Effects of Inhibiting Early Inflammation in Kidney Transplant Patients

• ClinicalTrials.gov Identifier: NCT02495077
• Recruitment Status: Completed
• First Posted: July 13, 2015
• Results First Posted: August 16, 2022
• Last Update Posted: August 16, 2022
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Clinical Trials in Organ Transplantation; Rho Federal Systems Division, Inc.
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 290 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
• Actual Primary Completion Date: July 23, 2021
• Actual Study Completion Date: July 23, 2021

Arms and Interventions

Arm	Intervention/treatment
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; 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; 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

Outcome Measures

Primary Outcome Measures :

1. The Difference Between the Mean eGFR (Modified MDRD) in the Experimental vs. Control Groups. [ Time Frame: 24-Month post-transplantation ]
   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.

Secondary Outcome Measures :

1. Percent of Participants With Biopsy Proven Acute Cellular Rejection (BPAR) [ Time Frame: 6 month post-transplantation ]
   Acute cellular rejection was defined based on central lab pathology interpretation using the Banff 2007 criteria. Participants with a Banff grade of greater than or equal to IA with or without clinical symptoms within 6 months of transplant were determined to have met the endpoint. Severity is graded as IA, IB, IIA, IIB, or III, with IA being the mildest form of cellular rejection and III being the most severe form of cellular rejection.Criteria include: IA-significant interstitial infiltration and foci of moderate tubulitis; IB-significant interstitial infiltration and foci of severe tubulitis; IIA-mild to moderate intimal arteritis; IIB-severe intimal arteritis; III-transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation.
2. Percent of Participants With Biopsy Proven Acute Cellular Rejection (BPAR). [ Time Frame: 24 months post-transplantation ]
   Acute cellular rejection was defined based on central lab pathology interpretation using the Banff 2007 criteria. Participants with a Banff grade of greater than or equal to IA with or without clinical symptoms within 24 months of transplant were determined to have met the endpoint. Severity is graded as IA, IB, IIA, IIB, or III, with IA being the mildest form of cellular rejection and III being the most severe form of cellular rejection. Criteria include: IA-significant interstitial infiltration and foci of moderate tubulitis; IB-significant interstitial infiltration and foci of severe tubulitis; IIA-mild to moderate intimal arteritis; IIB-severe intimal arteritis; III-transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation.
3. BANFF Grades of First Acute Cellular Rejections (ACR). [ Time Frame: 6 month post-transplantation ]
   Acute cellular rejection was defined based on central lab pathology interpretation using the Banff 2007 criteria. Participants with a Banff grade of greater than or equal to IA with or without clinical symptoms within 6 months of transplant were determined to have met the endpoint. Severity is graded as IA, IB, IIA, IIB, or III, with IA being the mildest form of cellular rejection and III being the most severe form of cellular rejection.Criteria include: IA-significant interstitial infiltration and foci of moderate tubulitis; IB-significant interstitial infiltration and foci of severe tubulitis; IIA-mild to moderate intimal arteritis; IIB-severe intimal arteritis; III-transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation.
4. Percent of Participants With Biopsy Proven Acute Cellular Rejection (BPAR) or Borderline Rejection. [ Time Frame: 6 months post-transplantation ]
   Acute cellular rejection was defined based on central lab pathology interpretation using the Banff 2007 criteria. Participants with a Banff grade of borderline or greater than or equal to IA with or without clinical symptoms within 6 months of transplant were determined to have met the endpoint. Severity is graded as Borderline, IA, IB, IIA, IIB, or III, with borderline representing possible cellular rejection, IA being the mildest form of cellular rejection, and III being the most severe form of cellular rejection.Criteria include: Borderline-no intimal arteritis is present but foci of mild tubulitis; IA-significant interstitial infiltration and foci of moderate tubulitis; IB-significant interstitial infiltration and foci of severe tubulitis; IIA-mild to moderate intimal arteritis; IIB-severe intimal arteritis; III-transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation.
5. Percent of Participants With Biopsy Proven Acute Cellular Rejection (BPAR) or Borderline Rejection [ Time Frame: 24 months post-transplantation ]
