Clinical trial NCT02495077: Effects of Inhibiting Early Inflammation in Kidney Transplant Patients
Official title: Randomized Controlled Trial of Infliximab (Remicade®) Induction Therapy for Deceased Donor Kidney Transplant Recipients (CTOT-19)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Kidney Transplant
Keywords: Kidney Transplantation
infliximab
Tissue Donors
Remicade
Induction Therapy
Deceased Donor Kidney Transplant Recipients
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Clinical Trials in Organ Transplantation
name: Rho Federal Systems Division, Inc.
First posted: 2015-07-13
Enrollment: 290
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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).

Eligibility criteria: 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.

Primary outcomes:
measure: The Difference Between the Mean eGFR (Modified MDRD) in the Experimental vs. Control Groups.
timeFrame: 24-Month post-transplantation
Secondary outcomes:
measure: Percent of Participants With Biopsy Proven Acute Cellular Rejection (BPAR)
timeFrame: 6 month post-transplantation
measure: Percent of Participants With Biopsy Proven Acute Cellular Rejection (BPAR).
timeFrame: 24 months post-transplantation
measure: BANFF Grades of First Acute Cellular Rejections (ACR).
timeFrame: 6 month post-transplantation
measure: Percent of Participants With Biopsy Proven Acute Cellular Rejection (BPAR) or Borderline Rejection.
timeFrame: 6 months post-transplantation
measure: Percent of Participants With Biopsy Proven Acute Cellular Rejection (BPAR) or Borderline Rejection
timeFrame: 24 months post-transplantation
measure: Percent of Participants With Biopsy Proven Acute Antibody Mediated Rejection (AMR)
timeFrame: 6 months post-transplantation
measure: Percent of Participants With Biopsy Proven Acute Antibody Mediated Rejection (AMR).
timeFrame: 24 months post-transplantation
measure: Percent of Participants With Biopsy Proven Acute Antibody Mediated Rejection AMR or Suspicious for AMR
timeFrame: 6 months post-transplantation
measure: Percent of Participants With Biopsy Proven Acute Antibody Mediated Rejection AMR or Suspicious for AMR.
timeFrame: 24 months post-transplantation
measure: BANFF Grades of First AMR.
timeFrame: 6 months post-transplantation
measure: Percent of Participants With BANFF Chronicity Scores > or Equal 2 on the 24 Month Biopsy.
timeFrame: 24 months post-transplantation
measure: Change in BANFF Chronicity Scores Between Implantation and the 24 Month Biopsy.
timeFrame: 24 months post-transplantation
measure: Percent of Participants With Locally Treated Rejection, Defined as Treatment Administered for Rejection Based on Clinical Signs or Biopsy Findings.
timeFrame: 6 months post-transplantation
measure: Percent of Participants With Locally Treated Rejection, Defined as Treatment Administered for Rejection Based on Clinical Signs or Biopsy Findings.
timeFrame: 24 months post-transplantation
measure: Change in eGFR Between 3 Months and 24 Months as Measured by MDRD
timeFrame: 3 months and 24 months post-transplantation
measure: Change in eGFR Between 3 Months and 24 Months as Measured by CKD-EPI
timeFrame: 3 months and 24 months post-transplantation
measure: Change in eGFR Between Post-transplant Nadir and 24 Months as Measured by MDRD
timeFrame: 6 months and 24 months post-transplantation
measure: Change in eGFR Between Post-transplant Nadir and 24 Months as Measured by CKD-EPI
timeFrame: 6 months and 24 months post-transplantation
measure: Change in eGFR Between 6 Months and 24 Months as Measured by MDRD
timeFrame: 6 months and 24 months post-transplantation
measure: Change in eGFR Between 6 Months and 24 Months as Measured by CKD-EPI
timeFrame: 6 months and 24 months post-transplantation
measure: eGFR Values as Measured by MDRD
timeFrame: Day 7 post-transplantation
measure: eGFR Values as Measured by MDRD
timeFrame: Days 30, 60, and 180 post-transplantation
measure: eGFR Values as Measured by CKD-EPI
timeFrame: Day 7 post-transplantation
measure: eGFR Values as Measured by CKD-EPI
timeFrame: Days 30, 90, and 180 post-transplantation
measure: Percent of Participants With Death or Graft Failure.
timeFrame: 24 months post-transplantation
measure: Percent of Participants With Only Graft Failure.
timeFrame: 24 months post-transplantation
measure: Percent of Participants That Required at Least One Dialysis Treatment.
timeFrame: 1 week post-transplantation
measure: Number of Dialysis Sessions.
timeFrame: 8 weeks post-transplantation
measure: Duration of Delayed Graft Function (DGF), Defined as Time From Transplantation to the Last Required Dialysis Treatment.
timeFrame: First post-transplant dialysis treatment to last post-transplant dialysis treatment
measure: Percent of Participants With Primary Non-Function (PNF), Defined as Dialysis-dependency for More Than 3 Months.
timeFrame: Transplantation through at least month 3 up to month 24
measure: Change From Baseline (Immediately After Surgery) in Serum Creatinine.
timeFrame: 24, 48 and 72 hours post-transplantation
measure: Days From Transplantation Until Event (ACR, AMR, or Hospitalization for Infection and/or Malignancy)
timeFrame: 24 months post-transplantation
measure: The Percent of Participants With a Serum Creatinine of More Than 3 mg/dL.
timeFrame: Day 5 post-transplantation
measure: Creatinine Reduction Ratio (CRR), Defined as the First Creatinine on Day 2 Divided by he First Creatinine After Surgery
timeFrame: Day 2 post-transplantation
measure: Creatinine Reduction Ratio (CRR), Defined as the First Creatinine on Day 5 Divided by the First Creatinine After Surgery.
timeFrame: Day 5 post-transplantation
measure: The Percent of Participants Whose Day 5 Serum CRR Was Less Than 70%.
timeFrame: Day 5 post-transplantation
measure: The Percent of Participants Whose Day 2 Serum CRR Was Less Than 30%.
timeFrame: Day 2 post-transplantation
measure: The Percent of Participants Who Need Dialysis After Week 1.
timeFrame: 1 week to 24 months post-transplantation
measure: Percent of Participants With de Novo DSA.
timeFrame: 24 months post-transplantation
measure: Percent of Participants With Any Infection Requiring Hospitalization or Resulting in Death.
timeFrame: 24 months post-transplantation
measure: Percent of Participants With Mycobacterial or Fungal Infections
timeFrame: 24 months post-transplantation
measure: Percent of Participants With CMV Viremia That Require a Change in Immunosuppression or Anti-viral Treatment as Per Standard of Care at the Site
timeFrame: 24 months post-transplantation
measure: Percent of Participants With BK Viremia That Require a Change in Immunosuppression or Anti-viral Treatment as Per Standard of Care at the Site.
timeFrame: 24 months post-transplantation
measure: Percent of Participants With Malignancy.
timeFrame: 24 months post-transplantation
measure: Percent of Participants With Impaired Wound Healing Manifested by Wound Dehiscence, Wound Infection, or Hernia at the Site of the Transplant Incision
timeFrame: 24 months post-transplantation
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St. Louis
state: Missouri
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai, Recanati Miller Transplant Institute
name: Peter S. Heeger, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospitals of Cleveland, Division of Nephrology & Hypertension
name: Donald E Hricik, MD
role: STUDY_CHAIR
References: