rATG Versus rATG Combined With Intravenous Immunoglobulin (IVIG) Induction Immunosuppression in HLA Incompatible Transplantation (INHIBIT)

Study Overview
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Brief Summary
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This study aims to prove similar efficacy of PE/rATG (intervention) and PE/rATG/IVIG (centre standard of care) induction regimens to prevent biopsy proven antibody-mediated changes and TCMR as composite endpoint within 12 months after HLA incompatible kidney transplantation.

Detailed Description
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There have been no published clinical studies evaluating rATG/IVIG induction protocol in comparison with rATG alone in defined cohort of HLA incompatible kidney transplant recipients. Prescribing IVIG in management of prevention of transplant rejection is considered off-label use, however IVIG remains part of induction protocols in many transplant centres. IVIG therapy is demanding due to high cost and limited resources of these human origin products. Trial participants will be end-stage renal disease (ESRD) patients listed for deceased donor / living donor kidney transplantation with anti HLA antibody screening performed within 12 months before transplantation and with last DSA 1 000 - 5 000 Mean Fluorescence Intensity (MFI) and negative CDC (Complement-dependent cytotoxicity crossmatch test) prior to transplantation. Participants will be randomized into one of the treatment groups (PE/PP(Plasmapheresis) + rATG + IVIG, PE/PP + rATG) and as a primary outcome a composite endpoint defined as occurrence of antibody- or T-cell mediated rejection within 12 months after transplantation will be evaluated.

Official Title
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rATG Versus rATG Combined With IVIG Induction Immunosuppression in HLA Incompatible Transplantation

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: Privigen
* Drug: Thymoglobulin
* Other: Plasma Exchange


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary deceased donor or living donor kidney transplantation (first transplantation or re-transplantation) Recipient age ≥ 18 years and < 70 years Donor age < 70 years Written Informed Consent and Consent for Processing Personal Data Last anti-HLA screening no longer than 12 months with positive results MFI DSA 1 000 - 5 000 (anti-HLA A, B, DR), MFI DSA 1000-15000 for anti DQ when available at randomization) Exclusion Criteria: Combined kidney transplantation with another organ Immunosuppressive therapy up to 6 months before transplantation AB0i (AB0 incompatible) transplantation Women in childbearing potential without adequate contraception HIV positivity Leukopenia < 3 000, thrombocytopenia < 75 000 Tuberculosis history Anti-HCV (Hepatitis C Virus) positivity, HBsAg (Hepatitis B Surface Antigen) positivity or HBV (Hepatitis B Virus) DNA positivity DSA (anti A, B, DR) measured by Luminex with MFI > 5 000 known at screening prior to transplant, anti DQ > 15000 if known FACS (flow-cytometry) T and B crossmatch positivity known at screening prior to transplant Positive CDC prior to transplantation Planned PP/PE and RTX (Rituximab) treatment post-transplant Advanced liver disease (Child-Pugh C or laboratory values of ALT or AST more than 3 times upper limit of normal range) Pregnancy, breastfeeding Study medication is contraindicated according to the SmPC Patient is enrolled in other clinical trial