   Acute cellular rejection was defined based on central lab pathology interpretation using the Banff 2007 criteria. Participants with a Banff grade of borderline or greater than or equal to IA with or without clinical symptoms within 24 months of transplant were determined to have met the endpoint. Severity is graded as Borderline, IA, IB, IIA, IIB, or III, with borderline representing possible cellular rejection, IA being the mildest form of cellular rejection, and III being the most severe form of cellular rejection. Criteria include: Borderline-no intimal arteritis is present but foci of mild tubulitis; IA-significant interstitial infiltration and foci of moderate tubulitis; IB-significant interstitial infiltration and foci of severe tubulitis; IIA-mild to moderate intimal arteritis; IIB-severe intimal arteritis; III-transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation.
6. Percent of Participants With Biopsy Proven Acute Antibody Mediated Rejection (AMR) [ Time Frame: 6 months post-transplantation ]
   Antibody mediated rejection (AMR) was defined based on central lab pathology interpretation using the Banff 2013 criteria. Participants with a Banff finding of AMR within 6 months of transplant were determined to have met the endpoint. AMR is classified as acute/active, chronic/active, or C4d staining positive.Criteria include: acute/active-histologic evidence of acute tissue injury, evidence of current/recent antibody interaction with vascular endothelium, and serologic evidence of donor-specific antibodies (DSAs); chronic/active-morphologic evidence of chronic tissue injury, evidence of current/recent antibody interaction with vascular endothelium, and serologic evidence of DSAs; C4d staining positive-linear C4d staining in peritubular capillaries, glomerulitis=0, peritubular capillary=0, chronic glomerulopathy=0, no acute cell-mediated rejection or borderline changes.
7. Percent of Participants With Biopsy Proven Acute Antibody Mediated Rejection (AMR). [ Time Frame: 24 months post-transplantation ]
   Antibody mediated rejection (AMR) was defined based on central lab pathology interpretation using the Banff 2013 criteria. Participants with a Banff finding of AMR within 24 months of transplant were determined to have met the endpoint. AMR is classified as acute/active, chronic/active, or C4d staining positive. Criteria include: acute/active-histologic evidence of acute tissue injury, evidence of current/recent antibody interaction with vascular endothelium, and serologic evidence of donor-specific antibodies (DSAs); chronic/active-morphologic evidence of chronic tissue injury, evidence of current/recent antibody interaction with vascular endothelium, and serologic evidence of DSAs; C4d staining positive-linear C4d staining in peritubular capillaries, glomerulitis=0, peritubular capillary=0, chronic glomerulopathy=0, no acute cell-mediated rejection or borderline changes.
8. Percent of Participants With Biopsy Proven Acute Antibody Mediated Rejection AMR or Suspicious for AMR [ Time Frame: 6 months post-transplantation ]
   Antibody mediated rejection (AMR) was defined based on central lab pathology interpretation using the Banff 2013 criteria. Participants with a Banff finding of AMR or suspicious for AMR within 6 months of transplant were determined to have met the endpoint. AMR is classified as acute/active, chronic/active, C4d staining positive, or suspicious. Criteria include: acute/active-histologic evidence of acute tissue injury, evidence of current/recent antibody interaction with vascular endothelium, and serologic evidence of donor-specific antibodies (DSAs); chronic/active-morphologic evidence of chronic tissue injury, evidence of current/recent antibody interaction with vascular endothelium, and serologic evidence of DSAs; C4d staining positive-linear C4d staining in peritubular capillaries, glomerulitis=0, peritubular capillary=0, chronic glomerulopathy=0, no acute cell-mediated rejection or borderline changes; suspicious-when 2 of 3 factors for acute/active are present.
9. Percent of Participants With Biopsy Proven Acute Antibody Mediated Rejection AMR or Suspicious for AMR. [ Time Frame: 24 months post-transplantation ]
   Antibody mediated rejection (AMR) was defined based on central lab pathology interpretation using the Banff 2013 criteria. Participants with a Banff finding of AMR or suspicious for AMR within 24 months of transplant were determined to have met the endpoint. AMR is classified as acute/active, chronic/active, C4d staining positive, or suspicious. Criteria include: acute/active-histologic evidence of acute tissue injury, evidence of current/recent antibody interaction with vascular endothelium, and serologic evidence of donor-specific antibodies (DSAs); chronic/active-morphologic evidence of chronic tissue injury, evidence of current/recent antibody interaction with vascular endothelium, and serologic evidence of DSAs; C4d staining positive-linear C4d staining in peritubular capillaries, glomerulitis=0, peritubular capillary=0, chronic glomerulopathy=0, no acute cell-mediated rejection or borderline changes; suspicious-when 2 of 3 factors for acute/active are present
