Use of Immune Globulin Intravenous (Human), 10% (IVIG), Plus Rituximab as Agents to Reduce Donor Specific Antibodies, Improve Transplant Rates and Outcomes in Highly-HLA Sensitized Patients Awaiting Deceased Donor Kidney Transplantation
Phase: PHASE1
Conditions: End Stage Renal Disease
Sponsor: Stanley Jordan, MD

Rituximab + IVIG for Desensitization 
Genentech U4810s 
Protocol Amendment No. 8 
February 5, 2015 
IND 109,067 
Serial #: 1 
Cedars-Sinai Medical Center 
Dr. Stanley C. Jordan 
Confidential and Proprietary 
P a g e  | 1 
 
 
    
 
 
 
 
Use of Immune Globulin Intravenous (Human), 10% (IVIG), plus Rituximab as Agents to 
Reduce Donor Specific Antibodies, Improve Transplant Rates and Outcomes in Highly-HLA 
Sensitized Patients Awaiting Deceased Donor Kidney Transplantation. 
NCT01178216 
 
 
 
 
 
Stanley C. Jordan, M.D. 
Director, Nephrology and Transplantation Immunology 
Department of Medicine/Pediatrics 
Cedars-Sinai Medical Center 
      8900 Beverly Blvd 
Los Angeles, California 90048 
 
 
 
 
Ashley A. Vo, Pharm.D 
Director, Transplant Immunotherapy Program 
Cedars-Sinai Medical Center 
8900 Beverly Blvd  
Los Angeles, CA. 90048 
 
 
 
 
 
 
 
 
 
 
 
A Protocol Presented to Genentech® South San Francisco, California 
Date: August 31, 2010 
 
Updated Submission: February 5, 2015 

Rituximab + IVIG for Desensitization 
Genentech U4810s 
Protocol Amendment No. 8 
February 5, 2015 
IND 109,067 
Serial #: 1 
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Dr. Stanley C. Jordan 
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A. RITUXIMAB + IVIG FOR DESENSITIZATION PROTOCOL SYNOPSIS 
 
PROTOCOL ID: 
CSMC: Rituximab + IVIG 2013 
TITLE: 
“Use of Immune Globulin Intravenous (Human), 10% (IVIG), plus Rituximab as Agents to 
Reduce Donor Specific Antibodies, Improve Transplant Rates and Outcomes in Highly-HLA 
Sensitized Patients Awaiting Deceased Donor Kidney Transplantation.” 
SHORT TITLE: 
Rituximab + IVIG for Desensitization 
IND SPONSOR: 
Genentech, Inc. South San Francisco, CA. 
PIs: 
Stanley C. Jordan, M.D. 
Director, Nephrology and Transplantation Immunology 
Department of Medicine/Pediatrics 
Cedars-Sinai Medical Center 
8900 Beverly Blvd Los Angeles, California 90048 
 
Ashley A. Vo, Pharm.D 
Director, Transplant Immunotherapy Program 
Cedars-Sinai Medical Center 
8900 Beverly Blvd Los 
Angeles, CA. 90048 
 
CLINICAL TRIAL 
MATERIAL: 
Immune Globulin Intravenous (Human), 10% 
Rituximab (Chimeric anti-CD20, anti-B-cell) 
MANUFACTURERS: 
Genentech Inc. South San Francisco, CA. 
STATISTICAL 
COORDINATING CENTER: 
Cedars-Sinai Medical Center 
 
 
 
 
 
 
 
CLINICAL 
COORDINATORS:                     Jua Choi, Pharm.D Kidney 
Transplant Program Cedars-
Sinai Medical Center 

Rituximab + IVIG for Desensitization 
Genentech U4810s 
Protocol Amendment No. 8 
February 5, 2015 
IND 109,067 
Serial #: 1 
Cedars-Sinai Medical Center 
Dr. Stanley C. Jordan 
Confidential and Proprietary 
P a g e  | 3 
 
 
 
 
 
8900 Beverly Blvd  L.A., 
CA. 90048 
 
 
 
