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Clinical Trial
. 2023 Jan 1;34(1):145-159.
doi: 10.1681/ASN.2022040454. Epub 2022 Oct 4.

Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial

Donald E Hricik  1 , Brian Armstrong  2 , Tarek Alhamad  3 , Daniel C Brennan  4 , Jonathan S Bromberg  5 , Suphamai Bunnapradist  6 , Sindhu Chandran  7 , Robert L Fairchild  8 , David P Foley  9 , Richard Formica  10 , Ian W Gibson  11 , Karen Kesler  2 , S Joseph Kim  12 , Roslyn B Mannon  13 , Madhav C Menon  10 , Kenneth A Newell  14 , Peter Nickerson  11 , Jonah Odim  15 , Emilio D Poggio  8 , Randall Sung  16 , Ron Shapiro  17 , Kathryn Tinckam  12 , Flavio Vincenti  7 , Peter S Heeger  17
Affiliations
Clinical Trial

Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial

Donald E Hricik et al. J Am Soc Nephrol. .

Abstract

Background: Ischemia-reperfusion (IR) of a kidney transplant (KTx) upregulates TNF α production that amplifies allograft inflammation and may negatively affect transplant outcomes.

Methods: We tested the effects of blocking TNF peri-KTx via a randomized, double-blind, placebo-controlled, 15-center, phase 2 clinical trial. A total of 225 primary transplant recipients of deceased-donor kidneys (KTx; 38.2% Black/African American, 44% White) were randomized to receive intravenous infliximab (IFX) 3 mg/kg or saline placebo (PLBO) initiated before kidney reperfusion. All patients received rabbit anti-thymocyte globulin induction and maintenance immunosuppression (IS) with tacrolimus, mycophenolate mofetil, and prednisone. The primary end point was the difference between groups in mean 24-month eGFR.

Results: There was no difference in the primary end point of 24-month eGFR between IFX (52.45 ml/min per 1.73 m 2 ; 95% CI, 48.38 to 56.52) versus PLBO (57.35 ml/min per 1.73 m 2 ; 95% CI, 53.18 to 61.52; P =0.1). There were no significant differences between groups in rates of delayed graft function, biopsy-proven acute rejection (BPAR), development of de novo donor-specific antibodies, or graft loss/death. Immunosuppression did not differ, and day 7 post-KTx plasma analyses showed approximately ten-fold lower TNF ( P <0.001) in IFX versus PLBO. BK viremia requiring IS change occurred more frequently in IFX (28.9%) versus PLBO (13.4%; P =0.004), with a strong trend toward higher rates of BKV nephropathy in IFX (13.3%) versus PLBO (4.9%; P =0.06).

Conclusions: IFX induction therapy does not benefit recipients of kidney transplants from deceased donors on this IS regimen. Because the intervention unexpectedly increased rates of BK virus infections, our findings underscore the complexities of targeting peritransplant inflammation as a strategy to improve KTx outcomes.Clinical Trial registry name and registration number:clinicaltrials.gov (NCT02495077).

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Conflict of interest statement

