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Effects of Inhibiting Early Inflammation in Kidney Transplant Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02495077
Recruitment Status : Active, not recruiting
First Posted : July 13, 2015
Last Update Posted : March 30, 2020
Sponsor:
Collaborator:
Clinical Trials in Organ Transplantation
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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.


Condition or disease Intervention/treatment Phase
Kidney Transplant Biological: Infliximab Drug: Methylprednisolone Drug: Mycophenolate Mofetil Drug: Tacrolimus Biological: Thymoglobulin® Drug: Acetaminophen Drug: Loratadine Biological: Placebo for Infliximab Drug: Prednisone Drug: Diphenhydramine Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 247 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Randomized Controlled Trial of Infliximab (Remicade®) Induction Therapy for Deceased Donor Kidney Transplant Recipients (CTOT-19)
Actual Study Start Date : November 2, 2015
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Infliximab

Arm Intervention/treatment
Experimental: Experimental Arm
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
A single dose, of 3mg/kg infusion
Other Name: Remicade®

Drug: Methylprednisolone
500mg will be Initiated just prior to or at the initiation of transplant surgery and prior to Infliximab and thymoglobulin infusion
Other Name: Solu-Medrol

Drug: Mycophenolate Mofetil
Administered at a target dose of 2000mg daily, as tolerated, until study closure
Other Names:
  • MMF
  • CellCept®

Drug: Tacrolimus
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
Other Names:
  • FK-506
  • FR-900506
  • Prograf®

Biological: Thymoglobulin®
Administered daily for 5 days with the intention of achieving a total dose of 4.5 to 6.0 mg/kg, as tolerated
Other Names:
  • Antithymocyte Globulin [Rabbit]
  • Rabbit ATG

Drug: Acetaminophen

30 to 60 minutes prior to the start of the infusion

  • Tylenol, 600 to 1000mg by mouth or
  • Suppository form
Other Name: Tylenol®

Drug: Loratadine

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
Other Name: Claritin®

Drug: Prednisone
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.

Drug: Diphenhydramine

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
Other Name: Benadryl

Active Comparator: Control group
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
500mg will be Initiated just prior to or at the initiation of transplant surgery and prior to Infliximab and thymoglobulin infusion
Other Name: Solu-Medrol

Drug: Mycophenolate Mofetil
Administered at a target dose of 2000mg daily, as tolerated, until study closure
Other Names:
  • MMF
  • CellCept®

Drug: Tacrolimus
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
Other Names:
  • FK-506
  • FR-900506
  • Prograf®

Biological: Thymoglobulin®
Administered daily for 5 days with the intention of achieving a total dose of 4.5 to 6.0 mg/kg, as tolerated
Other Names:
  • Antithymocyte Globulin [Rabbit]
  • Rabbit ATG

Drug: Acetaminophen

30 to 60 minutes prior to the start of the infusion

  • Tylenol, 600 to 1000mg by mouth or
  • Suppository form
Other Name: Tylenol®

Drug: Loratadine

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
Other Name: Claritin®

Biological: Placebo for Infliximab
A single dose is volume matched to Infliximab (250mL) infusion

Drug: Prednisone
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.

Drug: Diphenhydramine

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
Other Name: Benadryl




Primary Outcome Measures :
  1. The difference between the mean eGFR (modified MDRD) in the experimental vs. control groups. [ Time Frame: 24-Month post-transplantation ]

Secondary Outcome Measures :
  1. Proportion of subjects with biopsy proven acute cellular rejection (BPAR) [ Time Frame: 6 month post-transplantation ]
  2. Proportion of subjects with biopsy proven acute cellular rejection (BPAR). [ Time Frame: 2 years post-transplantation ]
  3. BANFF grades of first Acute Cellular Rejections (ACR). [ Time Frame: 6 month post-transplantation ]
    Based on BANFF 2007 Scoring Criteria

  4. Proportion of subjects with biopsy proven acute cellular rejection (BPAR) or borderline rejection. [ Time Frame: 6 months post-transplantation ]
  5. Proportion of subjects with biopsy proven acute cellular rejection (BPAR) or borderline rejection [ Time Frame: 2 years post-transplantation ]
  6. Proportion of subjects with biopsy proven acute antibody mediated rejection (AMR) [ Time Frame: 6 months post-transplantation ]
  7. Proportion of subjects with biopsy proven acute antibody mediated rejection (AMR). [ Time Frame: 2 years post-transplantation ]
  8. Proportion of subjects with biopsy proven acute antibody mediated rejection AMR or suspicious for AMR [ Time Frame: 6 months post-transplantation ]
  9. Proportion of subjects with biopsy proven acute antibody mediated rejection AMR or suspicious for AMR. [ Time Frame: 2 years post-transplantation ]
  10. BANFF grades of first AMR. [ Time Frame: 6 months post-transplantation ]
  11. Proportion of subjects with BANFF chronicity scores > or equal 2. [ Time Frame: 24 month post-transplantation ]
  12. Change in BANFF chronicity scores Change Between implantation and 24 month biopsies. [ Time Frame: 24 month post-transplantation ]
  13. Change in eGFR between 3 months and 24 months [ Time Frame: 24 month post-transplantation ]
    As measured by both MDRD and Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI)

