Effects of Inhibiting Early Inflammation in Kidney Transplant Patients

NCT02495077 | Completed Phase 2 Results DMC

• 3 other identifiers: DAIT CTOT-19U01AI063594NIAID CRMS ID#: 20678
• Study Type: interventional
• Target: 290
• Locations: 2 countries
• Sites: 15

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.

Conditions

Kidney Transplant

Keywords

Kidney Transplantation; infliximab; Tissue Donors; Remicade; Induction Therapy; Deceased Donor Kidney Transplant Recipients

Outcome Measures

Primary Outcomes (1)

• The Difference Between the Mean eGFR (Modified MDRD) in the Experimental vs. Control Groups.

  Glomerular filtration rate (GFR) is a measure of kidney function and helps determine the stage of kidney disease. eGFR was estimated using the Modification of Diet in Renal Disease (MDRD) equation. A value of 90+ means kidney function is normal. A value between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease. Values between 30 and 59 indicates moderately reduced kidney function. Values between 15 and 29 indicate severely reduced kidney function. Values below 15 indicate very severe or endstage kidney failure. eGFR values from months 1, 3, 6, 12, 18, and 24 were used to generate an estimate of the month 24 eGFR for each treatment group.

  24-Month post-transplantation

Secondary Outcomes (45)

• Percent of Participants With Biopsy Proven Acute Cellular Rejection (BPAR)

  6 month post-transplantation

• Percent of Participants With Biopsy Proven Acute Cellular Rejection (BPAR).

  24 months post-transplantation

• BANFF Grades of First Acute Cellular Rejections (ACR).

  6 month post-transplantation

• Percent of Participants With Biopsy Proven Acute Cellular Rejection (BPAR) or Borderline Rejection.

  6 months post-transplantation

• Percent of Participants With Biopsy Proven Acute Cellular Rejection (BPAR) or Borderline Rejection

  24 months post-transplantation

Study Arms (2)

Experimental

EXPERIMENTAL

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.

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

Control

ACTIVE COMPARATOR

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.

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

Interventions

Infliximab BIOLOGICAL

A single dose, of 3mg/kg infusion

Also known as: Remicade®

Experimental

Methylprednisolone DRUG

500mg will be Initiated just prior to or at the initiation of transplant surgery and prior to Infliximab and thymoglobulin infusion

Also known as: Solu-Medrol

Control; Experimental

Mycophenolate Mofetil DRUG

Administered at a target dose of 2000mg daily, as tolerated, until study closure

Also known as: MMF, CellCept®

Control; Experimental

Tacrolimus DRUG

Administered at a target dose of 0.1mg/kg BID, post-op, then adjusted to target trough levels of 8-12ng/ml during 1st 3-months post-op and finally adjusted to target trough levels of 5-8ng/ml until study closure

Also known as: FK-506, FR-900506, Prograf®

Control; Experimental

Thymoglobulin® BIOLOGICAL

Administered daily for 5 days with the intention of achieving a total dose of 4.5 to 6.0 mg/kg, as tolerated

Also known as: Antithymocyte Globulin [Rabbit], Rabbit ATG

Control; Experimental

Acetaminophen DRUG

30 to 60 minutes prior to the start of the infusion * Tylenol, 600 to 1000mg by mouth or * Suppository form

Also known as: Tylenol®

Control; Experimental

Loratadine DRUG

30 to 60 minutes prior to the start of the infusion * Claritin (Loratadine) 10mg by mouth or * Benadryl (Diphenhydramine) 25 or 50 mg by mouth

Also known as: Claritin®

Control; Experimental

Placebo for Infliximab BIOLOGICAL

A single dose is volume matched to Infliximab (250mL) infusion

Control

Prednisone DRUG

Prednisone will be administered peri-operatively according to center practice. Prednisone should be gradually tapered to no less than 5 mg/day or 10 mg every other day by 3 months post-transplant thereafter until study closure.

