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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: Thymoglobulin; Other: Plasma Exchange; Drug: Privigen

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.

• Study Type: Interventional
• Enrollment (Estimated): 138
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ondrej Viklicky, Prof.; Phone Number: +420 261364110; Email: ondrej.viklicky@ikem.cz

Study Locations

• Czechia
  • Prague, Czechia, 140 21
    • Recruiting
    • Institute for Clinical and Experimental Medicine
    • Contact: Ondrej Viklicky, Prof.; Phone Number: +420 261364110; Email: ondrej.viklicky@ikem.cz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: PE/rATG; 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; 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.; Other Names: rATG; Other: Plasma Exchange; All patient will undergo Plasma Exchange before transplantation.; Other Names: PE
Active Comparator: PE/rATG/IVIG; 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: Thymoglobulin; 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.; Other Names: rATG; Other: Plasma Exchange; All patient will undergo Plasma Exchange before transplantation.; Other Names: PE; Drug: Privigen; Patients randomized to PE/rATG/IVIG group will receive IVIG 0.5g/kg infusions, on 1st, 3rd and 5th postoperative day.; Other Names: IVIG; Kiovig

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institute for Clinical and Experimental Medicine
• Investigators: Principal Investigator: Ondrej Viklicky, Prof., Institute for Clinical and Experimental Medicine

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2020
• Primary Completion (Estimated): April 15, 2024
• Study Completion (Estimated): April 15, 2024

Study Registration Dates

• First Submitted: March 4, 2020
• First Submitted That Met QC Criteria: March 6, 2020
• First Posted (Actual): March 10, 2020

Study Record Updates

• Last Update Posted (Actual): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Donor specific antibodies; Antibody-mediated rejection; Intravenous immunoglobulin; Rabbit Anti-thymocyte Globulin
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Immunoglobulins, Intravenous; Thymoglobulin
• Other Study ID Numbers: Eudra CT: 2019-003723-37

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No