10. BANFF Grades of First AMR. [ Time Frame: 6 months post-transplantation ]
    Antibody mediated rejection (AMR) was defined based on central lab pathology interpretation using the Banff 2013 criteria. Participants with a Banff finding of AMR within 6 months of transplant were determined to have met the endpoint. AMR is classified as acute/active, chronic/active, or C4d staining positive. Criteria include: acute/active-histologic evidence of acute tissue injury, evidence of current/recent antibody interaction with vascular endothelium, and serologic evidence of donor-specific antibodies (DSAs); chronic/active-morphologic evidence of chronic tissue injury, evidence of current/recent antibody interaction with vascular endothelium, and serologic evidence of DSAs; C4d staining positive-linear C4d staining in peritubular capillaries, glomerulitis=0, peritubular capillary=0, chronic glomerulopathy=0, no acute cell-mediated rejection or borderline changes.
11. Percent of Participants With BANFF Chronicity Scores > or Equal 2 on the 24 Month Biopsy. [ Time Frame: 24 months post-transplantation ]
    The Banff 2013 classification involves scoring numerous characteristics of renal biopsy specimens. The ci (interstitial fibrosis) and ct (tubular atrophy) scores are two such characteristics. The scores can take values of 0, 1, 2, or 3 for each characteristic (ci and ct), indicating increasing severity of disease as the scores increase. Participants are considered to have met this endpoint if their ci + ct score on the 24 month biopsy summed to be > or equal to 2.
12. Change in BANFF Chronicity Scores Between Implantation and the 24 Month Biopsy. [ Time Frame: 24 months post-transplantation ]
    The Banff 2013 classification involves scoring numerous characteristics of renal biopsy specimens. The ci (interstitial fibrosis) and ct (tubular atrophy) scores are two such characteristics. The scores can take values of 0, 1, 2, or 3 for each characteristic (ci and ct), indicating increasing severity of disease as the scores increase. For this endpoint, the sum of ci+ct scores from the implantation biopsy was subtracted from the sum of the ci+ct scores from the month 24 biopsy and the difference between the two time points was classified as 0, 1, 2, or 3+. Higher values of this difference indicate more severe disease.
13. Percent of Participants With Locally Treated Rejection, Defined as Treatment Administered for Rejection Based on Clinical Signs or Biopsy Findings. [ Time Frame: 6 months post-transplantation ]
    Biopsies were read by the local pathologist at the hospital where the participant was a patient. These local reads informed clinical care for the participant, which may or may not include prescribing/administering medication to the participant to help with clinical concerns or findings noted on a biopsy. Participants were considered to have met this endpoint if they have a report of receiving treatment for clinical or biopsy-proven rejection during the first 6 months post-transplant.
14. Percent of Participants With Locally Treated Rejection, Defined as Treatment Administered for Rejection Based on Clinical Signs or Biopsy Findings. [ Time Frame: 24 months post-transplantation ]
    Biopsies were read by the local pathologist at the hospital where the participant was a patient. These local reads informed clinical care for the participant, which may or may not include prescribing/administering medication to the participant to help with clinical concerns or findings noted on a biopsy. Participants were considered to have met this endpoint if they have a report of receiving treatment for clinical or biopsy-proven rejection during the 24 month post-transplant follow-up.
15. Change in eGFR Between 3 Months and 24 Months as Measured by MDRD [ Time Frame: 3 months and 24 months post-transplantation ]
    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. The change in eGFR between months 3 and 24 was calculated as the month 24 eGFR minus the month 3 eGFR for each participant. A window of +/- 14 days was used for month 3 and +/- 1 month was used for month 24.
16. Change in eGFR Between 3 Months and 24 Months as Measured by CKD-EPI [ Time Frame: 3 months and 24 months post-transplantation ]
    Glomerular filtration rate (GFR) is a measure of kidney function and helps determine the stage of kidney disease. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 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. The change in eGFR between months 3 and 24 was calculated as the month 24 eGFR minus the month 3 eGFR for each participant. A window of +/- 14 days was used for month 3 and +/- 1 month was used for month 24.