Control; Experimental

Diphenhydramine DRUG

30 to 60 minutes prior to the start of the infusion * Claritin (Loratadine) 10mg by mouth or * Benadryl (Diphenhydramine) 25 or 50 mg by mouth

Also known as: Benadryl

Control; Experimental

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult (\>18 years of age) male and female recipients (all races and ethnicities)
• Subject must be able to understand and provide consent
• Recipients of deceased donor kidney transplants (including re-transplants)
• Negative crossmatch, actual or virtual, or a PRA of 0% on historic and current sera as determined by each participating study center
• Donor kidneys from deceased donors and donors after cardiac death (DCD) with Kidney Donor Profile Indices (KDPI) ranging from ≥20 to \<95
• Female participants of childbearing potential must have a negative pregnancy test upon study entry
• 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.

You may not qualify if:

• Inability or unwillingness of a participant to give written informed consent or comply with study protocol
• Recipients of living donor transplants
• Presence of other transplanted solid organ (heart, lung, liver, pancreas, small intestines) or co-transplanted organ
• Human immunodeficiency virus positive (HIV+) recipients
• Epstein-Barr virus Immunoglobulin G (EBV IgG) negative recipients
• Hepatitis B surface antigen positive kidney transplant recipients
• Hepatitis B core antibody positive kidney transplant recipients
• Hepatitis B negative kidney transplant recipients that receive transplants from Hepatitis B core antibody positive donor
• 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
• Recipients with a previous history of active TB
• Recipients with a positive test for latent TB infection (PPD, QuantiFERON, ELISPOT), regardless of previous therapy
• Any severe infection at the time of transplantation.
• Note: Severe infection determination will be made by the local site investigator.
• Severe congestive heart failure (NYHA functional class III or higher)
• Subjects with a known hypersensitivity to any murine/ mouse proteins

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Clinical Trials in Organ Transplantation: collaborator
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (15)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

University of California, Los Angeles

Los Angeles, California, 90024, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Yale University

New Haven, Connecticut, 06511, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

University of Maryland

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Washington University School of Medicine in St. Louis

St Louis, Missouri, 63110, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44106, United States

Location

University Hospitals of Cleveland

Cleveland, Ohio, 44106, United States

Location

University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

University of Manitoba

Winnipeg, Manitoba, R3A 1R9, Canada

Location

Toronto General Hospital

Toronto, Ontario, M5G 2C4, Canada

Location

Related Publications (2)

• Wajih Z, Karpe KM, Walters GD. Interventions for BK virus infection in kidney transplant recipients. Cochrane Database Syst Rev. 2024 Oct 9;10(10):CD013344. doi: 10.1002/14651858.CD013344.pub2.

  PMID: 39382091 DERIVED

• Hricik DE, Armstrong B, Alhamad T, Brennan DC, Bromberg JS, Bunnapradist S, Chandran S, Fairchild RL, Foley DP, Formica R, Gibson IW, Kesler K, Kim SJ, Mannon RB, Menon MC, Newell KA, Nickerson P, Odim J, Poggio ED, Sung R, Shapiro R, Tinckam K, Vincenti F, Heeger PS. Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial. J Am Soc Nephrol. 2023 Jan 1;34(1):145-159. doi: 10.1681/ASN.2022040454. Epub 2022 Oct 4.

  PMID: 36195441 DERIVED

Related Links

• Division of Allergy, Immunology, and Transplantation (DAIT)
• National Institute of Allergy and Infectious Diseases (NIAID)
• Clinical Trials in Organ Transplantation (CTOT)

MeSH Terms

Interventions

Infliximab; Methylprednisolone; Methylprednisolone Hemisuccinate; Mycophenolic Acid; Tacrolimus; thymoglobulin; Acetaminophen; Loratadine; Prednisone; Diphenhydramine

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Macrolides; Lactones; Acetanilides; Anilides; Amides; Aniline Compounds; Amines; Cyproheptadine; Dibenzocycloheptenes; Benzocycloheptenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pregnadienediols; Ethylamines; Benzhydryl Compounds; Benzene Derivatives

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Peter S. Heeger, MD

  Icahn School of Medicine at Mount Sinai, Recanati Miller Transplant Institute

  PRINCIPAL INVESTIGATOR

• Donald E Hricik, MD

  University Hospitals of Cleveland, Division of Nephrology & Hypertension

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 6, 2015
• First Posted: July 13, 2015
• Study Start: November 2, 2015
• Primary Completion: July 23, 2021
• Study Completion: July 23, 2021
• Last Updated: August 16, 2022
• Results First Posted: August 16, 2022

Record last verified: 2022-07

Locations

CA (2); US (13)