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Effects of Inhibiting Early Inflammation in Kidney Transplant Patients

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ClinicalTrials.gov Identifier: NCT02495077
Recruitment Status : Recruiting
First Posted : July 13, 2015
Last Update Posted : April 2, 2019
Sponsor:
Collaborator:
Clinical Trials in Organ Transplantation
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE July 6, 2015
First Posted Date  ICMJE July 13, 2015
Last Update Posted Date April 2, 2019
Actual Study Start Date  ICMJE November 2, 2015
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 8, 2015)
The difference between the mean eGFR (modified MDRD) in the experimental vs. control groups. [ Time Frame: 24-Month post-transplantation ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02495077 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2015)
  • Proportion of subjects with biopsy proven acute cellular rejection (BPAR) [ Time Frame: 6 month post-transplantation ]
  • Proportion of subjects with biopsy proven acute cellular rejection (BPAR). [ Time Frame: 2 years post-transplantation ]
  • BANFF grades of first Acute Cellular Rejections (ACR). [ Time Frame: 6 month post-transplantation ]
    Based on BANFF 2007 Scoring Criteria
  • Proportion of subjects with biopsy proven acute cellular rejection (BPAR) or borderline rejection. [ Time Frame: 6 months post-transplantation ]
  • Proportion of subjects with biopsy proven acute cellular rejection (BPAR) or borderline rejection [ Time Frame: 2 years post-transplantation ]
  • Proportion of subjects with biopsy proven acute antibody mediated rejection (AMR) [ Time Frame: 6 months post-transplantation ]
  • Proportion of subjects with biopsy proven acute antibody mediated rejection (AMR). [ Time Frame: 2 years post-transplantation ]
  • Proportion of subjects with biopsy proven acute antibody mediated rejection AMR or suspicious for AMR [ Time Frame: 6 months post-transplantation ]
  • Proportion of subjects with biopsy proven acute antibody mediated rejection AMR or suspicious for AMR. [ Time Frame: 2 years post-transplantation ]
  • BANFF grades of first AMR. [ Time Frame: 6 months post-transplantation ]
  • Proportion of subjects with BANFF chronicity scores > or equal 2. [ Time Frame: 24 month post-transplantation ]
  • Change in BANFF chronicity scores Change Between implantation and 24 month biopsies. [ Time Frame: 24 month post-transplantation ]
  • 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)
  • Change in eGFR between post-transplant nadir and 24 months [ Time Frame: 24 month post-transplantation ]
    As measured by both MDRD and CKD-EPI
  • eGFR Values [ Time Frame: On days 7, 30, 90, and 180 post-transplantation ]
    As measured by both MDRD and CKD-EPI
  • Proportion of subjects with death or graft failure. [ Time Frame: 2 years post-transplantation ]
  • Proportion of subjects with only graft failure. [ Time Frame: 2 years post-transplantation ]
  • Proportion of subjects that required at least one dialysis treatment. [ Time Frame: 1 week post-transplantation ]
  • Number of dialysis sessions. [ Time Frame: 8 weeks post-transplantation ]
  • Duration of delayed graft function (DGF) defined from transplantation to the last required dialysis treatment. [ Time Frame: 2 years post-transplantation ]
  • The incidence of primary non-function (PNF), defined as for dialysis-dependency for more than 3 months. [ Time Frame: 2 years post-transplantation ]
  • Change from baseline (immediately after surgery) in serum creatinine and serum creatinine concentration. [ Time Frame: 24, 48 and 72 hours post-transplantation ]
  • Event (ACR, AMR, or hospitalization for infection and or malignancy) [ Time Frame: 2 years post-transplantation ]
  • 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.
  • 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).
  • 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%
  • 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%
  • Proportion of Slow Graft Function [ Time Frame: 1 week post-transplantation ]
    Proportion of subjects who need dialysis after 1 week.
  • Proportion of subjects with any infection requiring hospitalization or resulting in death. [ Time Frame: 5 years post-transplantation ]
  • Proportion of subjects with Mycobacterial or fungal infections [ Time Frame: 5 years post-transplantation ]
  • 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.
  • 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.
  • Proportion of subjects with malignancy. [ Time Frame: 5 years post-transplantation ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effects of Inhibiting Early Inflammation in Kidney Transplant Patients
Official Title  ICMJE Randomized Controlled Trial of Infliximab (Remicade®) Induction Therapy for Deceased Donor Kidney Transplant Recipients (CTOT-19)
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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Kidney Transplant
Intervention  ICMJE
  • 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®
  • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Biological: Infliximab
    • Drug: Methylprednisolone
    • Drug: Mycophenolate Mofetil
    • Drug: Tacrolimus
    • Biological: Thymoglobulin®
    • Drug: Acetaminophen
    • Drug: Loratadine
    • Drug: Prednisone
    • Drug: Diphenhydramine
  • 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.
    Interventions:
    • Drug: Methylprednisolone
    • Drug: Mycophenolate Mofetil
    • Drug: Tacrolimus
    • Biological: Thymoglobulin®
    • Drug: Acetaminophen
    • Drug: Loratadine
    • Biological: Placebo for Infliximab
    • Drug: Prednisone
    • Drug: Diphenhydramine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 8, 2015)
300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02495077
Other Study ID Numbers  ICMJE DAIT CTOT-19
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Clinical Trials in Organ Transplantation
Investigators  ICMJE
Principal Investigator: Peter Heeger, MD Icahn School of Medicine at Mount Sinai
Study Chair: Donald E Hricik, MD University Hospitals Cleveland Medical Center
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP