Clinical trial NCT04302805: rATG Versus rATG Combined With Intravenous Immunoglobulin (IVIG) Induction Immunosuppression in HLA Incompatible Transplantation (INHIBIT)
Official title: rATG Versus rATG Combined With IVIG Induction Immunosuppression in HLA Incompatible Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Kidney Transplantation
Keywords: Antibody-mediated rejection
Intravenous immunoglobulin
Rabbit Anti-thymocyte Globulin
Donor specific antibodies
Lead sponsor: Institute for Clinical and Experimental Medicine
Sponsor class: OTHER_GOV
First posted: 2020-03-10
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: 12 months
Secondary outcomes:
measure: Incidence of active antibody-mediated rejection (ABMR) lesions within 12 months post-transplantation
timeFrame: 12 months
measure: Time to active antibody-mediated rejection (ABMR) within 12 months post-transplantation
timeFrame: 12 months
measure: Incidence of chronic active antibody-mediated rejection (ABMR) and C4d staining without evidence of rejection in protocol biopsies at Month 3 and Month 12
timeFrame: 3 and 12 months
measure: Incidence of transplant glomerulopathy (TG) in protocol biopsies at Month 3 and Month 12
timeFrame: 3 and 12 months
measure: Incidence of acute T-cell mediated rejection (TCMR) and chronic active TCMR in protocol biopsies at Month 3 and Month 12 post-transplantation
timeFrame: 3 and 12 months
measure: Estimated glomerular filtration rate (eGFR) at Month 3, Month 6 and Month 12
timeFrame: 3, 6 and 12 months
measure: Measured proteinuria and albuminuria at Month 3, Month 6 and Month 12
timeFrame: 3, 6 and 12 months
measure: Donor specific antibodies (DSA) at Month 3, Month 6 and Month12
timeFrame: 3, 6 and 12 months
measure: De novo donor specific antibodies (DSA) at Month 3, Month 6 and Month 12
timeFrame: 3, 6 and 12 months
measure: Mortality rate within 12 months post-transplantation
timeFrame: 12 months
measure: Graft survival (rate of graft loss) within 12 months post transplantation
timeFrame: 12 months
measure: Incidence of metabolic, malignant and cardiovascular co-morbidities
timeFrame: 12 months
measure: Incidence of viral and bacterial complications
timeFrame: 12 months
measure: 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
timeFrame: 3, 6 and 12 months
measure: Incidence of study treatment discontinuation
timeFrame: 12 months
measure: Incidence of molecular rejection in the 12-month protocol biopsies
timeFrame: 12 months
Other outcomes:
Locations:
city: Prague
country: Czechia
facility: Institute for Clinical and Experimental Medicine
Study officials:
affiliation: Institute for Clinical and Experimental Medicine
name: Ondrej Viklicky, Prof.
role: PRINCIPAL_INVESTIGATOR
References: