Kidney Transplantation
Conditions
Keywords
Antibody-mediated rejection, Intravenous immunoglobulin, Rabbit Anti-thymocyte Globulin, Donor specific antibodies
Brief summary
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
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.
Interventions
DRUGPrivigen
Patients randomized to PE/rATG/IVIG group will receive IVIG 0.5g/kg infusions, on 1st, 3rd and 5th postoperative day.
DRUGThymoglobulin
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.
OTHERPlasma Exchange
All patient will undergo Plasma Exchange before transplantation.
Sponsors
Institute for Clinical and Experimental Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 12 months | Number of biopsy-confirmed rejections |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to active antibody-mediated rejection (ABMR) within 12 months post-transplantation | 12 months | Time to active antibody-mediated rejection (ABMR) occurrence in 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 | 3 and 12 months | Number of chronic active antibody-mediated rejection (ABMR) and C4d staining without evidence of rejection in protocol biopsies at Month 3 and Month 12 |
| Incidence of transplant glomerulopathy (TG) in protocol biopsies at Month 3 and Month 12 | 3 and 12 months | Number of biopsies with transplant glomerulopathy |
| Incidence of acute T-cell mediated rejection (TCMR) and chronic active TCMR in protocol biopsies at Month 3 and Month 12 post-transplantation | 3 and 12 months | Number of acute T-cell mediated rejection (TCMR) and chronic active TCMR in protocol biopsies at Month 3 and Month 12 |
| Estimated glomerular filtration rate (eGFR) at Month 3, Month 6 and Month 12 | 3, 6 and 12 months | Estimated glomerular filtration rate (eGFR) will be assessed at all study visits by CKD-EPI formula. |
| Measured proteinuria and albuminuria at Month 3, Month 6 and Month 12 | 3, 6 and 12 months | Proteinuria is defined as ≥ 1 g/l and albuminuria as albumin/creatinine ratio \> 3 mg/mmol. |
| Donor specific antibodies (DSA) at Month 3, Month 6 and Month12 | 3, 6 and 12 months | Specification of antibodies directed at HLA class I and class II will be performed by LUMINEX method (solid phase assay). |
| Incidence of active antibody-mediated rejection (ABMR) lesions within 12 months post-transplantation | 12 months | Number of active active antibody-mediated rejection (ABMR) lesions within 12 months post-transplantation |
| Mortality rate within 12 months post-transplantation | 12 months | Number of deaths by any cause anytime during the trial. |
| Graft survival (rate of graft loss) within 12 months post transplantation | 12 months | Number graft of graft failures within 12 months |
| Incidence of metabolic, malignant and cardiovascular co-morbidities | 12 months | Number of metabolic, malignant and cardiovascular co-morbidities |
| Incidence of viral and bacterial complications | 12 months | Number of viral and bacterial complications |
| 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 | 3, 6 and 12 months | Number of patients with PCR (polymerase chain reaction) positive BK Virus (BKV), Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) replications |
| Incidence of study treatment discontinuation | 12 months | Cessation of trial medication treatment either by the clinician or by the participant himself/herself. |
| Incidence of molecular rejection in the 12-month protocol biopsies | 12 months | Number of molecular rejection cases evaluated by the Molecular Microscope Diagnostic System (MMDx) in the 12-month protocol biopsies. |
| De novo donor specific antibodies (DSA) at Month 3, Month 6 and Month 12 | 3, 6 and 12 months | Specification of antibodies directed at HLA class I and class II will be performed by LUMINEX method (solid phase assay). |
Countries
Czechia
Outcome results
None listed