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The present study is a prospective randomized single-centre open-label two-arm Phase III.b non-inferiority clinical trial. This trial aims to prove similar efficacy of PE/rATG and PE/rATG/IVIG (centre standard of care) induction regimens to prevent biopsy proven antibody-mediated changes and TCMR as composite endpoint within 12 months after HLA incompatible kidney transplantation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: PE/rATG<br>Study participants will undergo therapeutic plasma exchange (PE, 1 plasma volume) before the transplant surgery and receive rATG (Thymoglobuline®) induction (1.5 mg/kg intraoperatively and 1 mg/kg when possible daily within first week up to cumulative dose 5-7 mg/kg). | Drug: Thymoglobulin<br>* All patients will receive 1.5 mg/kg intraoperatively and 1 mg/kg when possible daily within first week up to cumulative dose 5-7 mg/kg.<br>* Other names: rATG;Other: Plasma Exchange<br>* All patient will undergo Plasma Exchange before transplantation.<br>* Other names: PE;|
| Active Comparator: PE/rATG/IVIG<br>Study participants will undergo therapeutic plasma exchange (PE, 1 plasma volume) before the transplant surgery and receive rATG (Thymoglobuline®) induction (1.5 mg/kg intraoperatively and 1 mg/kg when possible daily within first week up to cumulative dose 5-7 mg/kg) and IVIG 0.5g/kg intravenous infusions, on 1st, 3rd and 5th postoperative day. This is a center standard of care regimen. | Drug: Privigen<br>* Patients randomized to PE/rATG/IVIG group will receive IVIG 0.5g/kg infusions, on 1st, 3rd and 5th postoperative day.<br>* Other names: Kiovig;Drug: Thymoglobulin<br>* All patients will receive 1.5 mg/kg intraoperatively and 1 mg/kg when possible daily within first week up to cumulative dose 5-7 mg/kg.<br>* Other names: rATG;Other: Plasma Exchange<br>* All patient will undergo Plasma Exchange before transplantation.<br>* Other names: PE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined endpoint defined as biopsy proven antibody mediated changes (Banff 2017, Category 2) and/or TCMR (Banff 2017, Category 4) regardless the biopsy indication (for cause or protocol biopsy) in HLAi (HLA incompatible)kidney transplantation | Number of biopsy-confirmed rejections | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of active antibody-mediated rejection (ABMR) lesions within 12 months post-transplantation | Number of active active antibody-mediated rejection (ABMR) lesions within 12 months post-transplantation | 12 months | 
| Time to active antibody-mediated rejection (ABMR) within 12 months post-transplantation | Time to active antibody-mediated rejection (ABMR) occurrence in months | 12 months | 
| Incidence of chronic active antibody-mediated rejection (ABMR) and C4d staining without evidence of rejection in protocol biopsies at Month 3 and Month 12 | Number of chronic active antibody-mediated rejection (ABMR) and C4d staining without evidence of rejection in protocol biopsies at Month 3 and Month 12 | 3 and 12 months | 
| Incidence of transplant glomerulopathy (TG) in protocol biopsies at Month 3 and Month 12 | Number of biopsies with transplant glomerulopathy | 3 and 12 months | 
| Incidence of acute T-cell mediated rejection (TCMR) and chronic active TCMR in protocol biopsies at Month 3 and Month 12 post-transplantation | Number of acute T-cell mediated rejection (TCMR) and chronic active TCMR in protocol biopsies at Month 3 and Month 12 | 3 and 12 months | 
| Estimated glomerular filtration rate (eGFR) at Month 3, Month 6 and Month 12 | Estimated glomerular filtration rate (eGFR) will be assessed at all study visits by CKD-EPI formula. | 3, 6 and 12 months | 
| Measured proteinuria and albuminuria at Month 3, Month 6 and Month 12 | Proteinuria is defined as ≥ 1 g/l and albuminuria as albumin/creatinine ratio > 3 mg/mmol. | 3, 6 and 12 months | 
| Donor specific antibodies (DSA) at Month 3, Month 6 and Month12 | Specification of antibodies directed at HLA class I and class II will be performed by LUMINEX method (solid phase assay). | 3, 6 and 12 months | 
| De novo donor specific antibodies (DSA) at Month 3, Month 6 and Month 12 | Specification of antibodies directed at HLA class I and class II will be performed by LUMINEX method (solid phase assay). | 3, 6 and 12 months | 
| Mortality rate within 12 months post-transplantation | Number of deaths by any cause anytime during the trial. | 12 months | 
| Graft survival (rate of graft loss) within 12 months post transplantation | Number graft of graft failures within 12 months | 12 months | 
| Incidence of metabolic, malignant and cardiovascular co-morbidities | Number of metabolic, malignant and cardiovascular co-morbidities | 12 months | 
| Incidence of viral and bacterial complications | Number of viral and bacterial complications | 12 months | 
| Incidence of BK Virus (BKV), Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) replications detected by PCR (polymerase chain reaction) at Month 3, Month 6 and Month 12 | Number of patients with PCR (polymerase chain reaction) positive BK Virus (BKV), Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) replications | 3, 6 and 12 months | 
| Incidence of study treatment discontinuation | Cessation of trial medication treatment either by the clinician or by the participant himself/herself. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antibody-mediated rejection, Intravenous immunoglobulin, Rabbit Anti-thymocyte Globulin, Donor specific antibodies