the following criteria: Incompatible grafts rate ≥ 50% for the last available serum before transplantation < 3 months Anti-HLA antibodies positive Negative DSA by luminex method on historical serum and day serum T and B negative Cross match on historical and day serum Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at screening, and are required to practice an approved and reliable method of birth control for the duration of the study and for a period of 2 months after study medication discontinuation, even where there has been a history of infertility Patients who are willing and able to participate in the full course of the study and from whom written informed consent has been obtained. Patients affiliated to, or recipients of, a social security system Exclusion Criteria: Recipients of a multi-organ transplantation, including dual kidneys, or who have previously received non renal transplanted organs Recipients of a kidney from non-heart beating donor, or with ABO incompatibility against the donor or with a T positive cross match Patients with severe uncontrolled systemic infection or severe allergy requiring acute or chronic treatment Aspartate aminotransferase (ASAT), Alanine Amino Transferase (ALAT) or bilirubin ≥ 3 upper limit of the normal range (ULN) Known hypersensitivity or contra-indication to rabbit proteins, basiliximab, tacrolimus, mycophenolic acid or any of the product excipients Patients who are Hepatitis C positive (positive PCR and normal hepatic test may be included), HIV positive, or Hepatitis B surface antigen positive (AgHBs). Patients with thrombocytopenia < 75,000/mm3, an absolute neutrophils count < 1,500/mm3, leukocytopenia < 2,500/mm3, and/or hemoglobin < 8g/dL at inclusion visit Patients with any past or present malignancy within the last five years except excised squamous or basal cell carcinoma of the skin and treated in situ cervix uteri cancer Any surgical or medical condition, excluding transplantation which compromise the inclusion of the patient (investigator's opinion) Female patients who are pregnant, breast feeding or capable to become pregnant and not wishing or capable to practice a medically approved and reliable method of birth control Patients with symptoms of significant somatic or mental illness. Inability to cooperate or communicate with the investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simulect<br>Simulect IV 40 mg D0 and D4 | Drug: Simulect<br>* Simulect IV 40 mg/day D0 and D4 and oral use Tacrolimus 0.1 mg/ kg/ day + Myfortic 720 to 1440mg + Corticosteroids 5mg<br>* Other names: Corticosteroids 5mg;|
| Active Comparator: ATG Fresenius<br>ATG IV min dose 3 mg/ kg/ day D0, D1, D3, D5 | Drug: ATG Fresenius<br>* Simulect IV 40 mg/day D0 and D4 and oral use Tacrolimus 0.1 mg/ kg/ day + Myfortic 720 to 1440mg + Corticosteroids 5mg<br>* Other names: Corticosteroids 5mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment failure | Incidence of treatment failure (Biopsy Proved Reject, lost to follow up, graft loss or death) at 6 months post transplantation. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| feasibility estimating the number of informed consent obtained | Estimating the number of informed consent obtained | 12 months | 
| treatment efficacy | Treatment failure at 12 months post transplantation. premature discontinuation of study medication, discontinuation from the study and reasons. incidence of all acute rejection episodes requiring an anti-T and /or anti-B antibodies treatment within 12 months post transplantation. Incidence of C4d positive biopsy findings. Renal function at 3, 6 and 12 months post transplantation (abbreviated MDRD, serum creatinine and adjusted Cockcroft- Gault). | 12 months | 
| adverse events | Safety: - Adverse Events, Serious Adverse Events | 12 months | 
| patient enrolled in each center | Estimating the number of patient enrolled in each center and by year | 12 months | 
| number of patients lost from follow-up | Estimating the number of patients lost from from follow-up before 6 and before 12 months | 12 months | 
| rejection | acute rejection at 6 and 12 months post transplantation - Subclinical rejection at the 3 month per protocol renal biopsy. | 12 months | 
| Donor Specific Antibodies | Donor Specific Antibodies at D0, M3 and M12. | 12 months | 
| Incidence of BKV viremia | incidence of BKV viremia at 1, 3, 6 and 12 months post transplantation | 12 months | 
| values of hematologia : hemoglobine, leucocytes, plaquettes, hematies, neutrophiles |  | 12 months | 
| Incidence of BKV nephropathy | Incidence of BKV nephropathy at 1, 3, 6 and 12 months post transplantation | 12 months | 
| incidence of CMV post transplantation | incidence of CMV(PCR) post transplantation at 6, 9 and 12 months | 12 months | 
| incidence of infections | incidence of infections cancer and PTLD | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney transplant, luminex method, simulect ATG, immunosuppression