14 CLINICAL STUDIES

14.1 Prevention of Organ Rejection in Kidney Transplant Recipients

The efficacy and safety of NULOJIX in de novo kidney transplantation were assessed in two open-label, randomized, multicenter, active-controlled trials (Study 1 and Study 2). These trials evaluated two dose regimens of NULOJIX, the recommended dosage regimen [see Dosage and Administration (2.1)] and a regimen with higher cumulative doses and more frequent dosing than the recommended dosage regimen, compared to a cyclosporine control regimen. All treatment groups also received basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids.

Treatment Regimen

The NULOJIX recommended regimen consisted of a 10 mg per kg dose administered on Day 1 (the day of transplantation, prior to implantation), Day 5 (approximately 96 hours after the Day 1 dose), end of Weeks 2 and 4; then every four weeks through Week 12 after transplantation. Starting at Week 16 after transplantation, NULOJIX was administered at the maintenance dose of 5 mg per kg every four weeks (plus or minus three days). NULOJIX was administered as an intravenous infusion over 30 minutes [see Dosage and Administration (2.1)].

Basiliximab 20 mg was administered intravenously on the day of transplantation and four days later.

The initial dose of MMF was 1 gram twice daily and was adjusted as needed, based on clinical signs of adverse events or efficacy failure.

The protocol-specified dosing of corticosteroids in Studies 1 and 2 at Day 1 was methylprednisolone (as sodium succinate) 500 mg IV on arrival in the operating room, Day 2, methylprednisolone 250 mg IV, and Day 3, prednisone 100 mg orally. Actual median corticosteroid doses used with the NULOJIX recommended regimen from Week 1 through Month 6 are summarized in the table below (Table 6).

Table 6: Actual Corticosteroida Dosing in Studies 1 and 2
Day of Dosing	Median (Q1–Q3) Daily Doseb,c
	Study 1	Study 2
a Corticosteroid = prednisone or prednisolone. b The protocols allowed for flexibility in determining corticosteroid dose and rapidity of taper after Day 15. It is not possible to distinguish corticosteroid doses used to treat acute rejection versus doses used in a maintenance regimen. c Q1 and Q3 are the 25th and 75th percentiles of daily corticosteroid doses, respectively.
Week 1	31.7 mg (26.7-50 mg)	30 mg (26.7-50 mg)
Week 2	25 mg (20-30 mg)	25 mg (20-30 mg)
Week 4	20 mg (15-20 mg)	20 mg (15-22.5 mg)
Week 6	15 mg (10-20 mg)	16.7 mg (12.5-20 mg)
Month 6	10 mg (5-10 mg)	10 mg (5-12.5 mg)

Study 1 enrolled recipients of living donor and standard criteria deceased donor organs and Study 2 enrolled recipients of extended criteria donor organs. Standard criteria donor organs were defined as organs from a deceased donor with anticipated cold ischemia time of <24 hours and not meeting the definition of extended criteria donor organs. Extended criteria donors were defined as deceased donors with at least one of the following: (1) donor age ≥60 years; (2) donor age ≥50 years and other donor comorbidities (≥2 of the following: stroke, hypertension, serum creatinine >1.5 mg/dL); (3) donation of organ after cardiac death; or (4) anticipated cold ischemia time of the organ of ≥24 hours. Study 1 excluded recipients undergoing a first transplant whose current Panel Reactive Antibodies (PRA) were ≥50% and recipients undergoing a retransplantation whose current PRA were ≥30%; Study 2 excluded recipients with a current PRA ≥30%. Both studies excluded recipients with HIV, hepatitis C, or evidence of current hepatitis B infection; recipients with active tuberculosis; and recipients in whom intravenous access was difficult to obtain.

Efficacy data are presented for the NULOJIX recommended regimen and cyclosporine regimen in Studies 1 and 2.

The NULOJIX regimen with higher cumulative doses and more frequent dosing of belatacept was associated with more efficacy failures. Higher doses and/or more frequent dosing of NULOJIX are not recommended [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Study 1: Recipients of Living Donor and Standard Criteria Deceased Donor Kidneys

In Study 1 (NCT00256750), 666 patients were enrolled, randomized, and transplanted: 226 to the NULOJIX recommended regimen, 219 to the NULOJIX regimen with higher cumulative doses and more frequent dosing than recommended, and 221 to cyclosporine control regimen. The median age was 45 years; 58% of organs were from living donors; 3% were re-transplanted; 69% of the study population was male; 61% of patients were white, 8% were black/African-American, 31% were categorized as of other races; 16% had PRA ≥10%; 41% had 4 to 6 HLA mismatches; and 27% had diabetes prior to transplant. The incidence of delayed graft function was similar in all treatment arms (14% to 18%).