17. Change in eGFR Between Post-transplant Nadir and 24 Months as Measured by MDRD [ Time Frame: 6 months and 24 months post-transplantation ]
    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. Post-transplant nadir was defined as the lowest value of eGFR from the first 6 months post-transplant. The change in eGFR between nadir and month 24 was calculated as the month 24 eGFR minus the nadir eGFR for each participant. A window of +/- 21 days was used for month 6 and +/- 1 month was used for month 24.
18. Change in eGFR Between Post-transplant Nadir and 24 Months as Measured by CKD-EPI [ Time Frame: 6 months and 24 months post-transplantation ]
    Glomerular filtration rate (GFR) is a measure of kidney function and helps determine the stage of kidney disease. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 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. Post-transplant nadir was defined as the lowest value of eGFR from the first 6 months post-transplant. The change in eGFR between nadir and month 24 was calculated as the month 24 eGFR minus the nadir eGFR for each participant. A window of +/- 21 days was used for month 6 and +/- 1 month was used for month 24.
19. Change in eGFR Between 6 Months and 24 Months as Measured by MDRD [ Time Frame: 6 months and 24 months post-transplantation ]
    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. The change in eGFR between months 6 and 24 was calculated as the month 24 eGFR minus the month 6 eGFR for each participant. A window of +/- 21 days was used for month 6 and +/- 1 month was used for month 24.
20. Change in eGFR Between 6 Months and 24 Months as Measured by CKD-EPI [ Time Frame: 6 months and 24 months post-transplantation ]
    Glomerular filtration rate (GFR) is a measure of kidney function and helps determine the stage of kidney disease. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 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. The change in eGFR between months 6 and 24 was calculated as the month 24 eGFR minus the month 6 eGFR for each participant. A window of +/- 21 days was used for month 6 and +/- 1 month was used for month 24.
21. eGFR Values as Measured by MDRD [ Time Frame: Day 7 post-transplantation ]
    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 day 7 and months 1, 3, 6, 12, 18, and 24 were used to generate an estimate of the eGFR at each time point of interest for each treatment group.
22. eGFR Values as Measured by MDRD [ Time Frame: Days 30, 60, and 180 post-transplantation ]
    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 day 7 and months 1, 3, 6, 12, 18, and 24 were used to generate an estimate of the eGFR at each time point of interest for each treatment group.
23. eGFR Values as Measured by CKD-EPI [ Time Frame: Day 7 post-transplantation ]
    Glomerular filtration rate (GFR) is a measure of kidney function and helps determine the stage of kidney disease. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 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 day 7 and months 1, 3, 6, 12, 18, and 24 were used to generate an estimate of the eGFR at each time point of interest for each treatment group.
24. eGFR Values as Measured by CKD-EPI [ Time Frame: Days 30, 90, and 180 post-transplantation ]
    Glomerular filtration rate (GFR) is a measure of kidney function and helps determine the stage of kidney disease. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) 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 day 7 and months 1, 3, 6, 12, 18, and 24 were used to generate an estimate of the eGFR at each time point of interest for each treatment group.
25. Percent of Participants With Death or Graft Failure. [ Time Frame: 24 months post-transplantation ]
    Participants who died or experienced graft failure were considered to have met this endpoint. Graft failure was defined as the need for post-transplant dialysis for more than 56 days.
26. Percent of Participants With Only Graft Failure. [ Time Frame: 24 months post-transplantation ]
    Participants who experienced graft failure were considered to have met this endpoint. Graft failure was defined as the need for post-transplant dialysis for more than 56 days.
27. Percent of Participants That Required at Least One Dialysis Treatment. [ Time Frame: 1 week post-transplantation ]
    Dialysis within the first week post-transplant is used in the setting of delayed graft function (DGF). Participants are considered to have had DGF if they had at least one dialysis treatment in the first week post-transplant.
28. Number of Dialysis Sessions. [ Time Frame: 8 weeks post-transplantation ]
    The number of dialysis sessions a person had during their first 8 weeks post-transplant was used for this endpoint.