HYPOTHESIS 
Rates of transplantation for highly-HLA sensitized patients (HS) are exceedingly low 
(<10% of patients with PRAs > 30% receive DD kidneys each year). IVIG 10% has 
been demonstrated as an effective desensitization agent in placebo controlled trials (1). 
However, in this study, only 35% of treated patients vs 17% placebo were able to 
receive a working kidney transplant, most from DD. Recent uncontrolled data from our 
group demonstrated a robust effect on improvement of transplant rates for HS patients 
(80% treated) using a combination of IVIG + rituximab (2,3).  This was also associated 
with improved reductions in donor-specific antibody levels (DSA) and flow-cytometry 
crossmatches at the time of transplant (4-8). This protocol appeared to be particularly 
effective in improving rates of transplantation for HS patients awaiting DD 
transplantation. Our group has also developed novel methodologies to predict the risk 
of antibody-mediated rejection (ABMR) post-transplant based on DSA and FCMX 
results after desensitization. This allows us to improve the prediction of acceptable 
donor-specific antibody (DSA) levels that are permissive for allowing transplantation to 
go forward (3-8). 
 
With these considerations and observations in mind, we have formulated the following 
hypothesis. We believe that the addition of the novel B-cell depleting agent (Rituximab) 
to IVIG treatment will offer significant benefits in reducing anti-HLA (DSA) thus 
improving rates and outcomes of DD transplantation above that seen for highly-HLA 
sensitized patients awaiting DD transplant on the UNOS list. In addition, we will assess 
the ability of Rituximab to lower DSA levels and reduce allograft injury post- 
transplantation. Protocol biopsies will be performed at time of transplant and at 12M 
post-transplant to determine the incidence of chronic antibody mediated rejection 
(Transplant Glomerulopathy {TG}). These biopsies will be read by the pathologist at 
participating institutions and graded according to Banff Criteria (2005) (9). 
 
TARGET POPULATION: 
Patients with end-stage renal disease on dialysis (ESRD, CKD Stage V), ages 18-65 
years who are awaiting deceased donor (DD) kidney transplantation on the UNOS wait 
list have a Panel Reactive Antibody (PRA) >30% and a significant sensitization history 
(previous pregnancies, blood transfusions and/or previous transplants) with sufficient 
wait time to allow frequent DD offers with positive crossmatches (CMXs) that prohibit 
transplantation. 
 
STUDY OBJECTIVES: 
The primary objective of this revised protocol will be to examine the safety and 
efficacy of IVIG 2gm/kg (maximum dose 140g) given on day#0 & day #30 plus 
Rituximab 1gm given on day#15.Transplanted patients will receive additional doses of 
Rituximab 1gm at 3 months post-transplant if DSA levels remain or become +. OR at 
6M if de novo DSA occur. All transplanted patients who remain DSA-, will not receive 
additional Rituximab. All transplanted patients will have a protocol biopsy at 12 
months.   . 
 
This trial is designed to determine if Rituximab + IVIG is an effective and safe 
desensitization protocol and if DSAs persisting or arising at 3M and 6M post-transplant 
can be effectively reduced by additional doses of Rituximab. This should be reflected in 
reduced rates of TG for Rituximab-treated patients.  This is the PRIMARY END 
POINT. Secondary end points include and will be evaluated based on time line in 
appendix A: 
 
 
Renal allograft survival at 12M 

Rituximab + IVIG for Desensitization 
Genentech U4810s 
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February 5, 2015 
IND 109,067 
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Reduction in anti-HLA antibodies (class I/II) 
 
Recipient survival at 12M 
 
The number of acute rejection episodes 
 
Rates of serious infectious complications  (i.e., serious infections requiring 
hospitalizations and/or i.v. antibiotics) 
 
Adverse events, toxicity assessments 
 
Abnormal laboratory studies:  Hematology, Chemistry, Liver Function, and 
research tests on study 
 
Clinical significant abnormalities in physical examination, vital signs, weight, 
ECG or Chest X-ray on study 
 
Serial donor-specific antibody assessments 
 
Pre & Post-transplant determinations of CD4+/CD25+FoxP3+CD127+ & Th17 
cell populations (Cedars-Sinai Patients Only). 
 
Pre & Post-Transplant determinations of CD19+, CD38+, CD27+ cells (Cedars- 
Sinai Patients Only). 
 
Post-Transplant biopsy at T0 and T12M assessed by Banff Criteria. 
 
