Safety Use of ATeGe in Liver Transplant Recipients With Pre-transplant Renal Dysfunction

Study Overview
=================
Brief Summary
-----------------
Renal dysfunction in the context of liver transplantation is a major issue, with difficult patients' management and determining a worsened prognosis. Physiopathologically pretransplant renal dysfunction is dependent on multifactorial causes, including hypoperfusion-derived functional renal insufficiency, hepatorenal syndrome or interstitial parenchymatous insufficiency. On top, intra- or post-transplant events, including hypoperfusion or calcineurin inhibitors nephrotoxicity may aggravate this situation. At present MELD criteria favours allocation of organs to patients suffering from renal insufficiency, so at least 30% of the investigators liver transplant patients suffer from some degree of renal impairment pretransplant. After liver transplant impaired renal function tends to recover partially or completely, unless advanced parenchymatous lesions are significantly involved as a major cause of renal dysfunction. In this context, calcineurin inhibitors avoiding or sparing protocols may help in the recovery from renal insufficiency, improving long-term prognosis. The use of anti-CD25 antibodies is a good option, but provides a limited antirejection prophylaxis, limiting the use of these antibodies to a reduced cohort of liver transplant patients. Polyclonal antibodies might provide an advantage in management of liver transplant patients with renal insufficiency, without increasing acute rejection episodes of the allograft efficacy and security evaluation of low nephrotoxicity immunosuppression, based on the use of ATeGe, in liver transplant candidates with pre-transplant renal dysfunction. The aim of this study is to evaluate the efficacy and security use of immunosuppression based on ATeGe in liver transplant recipients with pre-transplant renal dysfunction.

Official Title
-----------------
Single Centre, Prospective, Open, Non Controlled, Pilot Study for Efficacy and Security Evaluation of Low Nephrotoxicity Immunosuppression, Based on the Use of ATeGe in Liver Transplant Recipients With Pre-transplant Renal Dysfunction

Conditions
-----------------
Renal Insufficiency

Intervention / Treatment
-----------------
* Drug: ATeGe-Fresenius


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with moderate pre-transplant renal dysfunction as defined serum creatinine levels higher than 1.5 mg/dl or eGFR (MDRD-4) <60ml/min. First liver transplant, including splits liver transplant. Patients aged 18-70 years Without a prior contraindication for protocol biopsy of allograft. Exclusion Criteria: Multiorgan transplantation and/or liver transplant from DCD and/or with ABO incompatibility. Uncontrolled concomitant infections (including HIV seropositivity) and/or diarrhoea, vomiting or active gastric ulcer. Fulminant hepatic insufficiency as first indication for liver transplant Hemodynamic instability prior to liver transplant. Recipient presenting present or previous neoplasia, except for non-metastatic basal or squamous cutaneous carcinoma or localized hepatocarcinoma with diameter <5 cm or < 3 known lesions with diameter <3 cm. Intolerance to study medication. Patients having received vaccination with attenuated living vaccines within the previous 4 weeks. Severe leukopenia (< 1.2 X 10E9/L) and/or thrombocytopenia (< 50x10E9/L) and/or lymphocyte counts (CD2+/CD3+) less than 10 cells/µl. Significant comorbidity. Breastfeeding or female patients at fertile age without negative pregnancy test and accepting the use of reliable fertility control method.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Basiliximab<br>Historical comparable cohort treated with Basiliximab 20mg iv administered at 0 and 4th day post-transplant | |
| Active Comparator: ATeGe-Fresenius<br> | Drug: ATeGe-Fresenius<br>* Administered at 1 , 3, 5 and 7 day post-transplant at 2-3mg/kg with dose adjustment according to CD2/CD3 levels<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal function improvement after liver transplant | Creatinine (mg/dL) and MDRD Glomerular Filtrate Rate (ml/min/1.73m2) will be measured following the time frame described above | Measurement will be performed at 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 14th and 28th day post-transplant, and 2nd, 3rd, 6th and 12th month post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of biopsy proven acute cellular rejection. | If liver dysfunction is detected, percutaneous liver biopsy will be performed and histological severity will be assed following BANF criteria | Evaluation at 1st , 3rd, 6th, 9th and 12th month post-transplant | 
| Patient and graft survival rates after 12 months, causes of death and retransplant |  | Evaluation at 1st , 3rd, 6th, 9th and 12th month post-transplant | 
| Relationship between ATeGe doses, immunological variables (lymphocyte counts) and clinical adverse events (acute rejection,infections, HCV recurrence and de novo tumor) |  | Evaluation at 1st , 3rd, 6th, 9th and 12th month post-transplant | 
| Incidence and severity of HCV infection recurrence, based on clinical and histological criteria. |  | Once liver dysfunction is detected and one year post-transplant by protocol. | 
| Evaluation of metabolic complications (diabetes mellitus, arterial hypertension and dyslipidemia) |  | Evaluation at 1st , 3rd, 6th, 9th and 12th month post-transplant | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute rejection, Infections, Hepatitis C recurrence, Renal insufficiency, Liver transplant