29. Duration of Delayed Graft Function (DGF), Defined as Time From Transplantation to the Last Required Dialysis Treatment. [ Time Frame: First post-transplant dialysis treatment to last post-transplant dialysis treatment ]
    Participants are considered to have had DGF if they had at least one dialysis treatment in the first week post-transplant. For this endpoint, duration was calculated as the date of last post-transplant dialysis treatment minus the date of the first post-transplant dialysis treatment.
30. Percent of Participants With Primary Non-Function (PNF), Defined as Dialysis-dependency for More Than 3 Months. [ Time Frame: Transplantation through at least month 3 up to month 24 ]
    Post-transplant dialysis is sometimes required in the setting of kidney transplant. If such dialysis continues for more than 3 months, the participant is considered to have PNF and, as such, meets this endpoint definition.
31. Change From Baseline (Immediately After Surgery) in Serum Creatinine. [ Time Frame: 24, 48 and 72 hours post-transplantation ]
    Serum creatinine (mg/dL) is used to measure kidney function. A normal result is 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for women. Higher results indicate poorer kidney function, as creatinine is removed from the body by the kidneys. eGFR values from 24, 48, and 72 hours post-transplant (i.e., days 1, 2, and 3) were used to generate an estimate of the serum creatinine at each time point of interest for each treatment group.
32. Days From Transplantation Until Event (ACR, AMR, or Hospitalization for Infection and/or Malignancy) [ Time Frame: 24 months post-transplantation ]
    Participants are considered to have met this endpoint if they experienced biopsy-proven T-cell mediated rejection (ACR) or antibody mediated rejection (AMR) based on central pathology reading or were hospitalized for infection and/or malignancy. For participants who met one or more of these three components, the earliest event date of the three components was used as the time of meeting the endpoint. Participants who did not meet any of the three components were censored at their last date of follow-up. Event (or censor) day was calculated as event (or censor) date minus transplant date.
33. The Percent of Participants With a Serum Creatinine of More Than 3 mg/dL. [ Time Frame: Day 5 post-transplantation ]
    Serum creatinine (mg/dL) is used to measure kidney function. A normal result is 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for women. Higher results indicate poorer kidney function, as creatinine is removed from the body by the kidneys. This endpoint is ascertaining slow graft function in the immediate days post-transplant. A participant was considered to have met this endpoint if their day 5 serum creatinine was greater than 3 mg/dL.
34. Creatinine Reduction Ratio (CRR), Defined as the First Creatinine on Day 2 Divided by he First Creatinine After Surgery [ Time Frame: Day 2 post-transplantation ]
    Serum creatinine (mg/dL) is used to measure kidney function. A normal result is 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for women. Higher results indicate poorer kidney function, as creatinine is removed from the body by the kidneys. CRR was calculated as the day 1 post-transplant creatinine value minus the day 2 creatinine value divided by the day 1 creatinine value and multiplied by 100, resulting in a percentage. Higher numbers indicate a greater reduction in serum creatinine and, thus, potentially better kidney function.
35. Creatinine Reduction Ratio (CRR), Defined as the First Creatinine on Day 5 Divided by the First Creatinine After Surgery. [ Time Frame: Day 5 post-transplantation ]
    Serum creatinine (mg/dL) is used to measure kidney function. A normal result is 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for women. Higher results indicate poorer kidney function, as creatinine is removed from the body by the kidneys. CRR was calculated as the day 1 post-transplant creatinine value minus the day 5 creatinine value divided by the day 1 creatinine value and multiplied by 100, resulting in a percentage. Higher numbers indicate a greater reduction in serum creatinine and, thus, potentially better kidney function.
36. The Percent of Participants Whose Day 5 Serum CRR Was Less Than 70%. [ Time Frame: Day 5 post-transplantation ]
    Serum creatinine (mg/dL) is used to measure kidney function. A normal result is 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for women. Higher results indicate poorer kidney function, as creatinine is removed from the body by the kidneys. CRR was calculated as the day 1 post-transplant creatinine value minus the day 5 creatinine value divided by the day 1 creatinine value and multiplied by 100, resulting in a percentage. Higher numbers indicate a greater reduction in serum creatinine and, thus, potentially better kidney function. A participant was considered to have met this endpoint if their day 5 serum CRR was less than 70%.