Premature discontinuation from treatment at the end of the first year occurred in 19% of patients receiving the NULOJIX recommended regimen and 19% of patients on the cyclosporine regimen. Among the patients who received the NULOJIX recommended regimen, 10% discontinued due to lack of efficacy, 5% due to adverse events, and 4% for other reasons. Among the patients who received the cyclosporine regimen, 9% discontinued due to adverse events, 5% due to lack of efficacy, and 5% for other reasons.

At the end of three years, 25% of patients receiving the NULOJIX recommended regimen and 34% of patients receiving the cyclosporine regimen had discontinued from treatment. Among the patients who received the NULOJIX recommended regimen, 12% discontinued due to lack of efficacy, 7% due to adverse events, and 6% for other reasons. Among the patients who received the cyclosporine regimen, 15% discontinued due to adverse events, 8% due to lack of efficacy, and 11% for other reasons.

Assessment of Efficacy

Table 7 summarizes the results of Study 1 following one and three years of treatment with the NULOJIX recommended dosage regimen and the cyclosporine control regimen. Efficacy failure at one year was defined as the occurrence of biopsy proven acute rejection (BPAR), graft loss, death, or lost to follow-up. BPAR was defined as histologically confirmed acute rejection by a central pathologist on a biopsy done for any reason, whether or not accompanied by clinical signs of rejection. Patient and graft survival was also assessed separately.

Table 7: Efficacy Outcomes by Years 1 and 3 for Study 1: Recipients of Living and Standard Criteria Deceased Donor Kidneys
Parameter	NULOJIX Recommended Regimen N=226 n (%)	Cyclosporine (CSA) N=221 n (%)	NULOJIX-CSA (97.3% CI)
a Patients may have experienced more than one event. b Patients known to be alive with a functioning graft.
Efficacy Failure by Year 1	49 (21.7)	37 (16.7)	4.9 (−3.3, 13.2)
Components of Efficacy Failurea
Biopsy Proven Acute Rejection	45 (19.9)	23 (10.4)
Graft Loss	5 (2.2)	8 (3.6)
Death	4 (1.8)	7 (3.2)
Lost to follow-up	0	1 (0.5)
Efficacy Failure by Year 3	58 (25.7)	57 (25.8)	−0.1 (−9.3, 9)
Components of Efficacy Failurea
Biopsy Proven Acute Rejection	50 (22.1)	31 (14)
Graft Loss	9 (4)	10 (4.5)
Death	10 (4.4)	15 (6.8)
Lost to follow-up	2 (0.9)	5 (2.3)
Patient and graft survivalb
Year 1	218 (96.5)	206 (93.2)	3.2 (−1.5, 8.4)
Year 3	206 (91.2)	192 (86.9)	4.3 (−2.2, 10.8)

In Study 1, the rate of BPAR at one year and three years was higher in patients treated with the NULOJIX recommended regimen than the cyclosporine regimen. Of the patients who experienced BPAR with NULOJIX, 70% experienced BPAR by Month 3, and 84% experienced BPAR by Month 6. By three years, recurrent BPAR occurred with similar frequency across treatment groups (<3%). The component of BPAR determined by biopsy only (subclinical protocol-defined acute rejection) was 5% in both treatment groups.