HACA determinations  at serial intervals 
 
PRELIMINARY DATA 
Our group recently reported on the use of a combination of intravenous immune 
globulin and rituximab to reduce levels of anti-HLA antibodies and improve 
transplantation rates in highly-HLA sensitized patients (HS). This was an open label, 
single center, phase I/II study that aimed to evaluate the effectiveness of IVIG + 
rituximab in reducing PRA levels and T-cell CMXs to improve transplant rates. This 
study enrolled 20 HS adults who were awaiting kidney transplantation. The results of 
this study showed that the combination reduced PRA values, improved crossmatch 
(CMX) results that allowed for transplantation of 80% of entered patients with  patient 
and graft survival (100%/94%) at 1 year without significant complications (2). It is 
important to note that the sensitization level of these patients would have prevented 
them from ever receiving a kidney transplant without this therapy.   The protocol 
required two 1gm doses of rituximab, however during routine monitoring we noted that 
excellent depletion of B-cells was achieved after a single 1gm dose. 
 
The aim of this report was to evaluate the efficacy of IVIG + rituximab on reduction of 
anti-HLA antibodies to a level that was permissive for LD or DD transplantation 
without incurring the risk of ABMR and immediate graft loss. Here we report on a 
modified approach to desensitization using IVIG (2gm/kg X2) + rituximab (1 gram) in 
HS patients awaiting kidney transplantation. 
 
PATIENTS AND METHODS 
Between July 2006 and February 2009, 76 HS patients awaiting LD or DD 
transplantation who met the following criteria for desensitization were evaluated.  All 
patients had flow cytometry PRAs >30% (75% of patients were >80%).  All patients 
had significant sensitizing risks such as multiple blood transfusions, pregnancies and/or 
previous transplants. All had positive pre-transplant T-cell flow cytometry 
crossmatches with prospective donors and/or had donor specific antibodies (DSA). 
Patients who had positive pre-transplant B-cell flow cytometry CMXs only, were 
eliminated from this analysis.  These patients received IVIG and rituximab therapy as 
described below (2, 4-8). 
 
IVIG/Rituximab Desensitization Protocol 
All HS patients received non-sucrose containing IVIG 10% [2.0 grams /kilogram 
(maximum 140gm per dose) on day 1 & day 30], plus rituximab [1gram administered 
on day 15]. A donor-specific flow cytometry crossmatch (FCMX) was performed pre- 
transplant. An acceptable CMX is defined as a negative CDC, at least at a 1:2 dilution 
of sera.  A positive T and B cell FCMX with a shift of <250 CS were also acceptable 
(Negative: < 100 MCS for B-cell & <50 MCS for T cell).   Solid phase antibody 
analysis was also used to define the specificity of the antibodies detected, to follow the 

Rituximab + IVIG for Desensitization 
Genentech U4810s 
Protocol Amendment No. 8 
February 5, 2015 
IND 109,067 
Serial #: 1 
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Dr. Stanley C. Jordan 
Confidential and Proprietary 
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effect of desensitization, and the strength of DSA as previously reported (4-8).   B-cell 
FCMX data obtained prior to June 2008 was not valid due to the presence of rituximab 
in test samples. However, pronase treatment of crossmatches was performed after that 
time. Insufficient numbers of pronase treated B cell crossmatches have been obtained to 
date and therefore, these data are not included in this study.  Thus, a heavier reliance on 
T-cell FCMX data and DSA values (<100,000 SFI units) were used as the primary 
determinants of crossmatch acceptability as previously described. (4-8). 
 
This strategy was also used in HS DD transplant candidates who were on the United 
Network of Organ Sharing (UNOS) list for >5 years who received frequent DD offers 
with positive cross matches.  After completion of the desensitization protocol, patients 
usually waited 4-6 months for acceptable cross match offers. Because the half-life of 
IVIG is only 30 days, an additional IVIG dose was given at the time of transplant. All 
transplanted patients received an additional dose of IVIG (2gm/kg, maximum dose 
140g) 10-14 days post-transplant. 
 
Data were gathered before and after each IVIG infusion, at time of transplant, and 
months 1, 6, 12, and 24 post-transplant. Safety data included monitoring patients for 
infusion related side effects (such as fever, headache, shortness of breath during and 
immediately after infusion), viral infections and CNS related side effects.  The patients 
were followed to determine the proportion with reductions in anti-HLA antibodies that 
subsequently obtained and retained a viable and functioning kidney allograft. The 
monitoring protocols were similar to those previously reported (2). 
 
All IVIG doses were infused over a 4 hour hemodialysis session as previously described 
(9).  Rituximab infusions were administered in an outpatient infusion center over a 6 
hour period with frequent monitoring of vital signs. To reduce the frequency of 
infusion-related side effects, all patients were pre-treated with intravenous 
methylprednisolone (40mg - 125mg), acetaminophen (650 milligrams by mouth) and 
diphenhydramine (50 mg by mouth) 30-60 minutes prior to scheduled IVIG and 
rituximab infusions. 
 