37. The Percent of Participants Whose Day 2 Serum CRR Was Less Than 30%. [ Time Frame: Day 2 post-transplantation ]
    Serum creatinine (mg/dL) is used to measure kidney function. A normal result is 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for women. Higher results indicate poorer kidney function, as creatinine is removed from the body by the kidneys. CRR was calculated as the day 1 post-transplant creatinine value minus the day 2 creatinine value divided by the day 1 creatinine value and multiplied by 100, resulting in a percentage. Higher numbers indicate a greater reduction in serum creatinine and, thus, potentially better kidney function. A participant was considered to have met this endpoint if their day 2 serum CRR was less than 30%.
38. The Percent of Participants Who Need Dialysis After Week 1. [ Time Frame: 1 week to 24 months post-transplantation ]
    Participants who needed dialysis after the first week post-transplant were considered to have met this endpoint.
39. Percent of Participants With de Novo DSA. [ Time Frame: 24 months post-transplantation ]
    Donor specific antibody (DSA) can be formed post-transplant as part of the recipient's alloimmune response to the transplanted organ. DSA was determined by a central laboratory. Participants with newly developed DSA (i.e., de novo) following transplant were considered to have met this endpoint.
40. Percent of Participants With Any Infection Requiring Hospitalization or Resulting in Death. [ Time Frame: 24 months post-transplantation ]
    Participants were considered to have met this endpoint if they had an infection that required hospitalization or resulted in death.
41. Percent of Participants With Mycobacterial or Fungal Infections [ Time Frame: 24 months post-transplantation ]
    Participants were considered to have met this endpoint if they had at least one mycobacterial of fungal infection.
42. Percent of Participants With CMV Viremia That Require a Change in Immunosuppression or Anti-viral Treatment as Per Standard of Care at the Site [ Time Frame: 24 months post-transplantation ]
    Participants were considered to have met this endpoint if they had a reported case of CMV viremia that required a change in their existing immunosuppression or the use of anti-viral therapy.
43. Percent of Participants With BK Viremia That Require a Change in Immunosuppression or Anti-viral Treatment as Per Standard of Care at the Site. [ Time Frame: 24 months post-transplantation ]
    Participants were considered to have met this endpoint if they had a reported case of BK viremia that required a change in their existing immunosuppression or the use of anti-viral therapy.
44. Percent of Participants With Malignancy. [ Time Frame: 24 months post-transplantation ]
    Participants were considered to have met this endpoint if they had a reported case of malignancy.
45. Percent of Participants With Impaired Wound Healing Manifested by Wound Dehiscence, Wound Infection, or Hernia at the Site of the Transplant Incision [ Time Frame: 24 months post-transplantation ]
    Participants were considered to have met this endpoint if they had a reported case of impaired wound healing at the site of the transplant incision manifested by one wound dehiscence, wound infection, or hernia.

Eligibility Criteria

• 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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

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 School of Medicine in St. Louis

Saint Louis, Missouri, United States, 63110

United States, New York

Mount Sinai Medical Center

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

Rho Federal Systems Division, Inc.

Investigators

• Principal Investigator: Peter S. Heeger, MD; Icahn School of Medicine at Mount Sinai, Recanati Miller Transplant Institute
• Study Chair: Donald E Hricik, MD; University Hospitals of Cleveland, Division of Nephrology & Hypertension

  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):

Study Protocol  [PDF] April 27, 2020

Statistical Analysis Plan  [PDF] December 14, 2021

More Information

Additional Information:

Division of Allergy, Immunology, and Transplantation (DAIT) 

National Institute of Allergy and Infectious Diseases (NIAID) 

Clinical Trials in Organ Transplantation (CTOT) 

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02495077
• Other Study ID Numbers: DAIT CTOT-19; U01AI063594 ( U.S. NIH Grant/Contract ); NIAID CRMS ID#: 20678 ( Other Identifier: DAIT NIAID )
• First Posted: July 13, 2015
• Results First Posted: August 16, 2022
• Last Update Posted: August 16, 2022
• Last Verified: July 2022

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:

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