Patients treated with the NULOJIX recommended regimen experienced episodes of BPAR classified as Banff grade IIb or higher (6% [14/226] at one year and 7% [15/226] at three years) more frequently compared to patients treated with the cyclosporine regimen (2% [4/221] at one year and 2% [5/221] at three years). Also, T cell-depleting therapy was used more frequently to treat episodes of BPAR in NULOJIX-treated patients (10%; 23/226) compared to cyclosporine-treated patients (2%; 5/221). At Month 12, the difference in mean calculated glomerular filtration rate (GFR) between patients with and without history of BPAR was 19 mL/min/1.73 m2 among NULOJIX-treated patients compared to 7 mL/min/1.73 m2 among cyclosporine-treated patients. By three years, 22% (11/50) of NULOJIX-treated patients with a history of BPAR experienced graft loss and/or death compared to 10% (3/31) of cyclosporine-treated patients with a history of BPAR; at that time point, 10% (5/50) of NULOJIX-treated patients experienced graft loss and 12% (6/50) of NULOJIX-treated patients had died following an episode of BPAR, whereas 7% (2/31) of cyclosporine-treated patients experienced graft loss and 7% (2/31) of cyclosporine-treated patients had died following an episode of BPAR. The overall prevalence of donor-specific antibodies was 5% and 11% for the NULOJIX recommended regimen and cyclosporine, respectively, up to 36 months post-transplant.

While the difference in GFR in patients with BPAR versus those without BPAR was greater in patients treated with NULOJIX than cyclosporine, the mean GFR following BPAR was similar in NULOJIX (49 mL/min/1.73 m2) and cyclosporine treated patients (43 mL/min/1.73 m2) at one year. The relationship between BPAR, GFR, and patient and graft survival is unclear due to the limited number of patients who experienced BPAR, differences in renal hemodynamics (and, consequently, GFR) across maintenance immunosuppression regimens, and the high rate of switching treatment regimens after BPAR.

Assessment of Efficacy in the EBV Seropositive Subpopulation

NULOJIX is recommended for use only in EBV seropositive patients [see Indications and Usage (1.2)].

In Study 1, approximately 87% of patients were EBV seropositive prior to transplant. Efficacy results in the EBV seropositive subpopulation were consistent with those in the total population studied.

By one year, the efficacy failure rate in the EBV seropositive population was 21% (42/202) in patients treated with the NULOJIX recommended regimen and 17% (31/184) in patients treated with cyclosporine (difference=4%, 97.3% CI [−4.8, 12.8]). Patient and graft survival was 98% (198/202) in NULOJIX-treated patients and 92% (170/184) in cyclosporine-treated patients (difference=5.6%, 97.3% CI [0.8, 10.4]).

By three years, efficacy failure was 25% in both treatment groups and patient and graft survival was 94% (187/202) in NULOJIX-treated patients compared with 88% (162/184) in cyclosporine-treated patients (difference=4.6%, 97.3% CI [−2.1, 11.3]).

Assessment of Glomerular Filtration Rate (GFR)

Glomerular Filtration Rate (GFR) was measured at one and two years and was calculated using the Modification of Diet in Renal Disease (MDRD) formula at one, two, and three years after transplantation. As shown in Table 8, both measured and calculated GFR was higher in patients treated with the NULOJIX recommended regimen compared to patients treated with the cyclosporine control regimen at all time points. As shown in Figure 1, the differences in GFR were apparent in the first month after transplant and were maintained up to three years (36 months). An analysis of change of calculated mean GFR between three and 36 months demonstrated an increase of 0.8 mL/min/year (95% CI [−0.2, 1.8]) for NULOJIX-treated patients and a decrease of 2.2 mL/min/year (95% CI [−3.2, −1.2]) for cyclosporine-treated patients.

Table 8: Measured and Calculated GFR for Study 1: Recipients of Living and Standard Criteria Deceased Donor Kidneys
Parameter	NULOJIX Recommended Regimen N=226	Cyclosporine (CSA) N=221	NULOJIX-CSA (97.3% CI)
a GFR was measured using the cold-iothalamate method. b Measured GFR was not assessed at Year 3. c GFR was calculated using the MDRD formula.
Measured GFRa mL/min/1.73 m2 mean (SD)
Year 1	63.4 (27.7)	50.4 (18.7)	13.0 (7.3, 18.7)
	(n=206)	(n=199)
Year 2b	67.9 (29.9)	50.5 (20.5)	17.4 (11.5, 23.4)
	(n=199)	(n=185)
Calculated GFRc mL/min/1.73 m2 mean (SD)
Year 1	65.4 (22.9)	50.1 (21.1)	15.3 (10.3, 20.3)
	(n=200)	(n=199)
Year 2	65.4 (25.2)	47.9 (23)	17.5 (12, 23.1)
	(n=201)	(n=182)
Year 3	65.8 (27)	44.4 (23.6)	21.4 (15.4, 27.4)
	(n=190)	(n=171)

Figure 1: Calculated (MDRD) GFR Through Month 36; Study 1: Recipients of Living and Standard Criteria Deceased Donor Kidneys

Assessment of Chronic Allograft Nephropathy (CAN)

The prevalence of chronic allograft nephropathy (CAN) at one year, as defined by the Banff ’97 classification system, was 24% (54/226) in patients treated with the NULOJIX recommended regimen and in 32% (71/219) of patients treated with the cyclosporine control regimen. CAN was not evaluated after the first year following transplantation. The clinical significance of this finding is unknown.

