# Presentation: 690588

## 	 RandomizationVariable	 Day* to Day 386
RAPA, Cmin, TN	0.765CsA, Cmin, TN	0.201Gender	0.117Increasing Recipient Age	0.199Cadaver	0.852HLA Mismatch	0.098Increasing Ischemia Time	0.919Increasing Donor Age	0.026# Rejections	31

**RAPA, C****min****, TN****	****0.765****CsA, C****min****, TN****	****0.201****Gender****	****0.117****Increasing Recipient Age****	****0.199****Cadaver****	****0.852****HLA Mismatch****	****0.098****Increasing Ischemia Time****	****0.919****Increasing Donor Age****	****0.026****# Rejections****	****31**

**Study 310: Univariate Logistic ****Regression - RAPA Group**

**TABLE 8.3E**

*******	****Randomization Day for Individual Patient, Approx. Day 90**

## Study 212Enrolled 19.1% Black Patients

**Study 212****Enrolled 19.1% Black Patients**

**Trial 310: 8 patients (1.5%) were black:**
**RAPA + CsA****	****5/215 (2.3%)**
**RAPA****	****2/215 (0.9%)**
**Nonrandomized****	****1/95 (1.1%)**
**Trial 212: 47 (19.1%) black**
**RAPA + CsA****	****18/97 (18.6%)**
**RAPA****	****15/100 (15%)**
**Nonrandomzied****	****14/49 (28.6%)**

**Notes:**
As only 8 (2%) of the patients in trial 310 were black, the focus of this document will be on trial 212, where 47 (19%) of the enrolled patients were of black ethnic origin.  Patients in the analyses, presented below, are grouped as black and white (demography and treatment-emergent adverse event [TEAE] tables for study 212) or as black and nonblack (all the other analyses).

## Study 212: All 13 Eligible Black Patients Successfully Eliminated CsA

**CsA withdrawal arm:**
**Enrolled****	****	****	****	****15**
**Eligible for CsA taper****	****	****13**
**2 patients with AR**
**Completed CsA taper****	****	****13**
**3 patients with AR post CsA withdrawal: ****35, 64, and 122 days after completing CsA elimination**

## Study 212:  Similar Rates of Acute Rejection at Months 2 and 12

**%**

**Study 212:  Similar Rates of Acute Rejection at Months 2 and 12**

**N =****	****    18****	****           15****	****	****     79 ****	****        85****	****	****     18****	****          15****	****	****        79****	****          85****	**

**Month 2**

**Month 12**

**P = NS**

## Study 212: Significantly Higher Calculated GFR at Month12 in the RAPA Group, Black Patients

**Study 212: Significantly Higher Calculated GFR at Month12 in the RAPA Group, Black Patients**

***P***** = .098**

***P***** = .0003**

** ****TABLE  3.3.3A**

**N =        15           13****	****	****    16****	****14****	****                15          13****	****	**

## Study 212:  Numerically Lower BP in RAPA Group - Black Patients

**N=               9           7                                9            7**

***P*****=0.069**

***P*****=0.541**

## Study 212: Patient & Graft Survival (%) By Ethnic Origin:  Month 12

**	****	****RAPA + CsA****	****RAPA****	**** Fisher’s Exact****	****	****(N = 97)****	****(N = 100)****	*****P *****value**
**Patient Survival****	****Black*****	*****17 (94.4)****	****15 (100)****	****1.000*****	*****Non-black****	****77 (97.5)****	****81 (95.3)****	****0.683****	**
**Graft Survival****                                        ****	**** ****	****Black*****	*****17 (94.4)****	****14 (93.3)****	****1.000*****	*****Non-black****	****73 (92.4)****	****81 (95.3)****	****0.524**

**Study 212: Patient & Graft Survival (%) By Ethnic Origin:  Month 12**

## Study 310: No (S.D.) Difference in CADI Score at 1 Year

**Inflammation**
**Fibrosis**
**Mes Matr Increase**
**Glomerular Sclerosis**
**Tubular Atrophy**
**Intimal Proliferation (VAS)**
**CADI***

