Effects of Inhibiting Early Inflammation in Kidney Transplant Patients

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The number of dialysis sessions a person had during their first 8 weeks post-transplant was used for this endpoint.

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.

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.

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.

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.

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.

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.

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.

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%.

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%.

Participants who needed dialysis after the first week post-transplant were considered to have met this endpoint.

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.

Participants were considered to have met this endpoint if they had an infection that required hospitalization or resulted in death.

Participants were considered to have met this endpoint if they had at least one mycobacterial of fungal infection.

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.

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.

Participants were considered to have met this endpoint if they had a reported case of malignancy.

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.