Effects of Inhibiting Early Inflammation in Kidney Transplant Patients

National Institute of Allergy and Infectious Diseases (NIAID)

Status and phase: Completed; Phase 2

Conditions: Kidney Transplant

Treatments: Biological: Thymoglobulin®; Drug: Loratadine; Drug: Diphenhydramine; Drug: Prednisone; Drug: Methylprednisolone; Drug: Tacrolimus; Biological: Placebo for Infliximab; Drug: Acetaminophen; Biological: Infliximab; Drug: Mycophenolate Mofetil

Study type: Interventional

Funder types: NETWORK; Industry; NIH

Identifiers

NCT02495077

DAIT CTOT-19

NIAID CRMS ID#: 20678 (Other Identifier)

U01AI063594 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

During transplant surgery, there is a period of time when a donated kidney is removed from a donor's body and stored until the time of the transplant surgery. The storage procedure results in buildup of various proteins within the kidney that can injure the donated kidney after it is transplanted. One of these proteins is tumor necrosis factor-alpha (TNF-alpha).

The purpose of this study is to evaluate whether taking infliximab, which blocks tumor necrosis factor alpha (TNF-alpha), just prior to transplant surgery, along with usual transplant medicines will protect the donated kidney from damage caused by TNF-alpha and help keep the transplanted kidney healthy for a longer period of time.

Full description

This is a Phase 2, multicenter, randomized, double blind (masked), placebo-controlled, 2-arm clinical trial of 300 deceased donor kidney transplant recipients. Participants will be randomized (1:1) to the experimental or control arm (150 subjects per arm).

Enrollment: 290 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Adult (>18 years of age) male and female recipients (all races and ethnicities)

2. Subject must be able to understand and provide consent

3. Recipients of deceased donor kidney transplants (including re-transplants)

4. Negative crossmatch, actual or virtual, or a PRA of 0% on historic and current sera as determined by each participating study center

5. Donor kidneys from deceased donors and donors after cardiac death (DCD) with Kidney Donor Profile Indices (KDPI) ranging from ≥20 to <95

6. Female participants of childbearing potential must have a negative pregnancy test upon study entry

7. Subjects must have a negative test result for latent tuberculosis (TB) infection (PPD, QuantiFERON, ELISPOT):

   • Subjects who have a negative test result for latent TB infection within 1 year of transplant date are eligible for enrollment and no further action is required
   • Subjects who have a negative test for latent TB infection that is greater than 1 year old are eligible for enrollment but are required to have a repeat test prior to transplantation.

Exclusion criteria

1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol

2. Recipients of living donor transplants

3. Presence of other transplanted solid organ (heart, lung, liver, pancreas, small intestines) or co-transplanted organ

4. Human immunodeficiency virus positive (HIV+) recipients

5. Epstein-Barr virus Immunoglobulin G (EBV IgG) negative recipients

6. Hepatitis B surface antigen positive kidney transplant recipients

7. Hepatitis B core antibody positive kidney transplant recipients

8. Hepatitis B negative kidney transplant recipients that receive transplants from Hepatitis B core antibody positive donor

9. Hepatitis C Virus positive (HCV+) patients who are either untreated or have failed to demonstrate sustained viral remission for more than 12 months after anti-viral treatment

10. Recipients with a previous history of active TB

11. Recipients with a positive test for latent TB infection (PPD, QuantiFERON, ELISPOT), regardless of previous therapy

12. Any severe infection at the time of transplantation.

    --Note: Severe infection determination will be made by the local site investigator.

13. Severe congestive heart failure (NYHA functional class III or higher)

14. Subjects with a known hypersensitivity to any murine/ mouse proteins

15. Subjects with any history of receiving any anti-tumor necrosis factor (anti- TNF) products

16. Subjects in whom rabbit anti-thymocyte globulin (Thymoglobulin®) or infliximab might not be tolerated

17. Subjects with a white blood cell count less than 3000/mm^3

18. Subjects with a platelet count less than 100,000/mm^3

19. Subjects with systolic blood pressure <100 mm/Hg

20. Subjects with symptomatic orthostatic hypotension or currently requiring Midodrine for blood pressure support

21. Subjects from, or who have traveled, to endemic areas with a history of active histoplasmosis or, with a chest x-ray consistent with previous active histoplasmosis (no serological testing required) :

    --Endemic regions determined by site based on local standard of care.

22. Subjects currently or formerly residing in regions of the United States that are highly endemic for coccidioidomycosis, and who have a positive serologic test for coccidioidomycosis:

    --Endemic regions determined by site based on local standard of care.

23. Recipients are excluded if the local site decides to treat the recipient with fluconazole because of diagnosis or suspicion of fungal infection the donor

24. Subjects that receive IVIG treatment within 3 months of transplant or planned intravenous immunoglobulin (IVIG) treatment peri-transplant

25. Use of an investigational agent within 4-weeks prior to study entry.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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290 participants in 2 patient groups

Experimental

Experimental group

Description:

rATG is co-administered with anti-TNFa (infliximab/Remicade®) plus maintenance therapy with tacrolimus, a mycophenolic acid derivative (either MMF or enteric coated MPA) and prednisone.

Treatment:

Drug: Mycophenolate Mofetil

Biological: Infliximab

Drug: Tacrolimus

Drug: Methylprednisolone

Drug: Prednisone

Drug: Loratadine

Drug: Acetaminophen

Biological: Thymoglobulin®

Drug: Diphenhydramine

Control

Active Comparator group

Description:

Rabbit anti-thymocyte globulin (rATG/Thymoglobulin®) plus placebo (Sterile normal saline) induction followed by maintenance therapy with tacrolimus, a mycophenolic acid derivative (either MMF or enteric coated MPA) and prednisone.

Treatment:

Drug: Mycophenolate Mofetil

Drug: Tacrolimus

Drug: Methylprednisolone

Drug: Prednisone

Drug: Loratadine

Biological: Placebo for Infliximab

Drug: Acetaminophen

Biological: Thymoglobulin®

Drug: Diphenhydramine