**RAPA + CsA**

**RAPA**

**Baseline**

**Baseline**

**12 Months**

**12 Months**

**0.07 (0.2)**
**0.33 (0.4)**
**0.26 (0.3)**
**0.28 (0.4)**
**0.07 (0.2)**
**0.19 (0.3)**
**1.2 (1.2)**

**0.5 (0.4)**
**1.1 (0.6)**
**0.5 (0.4)**
**0.3 (0.4)**
**0.64 (0.5) **
**0.46 (0.48)**
**3.5 (3.4)**

**0.03 (0.14)**
**0.36 (0.5)**
**0.3 (0.3)**
**0.3 (0.5)**
**0.10 (0.3) **
**0.14 (0.4) **
**1.2 (1.4)**

**0.8 (0.6)**
**1.1 (0.7)**
**0.5 (0.4)**
**0.3 (0.5)**
**0.6 (0.5) **
**0.37 (0.5)**
**3.6 (1.9)**

**N = 70**

**N = 56**

***Chronic Allograft Damage Index**

## Renal Function (Observed Mean)Patients With Biopsy Vs No Biopsy

**N****	****70****	****117****	*****P**********	****56****	****109****	*****P********
**Pre-Randomized****creatinine, μM****	****142****	****150****	****ns ****	****  155****	****  148****	****ns**
**12 Month****creatinine, μM****	****150****	****163****	****ns ****	****  149****	****  138****	****ns**
**Pre-Randomized****GFR, ml/mn****	****61****	****58 ****	****ns ****	****  56****	****  56 ****	****ns**
**12 month****GFR, ml/mn****	****59****	****55****	****ns ****	****  61****	****  64****	****ns**

**Renal Function (Observed Mean)****Patients With Biopsy Vs No Biopsy**

*******	*****P*****: Yes versus No < .05**

## Study 310: Nonrandomized Patients (Ninety-Five Discontinued Prior to Randomized at Month 3)

**Reasons for Discontinuation**
**70 (74%) adverse event**
**12 (13%) unsatisfactory response, efficacy**
**13 (13.6%) other causes**

## Study 310Adverse Events Leading to Discontinuation Prior to Randomization at Month 3

**Event****	****Number of Pts.**
**Infection and sepsis****	****10**
**Surgical complication****	****8**
**HUS****	****7**
**Thrombosed artery/vein****	****6**
**ATN****	****5**
**Hyperlipidemia****	****5**
**Thrombocytopenia****	****5**

**Event****	****Number of Pts.**
**Elevated LFTs****	****4**
**Pneumonia/pneumopathy****	****4**
**Renal dysfunction****	****4**
**Cardiovascular****	****3**
**CsA toxicity****	****3**
**Leukopenia****	****3**
**Other****	****3**

**HUS = Hemolytic uremic syndrome.****ATN = Acute tubular necrosis.****LFTs = Liver function tests.**

## Study 310: 70% of Patients With Acute Rejection Prerandomization – Eventually Randomized

**12 out of 95 (13%) non-randomized patients**
**9 mild/moderate acute rejection**
**1 severe acute rejection**
**1 graft loss**
**1 increased creatinine**
**70% of patients with acute rejection pre-randomization were eventually randomized**

## Study 310Nonrandomized Patients: Other causes of discontinuation 

**Other causes of discontinuation (n=13)**
**4 (4 %) patient request**
**4 (4%) protocol violation**
**3 (3%) other medical event**
**2 (2%) protocol stipulations**

## Study 310:  No Rejections in RAPA Group: 12-24 Months

## Renal Function at 12 Months Predicts Long Term Graft Survival

**	****105,743 renal transplant recipients from the UNOS/OPTN database between 1988 and 1998 **
**Creat. 12 Mos****	****   ******** Creat. 6 to 12 Mos     Graft t****1/2****	****(mg/dL)****	****(mg/dL)****	****(yrs)**
**	****	****<1.5****	****<0.3****	****11.6****	****<1.5****	****>0.3 ****	****  9.9****	****>1.5****	****<0.3****	****  8.9****	****>1.5****	****>0.3 ****	****  6.0**

**Johnson CP et al. Am J Transplantation, 2001; 1 (Suppl 1): 146.**

**Notes:**
For the second analysis, the all randomized patients (430) were divided into 4 equal groups based on serum creatinine at baseline (last value before randomization).

An ANCOVA analysis was performed on the change from baseline in the 348 patients on-therapy at 12 and 24 months. 

## Study 310: Predicted Long Term Graft Survival Better with RAPA

**Creat. 12 Mos     ******** Creat. 6 to 12 Mos****	****RAPA+CsA****	****RAPA****	****(mg/dL)****	****(mg/dL)****	****(%)****	**** (%)**
**	****	****<1.5****	****<0.3****	****34.6****	****60.7****	****<1.5 ****	****>0.3 ****	****2.6****	****  0.0****	****>1.5 ****	****<0.3 ****	****40.0****	****28.8****	****>1.5 ****	****>0.3 ****	****23.2****	****10.4**

**Study 310: Predicted Long Term Graft Survival Better with RAPA**

**CMH: *****P***** = 0.001**

**Notes:**
For the second analysis, the all randomized patients (430) were divided into 4 equal groups based on serum creatinine at baseline (last value before randomization).

An ANCOVA analysis was performed on the change from baseline in the 348 patients on-therapy at 12 and 24 months. 

## Slope of 1000/CreatinineAll Data Between 6 and 24 Months

**	****Slope****	****95% CI of slope****	*****P*****-value***
**RAPA + CsA****	****–0.013****	****(–0.017, –0.008)****	****< .001**
**RAPA****	****0.008****	****(0.004, 0.013)****	****< .001**
**Difference****	****–0.021****	****(–0.027, –0.014)****	****< .001****(RAPA + CsA – RAPA)**

***Significant *****P*****-value indicates non-zero change over time.**

## Slope of 1000/CreatinineAll Data Between 12 and 24 Months

**	****Slope****	****95% CI of slope****	*****P*****-value***
**RAPA + CsA****	****–0.015****	****(–0.021, –0.009)****	****< .001**
**RAPA****	****0.003****	****(–0.004, 0.009)****	**** .420**
**Difference****	****–0.018****	****(–0.026, –0.009)****	****< .001****(RAPA + CsA – RAPA)**

***Significant *****P*****-value indicates non-zero change over time.**

## Study 310 Histologic Grade of First Biopsy Confirmed-Acute Rejection by Grade: 12 Months

**	****Grade of****	****	****	****Nonrandomized****	****Period****	****rejection****	****RAPA + CsA****	****RAPA****	****      RAPA + CsA    *****P-v*****alue***
**Pre-****	****Mild****	****12/20 (60.0)****	****10/22 (45.5) ****	**** 9/27(33.3)****randomization****	****Moderate (2a) ****	****  3/20 (15.0)****	****  4/22 (18.2) ****	****7/27 (25.9)****	****	****Moderate (2b) ****	****  4/20 (20.0)****	****  6/22 (27.3) ****	****5/27 (18.5)****	****.336****	****Severe****	****1/20 (5.0)****	****2/22 (9.1) ****	****6/27 (22.2)**
**Post-****	****Mild****	****    5/6 (83.3)****	****14/21 (66.7) ****	****-****	****randomization****	****Moderate (2a) ****	****    1/6 (16.7)****	****  6/21 (28.6) ****	****-****	****.421****	****Moderate (2b) ****	****-****	****1/21 (4.8) ****	****-**
**Follow up****	****Mild****	****    2/3 (66.7)****	****- ****	****3/7 (42.9)****	****	****Moderate (2b) ****	****    1/3 (33.3)****	****- ****	****2/7 (28.6)****	****-****	****Severe ****	****-****	****- ****	****2/7 (28.6)**
**Total****	****Mild****	****  19/29 (65.5)****	**** 24/43 (55.8) ****	****12/34 (35.8)****	****	****Moderate (2a) ****	****    4/29 (13.8)****	**** 10/43 (16.3) ****	****7/34 (20.6)****	****.514****	****Moderate (2b) ****	****    5/29 (17.2)****	****   7/43 (16.3) ****	****7/34 (20.6)****	****Severe ****	****  1/29 (3.4)****	**** 2/43 (4.7) ****	****8/34 (23.5)****	**