Study 2: Recipients of Extended Criteria Donor Kidneys

In Study 2 (NCT00114777), 543 patients were enrolled, randomized, and transplanted: 175 to the NULOJIX recommended regimen, 184 to the NULOJIX regimen with higher cumulative doses and more frequent dosing than recommended, and 184 to the cyclosporine control regimen. The median age was 58 years; 67% of the study population was male; 75% of patients were white, 13% were black/African-American, 12% were categorized as of other races; 3% had PRA ≥10%; 53% had 4 to 6 HLA mismatches; and 29% had diabetes prior to transplantation. The incidence of delayed graft function was similar in all treatment arms (47% to 49%).

Premature discontinuation from treatment at the end of the first year occurred in 25% of patients receiving the NULOJIX recommended regimen and 30% of patients receiving the cyclosporine control regimen. Among the patients who received the NULOJIX recommended regimen, 14% discontinued due to adverse events, 9% due to lack of efficacy, and 2% for other reasons. Among the patients who received the cyclosporine regimen, 17% discontinued due to adverse events, 7% due to lack of efficacy, and 6% for other reasons.

At the end of three years, 35% of patients receiving the NULOJIX recommended regimen and 44% of patients receiving the cyclosporine regimen had discontinued from treatment. Among the patients who received the NULOJIX recommended regimen, 20% discontinued due to adverse events, 9% due to lack of efficacy, and 6% for other reasons. Among the patients who received the cyclosporine regimen, 25% discontinued due to adverse events, 10% due to lack of efficacy, and 10% for other reasons.

Assessment of Efficacy

Table 9 summarizes the results of Study 2 following one and three years of treatment with the NULOJIX recommended dosage regimen and the cyclosporine control regimen. Efficacy failure at one year was defined as the occurrence of biopsy proven acute rejection (BPAR), graft loss, death, or lost to follow-up. BPAR was defined as histologically confirmed acute rejection by a central pathologist on a biopsy done for any reason, whether or not accompanied by clinical signs of rejection. Patient and graft survival was also assessed.

Table 9: Efficacy Outcomes by Years 1 and 3 for Study 2: Recipients of Extended Criteria Donor Kidneys
Parameter	NULOJIX Recommended Regimen N=175 n (%)	Cyclosporine (CSA) N=184 n (%)	NULOJIX-CSA (97.3% CI)
a Patients may have experienced more than one event. b Patients known to be alive with a functioning graft.
Efficacy Failure by Year 1	51 (29.1)	52 (28.3)	0.9 (−9.7, 11.5)
Components of Efficacy Failurea
Biopsy Proven Acute Rejection	37 (21.1)	34 (18.5)
Graft Loss	16 (9.1)	20 (10.9)
Death	5 (2.9)	8 (4.3)
Lost to follow-up	0	2 (1.1)
Efficacy Failure by Year 3	63 (36)	68 (37)	−1.0 (−12.1, 10.3)
Components of Efficacy Failurea
Biopsy Proven Acute Rejection	42 (24)	42 (22.8)
Graft Loss	21 (12)	23 (12.5)
Death	15 (8.6)	17 (9.2)
Lost to follow-up	1 (0.6)	5 (2.7)
Patient and graft survivalb
Year 1	155 (88.6)	157 (85.3)	3.2 (−4.8, 11.3)
Year 3	143 (81.7)	143 (77.7)	4.0 (−5.4, 13.4)

In Study 2, the rate of BPAR at one year and three years was similar in patients treated with NULOJIX and cyclosporine. Of the patients who experienced BPAR with NULOJIX, 62% experienced BPAR by Month 3, and 76% experienced BPAR by Month 6. By three years, recurrent BPAR occurred with similar frequency across treatment groups (<3%). The component of BPAR determined by biopsy only (subclinical protocol-defined acute rejection) was 5% in both treatment groups.

