12-Month Outcomes of a Prospective Randomized Trial Investigating Effects of IVIG on Top of rATG Versus rATG Alone in Pre-Sensitized Kidney Transplant Recipients: The INHIBIT Study

Abstract

Intravenous immunoglobulins (IVIG) are commonly used in peri-transplant desensitization, but evidence supporting their efficacy is limited. We conducted a prospective, randomized single-center, open-label, Phase IIIb non-inferiority clinical pilot trial to compare the efficacy of IVIG (administered at a dose of 3 × 0.5 g/kg) versus no IVIG, in conjunction with rabbit anti-thymocyte globulin (5-7 mg/kg) induction, in pre-sensitized patients with donor-specific antibodies who had negative pre-transplantation Flow- and CDC-crossmatches, between July 2020 and November 2022. The primary endpoint was the rate of efficacy failure, defined as biopsy-proven rejection within 12-month post-transplant. Secondary endpoints included the incidence of rejection at protocol biopsies, evaluated by histology and biopsy-based transcripts diagnostics. Of the screened patients, 53 (72.6%) were excluded due to crossmatch positivity. Ten patients were randomized to the IVIG+, and 7 to the IVIG-arm. The trial was prematurely terminated due to futility at interim analysis. In the IVIG-arm, 3 patients (43%) experienced the primary endpoint compared to none in the IVIG+ arm (p = 0.026). MMDx identified one molecular ABMR in the IVIG+ and 2 in the IVIG-arm in 12-month protocol biopsies. There was one graft loss in the IVIG-arm. The results of this pilot study, although not definitive, do not support the use of IVIG-sparing regimens in HLA-incompatible kidney transplantation (NCT04302805). This study is registered on ClinicalTrials.gov under the identifier NCT04302805.

Keywords: HLA-incompatible transplantation; IVIG; desensitization; induction; kidney transplantation.

FIGURE 1

Study flow chart. A total of 666 patients were screened during the study period; 593 did not meet the inclusion criteria, mainly by the absence of donor specific antibodies (DSA). From the 73 DSA positive patients who met the other inclusion criteria, 56 could not be enrolled due to CDC and/or FCXM crossmatch positivity. Finally, 17 patients undergoing HLA-incompatible transplantation were enrolled, 10 were randomized into the rATG/IVIG (IVIG+) group, and 7 were randomized into the rATG without IVIG (IVIG-) group.

FIGURE 2

Interim analysis. Rates of the primary outcome at the time of the interim analysis estimated with the use of the Kaplan-Meier method. The primary outcome measure was efficacy failure defined as a biopsy proven antibody mediated rejection and/or T-cell mediated rejection up to 12 months post-transplantation.

FIGURE 3

Development of immunodominant donor-specific antibodies (DSA) of each enrolled patient during the 12-month study period DSA were measured during the predefined timepoints at month 3, 6, and 12. Immunodominant DSA was defined as the DSA with the highest mean fluorescent intensity prior to transplantation.