T. Alhamad reports consultancy for CareDx, Mallinckrod, and Veloxis; research funding from Angion, CareDx, Europhines, and Natera; honoraria from CareDx, Sanofi, and Veloxis; an advisory or leadership role for CareDx, Europhines, and QSANT; and participation in a speakers’ bureau for CareDx, Sanofi, and Veloxis. D.C. Brennan reports consultancy for CareDx, Hansa, Medeor Therapeutics, Sanofi, and Vera Therapeutics; research funding from Amplyx (Vera Therapeutics), Allovir, CareDx, and Natera; honoraria from CareDx and Sanofi; and an advisory or leadership role for Transplantation and UpToDate (on editorial boards). J.S. Bromberg reports consultancy for Eurofins and Pfizer; research funding from Angion, Astellas, CareDx, Natera, Novartis, and Quark; and an advisory or leadership role for the National Institutes of Health and Transplantation. S. Bunnapradist reports consultancy for CareDx, Natera, Nephrosant, Takeda, Transplant Genomics, and Veloxis; research funding from Allovir, Astellas, CareDx, Merck, Natera, and Transplant Genomics; honoraria from Astellas, Allovir, CareDx, Merck, Natera, Nephrosant, Sanofi, Takeda, Transplant Genomics, and Veloxis; and participation in a speakers’ bureau for CareDx, Natera, Nephrosant, Sanofi, Takeda, Transplant Genomics, and Veloxis. S. Chandran reports consultancy for Bridge Bio Gene Therapy and Everest Clinical Research. R.L. Fairchild reports consultancy for Eurofins/Viracor; royalties from Eurofins/Viracor for a license monitoring urine RNA from kidney transplant patients for gene expression signature indicating T cell–mediated rejection; and an advisory or leadership role for Eurofins/Viracor (scientific advisory board). R. Formica reports consultancy for Mallinckrodt Pharmaceuticals, Sanofi, and Veloxis Pharmaceuticals; participation in a speakers’ bureau for Sanofi (nonbranded educational lectures); and other interests or relationships with OPTN (member of the board of directors). K. Kesler reports being an employee of Rho, Inc. S.J. Kim reports an advisory or leadership role for the Canadian Blood Services, Canadian Organ Replacement Register, Canadian Society of Transplantation, Eledon Pharmaceuticals (Data Monitoring Committee member for phase 1b trial; paid), and Health Canada. R.B. Mannon reports research funding from Transplant Genomics, Inc., Verici DX; honoraria from CSL Behring, Olaris Inc., and Vitaerris; patents or royalties for Eurofins; an advisory or leadership role for Verici Dx (steering committee) and the Vitaerris VKTX01 IMAGINE Trial (steering committee); and other interests or relationships with the American Society of Nephrology (grants committee, chair of the policy and advocacy committee), the Data and Safety Monitoring Board, the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, the Scientific Registry of Transplant Recipients Review Committee (co-chair), TTS 2020 and 2022 (program committee), and Women in Transplantation (chair). M.C. Menon reports ownership interest in Renalytix AI; research funding from Natera Pharmaceuticals and the National Institute of Diabetes and Digestive and Kidney Diseases; and an advisory or leadership role for the American Society of Transplantation (scientific review committee), Clinical Transplantation (associate editor), JASN (editorial fellow of the transplantation section 2020), and the Journal of Clinical Medicine (editorial board). K.A. Newell reports consultancy for Care Dx, CSL Behring, Hansa, Immucor, Sangamo, Takeda, and Talaris Therapeutics. P. Nickerson reports consultancy for CSL Behring and Paladin Labs; research funding from the National Institutes of Health; and honoraria from Astellas and One Lambda. E.D. Poggio reports consultancy for CareDx, Transplant Genomics, and Verici; and honoraria from CareDx, Gador, Natera, Sanofi, and Scienzia. R. Sung reports research funding from Talaris Therapeutics and other interests or relationships with the American Society of Transplant Surgeons, Gift of Life Michigan, National Kidney Foundation of Michigan, and Organ Donation and Transplantation Alliance. R. Shapiro reports other interests or relationships with Clinical Transplantation (editor in chief). F. Vincenti reports research funding from Angion, Astellas, CSL Behring, Merck, Novartis, Pfizer, and Viela Bio; and honoraria from Veloxis. P.S. Heeger reports consultancy for Mallinckrodt Pharmaceuticals and Vertex; honoraria from Mallinckrodt Pharmaceuticals and Vertex; and an advisory or leadership role for Mallinckrodt Pharmaceuticals (paid scientific consultant) and Vertex (paid scientific consultant). All remaining authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Two hundred twenty-five subjects were evaluable for the primary end point. Flow of all patients who provided consent through the study. Reasons for termination before and after transplant are provided. For randomized and transplanted patients, disposition is presented, along with a summary of data available for primary end point analysis. AE, adverse event.
Figure 2.
Figure 2.
IFX reduces serum levels of TNF among other proinflammatory cytokines. Plasma levels (pg/ml) of (A) TNF, (B) IL-1β, (C) IL-6, and (D) IL-8 are presented at study visits 7 (day 7 after transplant or discharge visit, whichever occurred first) and visit 9 (day 30/month 1 after transplant) for the IFX (red dots) and PLBO (blue dots) groups. Horizontal black lines within each group represent the mean cytokine level at the indicated visit. P values for between-group comparisons result from a two-sample t test; P values for within-group comparisons between visits 7 and 9 result from a paired t test.
<b>Figure 3</b>.
Figure 3.
The 24-month eGFR did not differ between study arms. eGFR values are plotted over time for each patients in the IFX (red) and PLBO (blue) groups. A longitudinal repeated-measures mixed model with random effects for the intercept and day of eGFR sample collection estimated the month 24 treatment group difference to be –4.9 ml/min (95% CI, –10.73 to 0.93; P=0.1). The bold red and blue lines represent the treatment group-specific predicted lines resulting from the mixed model. I, infliximab; P, placebo; M24/D730, month 24/day 730.
Figure 4.
Figure 4.
BK viremia occurred more frequently in the IFX-treated subjects. Number of patients at risk is presented at selected days after transplant and includes all patients who received IFX (n=114, red) or PLBO (n=112, blue) infusion. Patients are censored at day of last follow-up. P value results from log-rank test comparing the treatment groups. BK viremia defined as BK virus infection requiring a change in immunosuppression or antiviral therapy.
See this image and copyright information in PMC

References

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