A similar proportion of patients in the NULOJIX recommended regimen group experienced BPAR classified as Banff grade IIb or higher (5% [9/175] at one year and 6% [10/175] at three years) compared to patients treated with the cyclosporine regimen (4% [7/184] at one year and 5% [9/184] at three years). Also, T cell-depleting therapy was used with similar frequency to treat any episode of BPAR in NULOJIX-treated patients (5% or 9/175) compared to cyclosporine-treated patients (4% or 7/184). At Month 12, the difference in mean calculated GFR between patients with and without a history of BPAR was 10 mL/min/1.73 m2 among NULOJIX-treated patients compared to 14 mL/min/1.73 m2 among cyclosporine-treated patients. By three years, 24% (10/42) of NULOJIX-treated patients with a history of BPAR experienced graft loss and/or death compared to 31% (13/42) of cyclosporine-treated patients with a history of BPAR; at that time point, 17% (7/42) of NULOJIX-treated patients experienced graft loss and 14% (6/42) of NULOJIX-treated patients had died following an episode of BPAR, whereas 19% (8/42) of cyclosporine-treated patients experienced graft loss and 19% (8/42) of cyclosporine-treated patients had died following an episode of BPAR. The overall prevalence of donor-specific antibodies was 6% and 15% for the NULOJIX recommended regimen and cyclosporine, respectively, up to 36 months post-transplant.

The mean GFR following BPAR was 36 mL/min/1.73 m2 in NULOJIX patients and 24 mL/min/1.73 m2 in cyclosporine-treated patients at one year. The relationship between BPAR, GFR, and patient and graft survival is unclear due to the limited number of patients who experienced BPAR, differences in renal hemodynamics (and, consequently, GFR) across maintenance immunosuppression regimens, and the high rate of switching treatment regimens after BPAR.

Assessment of Efficacy in the EBV Seropositive Subpopulation

NULOJIX is recommended for use only in EBV seropositive patients [see Indications and Usage (1.2)].

In Study 2, approximately 91% of the patients were EBV seropositive prior to transplant. Efficacy results in the EBV seropositive subpopulation were consistent with those in the total population studied.

By one year, the efficacy failure rate in the EBV seropositive population was 29% (45/156) in patients treated with the NULOJIX recommended regimen and 28% (47/168) in patients treated with cyclosporine (difference=0.8%, 97.3% CI [−10.3, 11.9]). Patient and graft survival rate in the EBV seropositive population was 89% (139/156) in the NULOJIX-treated patients and 86% (144/168) in cyclosporine-treated patients (difference=3.4%, 97.3% CI [−4.7, 11.5]).

By three years, efficacy failure was 35% (54/156) in NULOJIX-treated patients and 36% (61/168) in cyclosporine-treated patients. Patient and graft survival was 83% (130/156) in NULOJIX-treated patients compared with 77% (130/168) in cyclosporine-treated patients (difference=5.9%, 97.3% CI [−3.8, 15.6]).

Assessment of Glomerular Filtration Rate (GFR)

Glomerular Filtration Rate (GFR) was measured at one and two years and was calculated using the Modification of Diet in Renal Disease (MDRD) formula at one, two, and three years after transplantation. As shown in Table 10, both measured and calculated GFR was higher in patients treated with the NULOJIX recommended regimen compared to patients treated with the cyclosporine control regimen at all time points. As shown in Figure 2, the differences in GFR were apparent in the first month after transplant and were maintained up to three years (36 months). An analysis of change of calculated mean GFR between Month 3 and Month 36 demonstrated a decrease of 0.8 mL/min/year (95% CI [−1.9, 0.3]) for NULOJIX-treated patients and a decrease of 2.0 mL/min/year (95% CI [−3.1, −0.8]) for cyclosporine-treated patients.

