Tacrolimus After rATG and Infliximab Induction Immunosuppression (RIMINI)

Study Overview
=================
Brief Summary
-----------------
International multicenter open-label single-arm confidence-interval-estimation based Phase II clinical trial, aiming to estimate a plausible range of the proportion of patients experiencing efficacy failure in the population, to provide evidence for efficacy and safety of the induction regimen with rATG and infliximab and a go/no go rule for further clinical development.

Detailed Description
-----------------
A total of 75 patients will receive the proposed induction regimen, with expected 68 completers accounting for drop-outs and non-compliances with the protocol. If up to 27 out of the 68 completers experience efficacy failure, a progression into a larger trial will be considered justifiable. If the number of patients experiencing efficacy failure is between 28 and 34 out of 68, the merits of a larger non-inferiority design will be considered depending on the risk/benefit assessment. If more than 34 out of the 68 completers experience efficacy failure, a progression into a larger trial would be considered unjustifiable. 1st kidney transplant recipients (low risk: PRA/cPRA < 20%, no DSA) will receive short rATG induction (2x1.5 mg/kg) given perioperatively and on first postoperative day. All patients will receive one shot Infliximab mAb at day 2. Since POD1, maintenance IS consists of Tac and tapered steroids therapy. All patients will be followed up for one year. At the POD 0 the first rATG dose (1.5mg/kg) will be given according to the local practice and Methyprednisolon 500mg will be given before reperfusion. At the POD 1 patients will receive methylprednisolon 500mg i.v. followed by second rATG dose (1.5mg/kg). Infliximab 5mg/kg b.w. will be given in slow infusion on POD2. Tacrolimus will be given the first dose before surgery at dose 0.1 mg/kg and next from POD1 at 0.2mg/kg/day and doses adjusted according to blood trough levels (10-15 ng/mL, POD1-POD13, 5-8ng/mL POD 14-90, 4-6ng/mL POD >90. Prednison (or appropriate dose of methylprednisolone) will be initiated POD 2 at a dose of 20mg/day and slowly tapered down to 5 mg at the POD 7 (POD2: 20mg, POD3: 15mg, POD4-5: 10mg, POD6-7: 7,5mg, > POD7: 5mg).

Official Title
-----------------
Tacrolimus After rATG and Infliximab Induction Immunosuppression (RIMINI)

Conditions
-----------------
Renal Transplant Rejection

Intervention / Treatment
-----------------
* Drug: Antithymocyte Immunoglobulin (Rabbit)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Primary deceased-donor or living-donor kidney transplantation XML File Identifier: CJub4EkHas0e/mXDp2mGyZzEe9E= Page 22/33 Men and women (recipient) age >18 years and <70 years Panel reactive antibody frequency/ calculated panel reactive antibody frequency (peak PRA/cPRA) <20% Written informed consent Diagnosis of end stage renal disease Women of Childbearing Potential (WOCBP) must be using a highly effective method of contraception (Pearl-Index < 1) to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL]. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of clinical trial. Male participants with pregnant or nonpregnant WOCBP partner must use condoms. Exclusion Criteria: Previous transplantation Combined kidney transplantation with other organ Subjects receiving an allograft from a donor older than 65 years with elevated serum creatinine levels and/or treated diabetes. Immunosuppressive therapy up to 6 months before transplantation Planned induction therapy with depletion agents EBV seronegativity HIV positivity Leukopenia < 3000 cells per microliter, thrombocytopenia < 100 000 cells per microliter Biological therapy history with ATG, OKT3, anti TNF agents Tuberculosis history Cancer history (skin non-melanoma cancer excluded) Anti HCV positivity, HBsAg positivity or HBV DNA positivity Detectable donor specific antibodies (DSA) by solid phase assay (Luminex®) Subjects with a known hypersensibility to any of the drugs used in this protocol Subjects who have used any investigational drug within 30 days prior to enrolment in this clinical trial WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period, women who are pregnant or breastfeeding or women with a positive pregnancy test on enrolment Subjects who are legally detained in an official institution All contraindications against study medication (including auxiliary substances) Interactions with study medication Current treatment with one of the following substances: cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, rituximab, prednisone Patients unwilling to consent to saving and propagation of pseudonymized medical data and/or biological samples for study reasons Chronic heart failure (NYHA III, IV) at transplantation Participation in other clinical trials (pharmaceutical trials) persons dependent of the sponsor, investigator or investigative site positive Quantiferon test (for TBC) live vaccine treatment 30 days prior to enrolment in this clinical trial