**TABLE 9.3.2.1C**

*******	****Between randomized groups**

## Study 310: Decreasing Doses of CsA in RAPA Group With Time to First Rejection

**Study 310: Decreasing Doses of CsA in RAPA Group With Time to First Rejection**

**Days Post-transplant**

**0**

**30**

**60**

**90**

**120**

**150**

**180**

**210**

**240**

**270**

**300**

**330**

**360**

**390**

**CsA Concentration ng/ml**

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**% Primary Acute Graft Rejection**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**Mean CsA Troughs RAPA**

**RAPA Acute rejection**

**RAPA + CsA Acute rejection**

**TABLE 9.3.2.1A**

## Study 310Thirty-One Patients Discontinued at the3 Month Visit (Days 75-140)

**10 (32%)****	****Adverse event (3 HUS, 2 poor wound healing, 2 ****	****hyperlipidemia, 1abdominal LFTs,****	****1 surgical complication, 1 pain)**
**6 (19%)****	****Acute rejection/unsatisfactory response**
**5 (16%)****	****Creatinine > 4.5 mg/dL**
**5 (16%)****	****Renal dysfunction/dialysis**
**3 (10%)****	****Patient non-compliance**
**2 (7%)****	****Patient request**

## Study 310: Lower Mean SerumPotassium (mmol/L) Levels Following Cyclosporine Withdrawal

**	****RAPA + CsA****	****RAPA****	****ANCOVA****Time  ****	****(n = 215)****	****(n = 215)****	*****P *****value**
**Month 1****	****4.32 ****** **0.04****	****4.34 ******** 0.04****	****-****	****(211)****	****(210)**
**Month 2****	****4.17 ******** 0.04****	****4.22 ******** 0.04****	****-****	****(208)****	****(197)**
**Month 3****	****4.13 ******** 0.04****	****4.09 ******** 0.04****	**** .158****	****(186)****	****(191)**
**Month 6****	****4.11 ******** 0.04****	****3.86 ******** 0.03****	****< .001****	****(185)****	****(182)**
**Month 9****	****4.09 ******** 0.04****	****3.82 ******** 0.04****	****< .001****	****(184)****	****(165)**
**Month 12****	****4.07 ******** 0.04****	****3.77 ******** 0.04****	****< .001****	****(185)****	****(163)**
**Month 15****	****4.09 ******** 0.04****	****3.84 ******** 0.04****	****< .001****	****(153)****	****(146)**
**Month 18****	****4.22 ******** 0.05****	****3.98 ******** 0.04****	****< .001****	****(119)****	****(110)**
**Month 24****	****4.31 ******** 0.14****	****3.86 ******** 0.11****	****  .004****	****(24)****	****(22)**

**Study 310: Lower Mean Serum****Potassium (mmol/L) Levels Following Cyclosporine Withdrawal**

## Study 310: Mean Sirolimus Troughs/Levels and Doses Through 24 Months

**8.29 mg**

**2.15 mg**

**6.05 mg**

**2.05 mg**

**Study 310: Mean Sirolimus Troughs/Levels and Doses Through 24 Months**

## Study 310: Lower Serum Creatinine Following CsA Elimination - Completers Through 24 Months

**N = 143**

**N = 144**

*** *****P***** < 0.01**

**Notes:**
An important finding of this study as you can see in graph before you is the clearly better renal function in those patient who had CsA withdrawn.

## Study 310: PK-PD Analysis Confirms Flexibility of the RAPAMUNE - CsA Combination

**(Immunoassay)**

**Study 310: PK-PD Analysis Confirms Flexibility of the RAPAMUNE - CsA Combination**

## Studies 207 Plus 210: Lipid Levels vs RAPA Trough Concentrations

**Studies 207 Plus 210: Lipid ****Levels vs RAPA Trough Concentrations**

## Studies 207 Plus 210 SGPT  Values

**Studies 207 Plus 210 ****SGPT  Values**

## Study 207Concentration - Effect

**Study 207****Concentration - Effect**