Table 10: Measured and Calculated GFR for Study 2: Recipients of Extended Criteria Donor Kidneys
Parameter	NULOJIX Recommended Regimen N=175	Cyclosporine (CSA) N=184	NULOJIX-CSA (97.3% CI)
a GFR was measured using the cold-iothalamate method. b Measured GFR was not assessed at Year 3. c GFR was calculated using the MDRD formula.
Measured GFRa mL/min/1.73 m2 mean (SD)
Year 1	49.6 (25.8)	45.2 (21.1)	4.3 (−1.5, 10.2)
	(n=151)	(n=154)
Year 2b	49.7 (23.7)	45.0 (27.2)	4.7 (−1.8, 11.3)
	(n=139)	(n=136)
Calculated GFRc mL/min/1.73 m2 mean (SD)
Year 1	44.5 (21.8)	36.5 (21.1)	8.0 (2.5, 13.4)
	(n=158)	(n=159)
Year 2	42.8 (24.1)	34.9 (21.6)	8.0 (1.9, 14)
	(n=158)	(n=154)
Year 3	42.2 (25.2)	31.5 (22.1)	10.7 (4.3, 17.2)
	(n=154)	(n=143)

Figure 2: Calculated (MDRD) GFR Through Month 36; Study 2: Recipients of Extended Criteria Donor Kidneys

Assessment of Chronic Allograft Nephropathy (CAN)

The prevalence of chronic allograft nephropathy (CAN) at one year, as defined by the Banff ’97 classification system, was 46% (80/174) in patients treated with the NULOJIX recommended regimen and 52% (95/184) of patients treated with the cyclosporine control regimen. CAN was not evaluated after the first year following transplantation. The clinical significance of this finding is unknown.

14.2 Long-Term Extension (LTE) of Study 1 and Study 2

Although initially designed as three-year studies, Studies 1 and 2 were subsequently extended to seven years to provide descriptive long-term safety and efficacy data. Only patients who completed the assigned treatment for three years and consented to remain on the assigned treatment from three to seven years were eligible for the long-term extension (LTE) studies.

Long-Term Extension of Study 1

In the LTE of Study 1, of the 666 originally randomized and transplanted patients, 457 (69%) patients enrolled into the LTE study: 73% (166/226) in the NULOJIX recommended regimen group, 71% (155/219) in the NULOJIX nonrecommended regimen group, and 62% (136/221) in the cyclosporine group. Fourteen (2%) patients who completed the assigned treatment at the end of Year 3 did not enroll into the LTE study: 4 in the NULOJIX recommended regimen group, 3 in the NULOJIX nonrecommended regimen group, and 7 in the cyclosporine group.

Of the 457 patients enrolled in the LTE study, 356 (79%) patients completed the assigned treatment at the end of Year 7: 82% (136/166) in the NULOJIX recommended regimen group, 83% (128/155) in the NULOJIX nonrecommended regimen group, and 68% (92/136) in the cyclosporine group. The most common reasons for discontinuation from the LTE study included adverse events and death.

Seven (4.2%) deaths and 2 (1.2%) graft losses were reported in the NULOJIX recommended regimen group while 7 (4.5%) deaths and no graft loss were reported in the NULOJIX nonrecommended regimen group, and 10 (7.4%) deaths and 6 (4.4%) graft losses were reported in the cyclosporine group.

No PTLD was reported in the NULOJIX groups while 1 case of non-CNS PTLD was reported in the cyclosporine group, in a patient who was EBV seropositive at the time of transplant.

No PML was reported in the NULOJIX groups while 1 case of PML was reported in the cyclosporine group at 82 months post-transplant (56 days after discontinuing therapy).

The higher calculated GFR observed in NULOJIX-treated patients compared to cyclosporine-treated patients during the first three years was maintained during the LTE period.

Table 11: Events Reported in Long-Term Extension from 36 to 84 Months Post-Transplant of Study 1: Recipients of Living and Standard Criteria Deceased Donor Kidneys
	NULOJIX Recommended Regimen N=166 n (%)	NULOJIX Nonrecommended Regimen N=155 n (%)	Cyclosporine N=136 n (%)
a This patient was EBV seropositive at the time of transplant.

Death	7 (4.2)	7 (4.5)	10 (7.4)
Graft Loss	2 (1.2)	0 (0)	6 (4.4)
Death or Graft Loss	9 (5.4)	7 (4.5)	14 (10.3)
PTLD	0 (0)	0 (0)	1a (0.7)
PML	0 (0)	0 (0)	1 (0.7)

Long-Term Extension of Study 2

In the LTE of Study 2, of the 543 originally randomized and transplanted patients, 304 (56%) patients enrolled into the LTE study: 65% (113/175) in the NULOJIX recommended regimen group, 57% (104/184) in the NULOJIX nonrecommended regimen group, and 47% (87/184) in the cyclosporine group. Nineteen (3.5%) patients who completed the assigned treatment at the end of Year 3 did not enroll into the LTE study: 1 in the NULOJIX recommended regimen group, 5 in the NULOJIX nonrecommended regimen group, and 13 in the cyclosporine group.