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: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a confidence-interval-estimation based early phase design, aiming to estimate a plausible range of the population treatment effect which is not bound to a formal hypothesis.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Antithymocyte Immunoglobulin (Rabbit)<br>rATG induction on day 0 & 1 post op | Drug: Antithymocyte Immunoglobulin (Rabbit)<br>* 1st kidney transplant recipients (low risk: PRA/cPRA < 20%, no DSA) will receive short rATG induction (2x1.5 mg/kg) given perioperatively and on first postoperative day. All patients will receive one shot Infliximab mAb at day 2. Since POD1, maintenance IS consists of Tac and tapered steroids therapy.<br>* Other names: Prednisolone;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite endpoint of efficacy failure [(treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up) and renal function (estimated glomerular filtration rate)] of the induction regimen | Composite endpoint of efficacy failure of the induction regimen defined as occurrence of any of the following individual outcomes up to 12 months post transplantation (start of follow up at transplantation): acute rejection, graft loss or poor graft function defined as eGFR<40 ml/min. | 12 months post transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of biomarker signatures at 6, 12 months of follow-up. | The following biomarker analyses are implemented in the trial: ELISpot/CTLp EBV/CMV/BKV load + CMV/EBV T-Ly Multi-parameter flow cytometry gene expression profiling alloantibodies urinary IP-10 HO-1 polymorphisms histology (protocol/induced biopsies) | 6, 12 months of follow-up | 
| Incidence of death by 12 months post-transplantation | incidence of death by 12 month post transplantation | 12 months post-transplantation | 
| Incidence of graft loss by 12 months post-transplantation | Incidence of graft loss by 12 months post-transplantation | 12 months post-transplantation | 
| Incidence of metabolic and cardiovascular co-morbidity by 12 months post-transplantation | Incidence of metabolic and cardiovascular co-morbidity by 12 months post-transplantation (post-transplant diabetes mellitus, dyslipidemia, hypertension, myocardial infarction, stroke, peripheral vascular disease) | 12 months post-transplantation | 
| Proportion of subjects who remain on tacrolimus/steroids therapy at 12 months post-transplantation | Proportion of subjects who remain on tacrolimus/steroids therapy at 12 months post-transplantation | 12 months post-transplantation | 
| Incidence of acute and chronic lesions assessed by the Banff 07 score in protocol biopsy at 12months post-transplantation | Banff classification: Normal Antibody mediated rejection Borderline T cell mediated rejection: Type IA: cases with significant interstitial infiltration (> 25% of parenchyma affected, i2 or i3) & foci of moderate tubulitis (t2) Type IB: cases with significant interstitial infiltration (> 25% of parenchyma affected, i2 or i3) & foci of severe tubulitis (t3) Type IIA: cases with mild to moderate intimal arteritis (v1) Type IIB: cases with severe intimal arteritis comprising > 25% of luminal area (v2) Type III: cases with transmural arteritis or arterial fibrinoid change & necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation (v3) Chronic allograft arteriopathy - Interstitial fibrosis and tubular atrophy: Grade I: mild interstitial fibrosis & tubular atrophy Grade II: moderate interstitial fibrosis & tubular atrophy Grade III: severe interstitial fibrosis & tubular atrophy/loss | 12 months post-transplantation | 
| Incidence of discontinuation of study treatment | Incidence of discontinuation of study treatment | 12 month | 
| Donor specific antibody (DSA) at 12M | Assessment of donor specific antibody at 12M Method of assessment: Luminex assay | 12 months post-transplantation | 
| Overall safety of tacrolimus/steroids therapy immunosuppressive regimen measured by the occurrence of viral and bacterial infections, malignancies and autoimmunity. | Overall safety of tacrolimus/steroids therapy immunosuppressive regimen measured by the occurrence of viral and bacterial infections, malignancies and autoimmunity | 12 month | 
| Health-related quality of life using SF-36v2 questionnaires at baseline (pre Transplantation), Month 1, Month 3, Month 6, and Month 12 | The SF-36v2 provides scores for each of the eight health domains and psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. The eight sections are: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health | baseline (pre transplantation), Month 1, Month 3, Month 6, and Month12 | 
| Assessment of patient-specific resource consumption using a trial specific questionnaire at initial discharge, Month 3, Month 6, Month 12, and in cases of repeated hospitalization | The questionnaires capture relevant apsects of resource consumption: In which ward(s) a patient was hospitalized Additional services (diagnostics / procedures / operations) Potential dialysis procedures (past and expected frequency in the future) Potential outpatient visits and the services consumed Employment status and potential depency on care-giving The completion requires a review of inpatient records. Part II and Part III also require a short interview with the patient about potential outpatient visits during the study period, their employment status, and potential depedency on care-giving. | initial discharge, Month 3, Month 6, Month 12, and in cases of repeated hospitalization | 
| Health-related quality of life using EQ5D-5L questionnaires at baseline (pre Transplantation), Month 1, Month 3, Month 6, and Month 12 | EQ-5D is a standardized instrument for measuring generic health status. It has been widely used in population health surveys, clinical studies, economic evaluation and in routine outcome measurement in the delivery of operational healthcare. The EQ-5D-5L is a Patient Reported Outcome (PRO) instrument that can generally assess the quality of life of patients, regardless of their disease, over 6 questions. It also includes a vertical EQ visual analog scale (EQ VAS, 0-100 points) and a descriptive EQ-5D-5L system, which considers the following 5 dimensions or subscales over 5 levels or possible answers. dimensions: mobility, self-sufficiency, General Activities, Pain / Physical complaints, fear / dejectedness levels: Level 1: No problems/ No pain/ Not afraid; Level 2: Slight problems/ Slight pain/ A little anxious; Level 3: Moderate problems/ Moderate pain/ Moderate anxiety; Level 4: Major problems / Severe pain/ Very anxious; Level 5: Not able to/ Extreme pain/ Extremely anxious | baseline (pre transplantation), Month 1, Month 3, Month 6, and Month12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
transplant medicine