  14. Change in eGFR between post-transplant nadir and 24 months [ Time Frame: 24 month post-transplantation ]
    As measured by both MDRD and CKD-EPI

  15. eGFR Values [ Time Frame: On days 7, 30, 90, and 180 post-transplantation ]
    As measured by both MDRD and CKD-EPI

  16. Proportion of subjects with death or graft failure. [ Time Frame: 2 years post-transplantation ]
  17. Proportion of subjects with only graft failure. [ Time Frame: 2 years post-transplantation ]
  18. Proportion of subjects that required at least one dialysis treatment. [ Time Frame: 1 week post-transplantation ]
  19. Number of dialysis sessions. [ Time Frame: 8 weeks post-transplantation ]
  20. Duration of delayed graft function (DGF) defined from transplantation to the last required dialysis treatment. [ Time Frame: 2 years post-transplantation ]
  21. The incidence of primary non-function (PNF), defined as for dialysis-dependency for more than 3 months. [ Time Frame: 2 years post-transplantation ]
  22. Change from baseline (immediately after surgery) in serum creatinine and serum creatinine concentration. [ Time Frame: 24, 48 and 72 hours post-transplantation ]
  23. Event (ACR, AMR, or hospitalization for infection and or malignancy) [ Time Frame: 2 years post-transplantation ]
  24. Proportion of Slow Graft Function (SGF) [ Time Frame: Day 5 post-transplantation ]
    The proportion of patients with a serum creatinine of more than 3 mg/dL.

  25. Ratio of Slow Graft Function (SGF) [ Time Frame: Day 2 and 7 post-transplantation ]
    Creatinine reduction ratio (CRR) defined as the first creatinine on the day divided by the first creatinine after surgery).

  26. Proportion of Slow Graft Function (SGF) [ Time Frame: Day 5 post-transplantation ]
    The proportion of patients whose day 5 serum CRR was less than 70%

  27. Proportion of Slow Graft Function (SGF) [ Time Frame: Day 2 post-transplantation ]
    The proportion of patients whose day 2 serum CRR was less than 30%

  28. Proportion of Slow Graft Function [ Time Frame: 1 week post-transplantation ]
    Proportion of subjects who need dialysis after 1 week.

  29. Proportion of subjects with any infection requiring hospitalization or resulting in death. [ Time Frame: 5 years post-transplantation ]
  30. Proportion of subjects with Mycobacterial or fungal infections [ Time Frame: 5 years post-transplantation ]
  31. Proportion of subjects with CMV viremia require a change in immunosuppression or anti-viral treatment as per standard of care at the site [ Time Frame: 5 years post-transplantation ]
    as per standard of care at the site.

  32. Proportion of subjects with BK viremia that require a change in immunosuppression or anti-viral treatment as per standard of care at the site. [ Time Frame: 5 years ]
    as per standard of care at the site.

  33. Proportion of subjects with malignancy. [ Time Frame: 5 years post-transplantation ]
  34. Proportion of subjects with impaired wound healing manifested by wound dehiscence, wound infection, or hernia at the site of the transplant incision [ Time Frame: 5 years post-transplantation ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02495077


Locations
Layout table for location information
United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35294
United States, California
University of California, Los Angeles
Los Angeles, California, United States, 90024
University of California, San Francisco
San Francisco, California, United States, 94143
United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06511
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Maryland
University of Maryland
Baltimore, Maryland, United States, 21201
Johns Hopkins University
Baltimore, Maryland, United States, 21287
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Missouri
Washington University
Saint Louis, Missouri, United States, 63110
United States, New York
Icahn School of Medicine at Mount Sinai
New York, New York, United States, 10029
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44106
University Hospitals of Cleveland
Cleveland, Ohio, United States, 44106
United States, Wisconsin
University of Wisconsin
Madison, Wisconsin, United States, 53792
Canada, Manitoba
University of Manitoba
Winnipeg, Manitoba, Canada, R3A 1R9
Canada, Ontario
Toronto General Hospital
Toronto, Ontario, Canada, M5G 2C4
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Trials in Organ Transplantation
Investigators
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Principal Investigator: Peter Heeger, MD Icahn School of Medicine at Mount Sinai
Study Chair: Donald E Hricik, MD University Hospitals Cleveland Medical Center
Additional Information:
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02495077    
Other Study ID Numbers: DAIT CTOT-19
First Posted: July 13, 2015    Key Record Dates
Last Update Posted: March 30, 2020
Last Verified: March 2020
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Kidney Transplantation
infliximab
Tissue Donors
Remicade
Induction Therapy
Deceased Donor Kidney Transplant Recipients
Additional relevant MeSH terms:
Layout table for MeSH terms
Acetaminophen
Diphenhydramine
Promethazine
Loratadine
Mycophenolic Acid
Prednisone
Methylprednisolone
Methylprednisolone Hemisuccinate
Infliximab
Tacrolimus
Thymoglobulin
Antilymphocyte Serum
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Antipyretics
Antibiotics, Antineoplastic