Of the 304 patients enrolled in the LTE study, 215 (71%) patients completed the assigned treatment at the end of Year 7: 74% (84/113) in the NULOJIX recommended regimen group, 71% (74/104) in the NULOJIX nonrecommended regimen group, and 66% (57/87) in the cyclosporine group. The most common reasons for discontinuation from the LTE study included adverse events and death.

Twenty-one (18.6%) deaths and 1 (0.9%) graft loss were reported in the NULOJIX recommended regimen group while 14 (13.5%) deaths and 2 (1.9%) graft losses were reported in the NULOJIX nonrecommended regimen group, and 9 (10.3%) deaths and 6 (6.9%) graft losses were reported in the cyclosporine group.

Six cases of PTLD were reported among the three treatment groups: 4 in the NULOJIX recommended regimen group, 1 in the NULOJIX nonrecommended regimen group, and 1 in the cyclosporine group. Three of these cases (1 in each treatment group) occurred in patients who were EBV seropositive at the time of transplant and the other 3 cases (in NULOJIX recommended regimen) occurred in patients who were EBV seronegative. No case of PML was reported among the three treatment groups.

The higher mean calculated GFR observed in NULOJIX-treated patients compared to cyclosporine-treated patients during the first three years was maintained during the LTE period.

Table 12: Events Reported in Long-Term Extension from 36 to 84 Months Post-Transplant of Study 2: Recipients of Extended Criteria Donor Kidneys
	NULOJIX Recommended Regimen N=113 n (%)	NULOJIX Nonrecommended Regimen N=104 n (%)	Cyclosporine N=87 n (%)
a Three of these patients were EBV seronegative at the time of transplant.
Death	21 (18.6)	14 (13.5)	9 (10.3)
Graft Loss	1 (0.9)	2 (1.9)	6 (6.9)
Death or Graft Loss	22 (19.5)	16 (15.4)	14 (16.1)
PTLD	4a (3.6)	1 (1.0)	1 (1.2)
PML	0 (0)	0 (0)	0 (0)

14.3 Follow-Up Data of Patients with Complete 7-Year Patient and Graft Survival

In Study 1, of the original intention-to-treat (ITT) population (N=666), 72% (163/226) of patients in the NULOJIX recommended regimen group, 70% (153/219) of patients in the NULOJIX nonrecommended regimen group and 60% (132/221) of patients in the cyclosporine group had complete 7-year patient and graft survival follow-up data. Among these completers, the proportion of patients who died or had graft loss was 17% (27/163) in the NULOJIX recommended regimen group, 16% (25/153) in the NULOJIX nonrecommended regimen group and 30% (40/132) in the cyclosporine group.

In Study 2, of the original ITT population (N=543), 79% (138/175) of patients in the NULOJIX recommended regimen group, 128/184 (70%) of patients in the NULOJIX nonrecommended regimen group and 59% (108/184) of patients in the cyclosporine group had complete 7-year patient and graft survival follow-up data. Among these completers, the proportion of patients who died or had graft loss was 39% (54/138) in the NULOJIX recommended regimen group, 42% (54/128) in the NULOJIX nonrecommended regimen group and 48% (52/108) in the cyclosporine group.

Table 13: Events Reported in Patients with Complete 7-Year Patient and Graft Survival Follow-Up Data
	NULOJIX Recommended Regimen n (%)	NULOJIX Nonrecommended Regimen n (%)	Cyclosporine n (%)
Study 1	N=163	N=153	N=132
Death	17 (10%)	17 (11%)	26 (20%)
Graft Loss	11 (7%)	10 (7%)	17 (13%)
Death or Graft Loss	27 (17%)	25 (16%)	40 (30%)
Study 2	N=138	N=128	N=108
Death	37 (27%)	37 (29%)	29 (27%)
Graft Loss	23 (17%)	21 (16%)	29 (27%)
Death or Graft Loss	54 (39%)	54 (42%)	52 (48%)