Donor-Specific Crossmatching and Anti-HLA Antibody Analysis 
The FCMX and CDC were performed as previously described (4-8). Three-color 
FCMXs were performed according to the method of Bray et al (10), using FACScan 
cytometer (Becton-Dickinson, San Jose, CA).  T-cell FCMXs were considered positive 
at more than 50 mean channel shifts (MCS) and B-cell FCMX were considered positive 
at more than 100 MCS.  B-cell cross matches were always positive after rituximab 
therapy for up to 6 months or longer.   These B cell cross match results were considered 
invalid.  To address this issue, pronase treated B & T-cell cross matches have been 
performed since June 2008 (4-8). The negative cut off values for pronase treated cells 
is 70 MCS for T cells and 130 MCS for B cells. 
 
The binding level of DSA was determined by the multianalyte bead assay performed on 
the Luminex platform. The single antigen Luminex bead assay was standardized with 
Quantiplex beads (One Lambda, Inc., Canoga Park, CA) and results were expressed as 
standard fluorescence intensity (SFI) as previously reported (4-8).  These data were 
obtained on sera from patients treated after June 2007. Flow PRA Screening was 
performed  per  manufacturer’s  instructions  as  previously described.    Briefly,  25  µl 
patient  serum  was  mixed  with  5µl  of  FlowPRA®  screening  beads  (One  Lambda 
Canoga Park, CA).  Any significant shift of the bead population to the right of the 
negative control marker >50% is considered as positive.  The percentage of Flow PRA 
Screening was calculated from the positive reactivity bead population. 
 
RESULTS 
 
Success of Desensitization 
76 HS patients who met criteria for desensitization were successfully transplanted 

Rituximab + IVIG for Desensitization 
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(31LD/45DD). The mean follow-up time was 12.2 ± 8.4 months and 37% of patients 
had 12-24 months follow-up (table 1).  All patients in this group were deemed to have 
high immunologic risk (54% had more than one previous transplant, 25% had PRA 30- 
79% and 75% had PRA>80% {table 2}). 
 
Effects of Desensitization on cPRA, Crossmatch and DSA Results 
The effect of desensitization on flow cytometry PRA determinations were performed on 
a subset of 39 HS patients. This data show that the mean pre-treatment class I PRA was 
79.7±25.6 % vs post-treatment 67.1±28.6%, (p=0.0001). The mean pre-treatment class 
II PRA was 59.7±29.2 vs. post-treatment 49.7±27.8, (p=0.01). This reduction is less 
than reported previously (2). Reasons for this difference include a change in technique 
from cytotoxicity-based PRA determinations to solid phase antibody testing using flow 
cytometry and luminex bead technologies. Both cytotoxicity and solid phase assays are 
susceptible to interference from IVIG but only for a period of less than a week after 
IVIG administration.  Twenty five percent of treated patients experienced a reduction in 
flow cytometry PRA of 25% or greater. Analyses of transplantation and outcomes by 
flow cytometry PRA (Class I or II) and donor type are shown in figure 1. Seventy five 
percent of patients had flow cytometry PRA >80% (19LD/38DD) before 
desensitization. These patients also experienced more ABMR episodes.  A significant 
reduction was seen in FCMX positivity against donor T-cells for patients receiving LD 
and DD transplants after desensitization (Fig 2A & 2B).  Figure 2A shows the MCS 
results for T-cell FCMXs for all 31 individual LD recipients were available. Figure 2A 
shows the mean values for MCS pre-treatment and at transplant. Briefly, T-cell FCMX 
were significantly reduced from 183±98 MCS prior to therapy to 68±58 MCS at time of 
transplant (p<0.000006).   T-cell FCMX data for DD recipients pre-treatment and at 
transplant are shown in figure 2B. Briefly, a significant reduction in mean T-cell 
FCMX was seen after desensitization in DD recipients (162±41 MCS pre-treatment vs. 
125±49 MCS at transplant {p=0.05}).   Table 3 shows rejection type and graft loss by 
DSA. 
 
An analysis of AR (CMR and ABMR) over the 24 month observation period is shown 
in table 3. Briefly, 37% of patients had AR episodes (8%CMR and 29% ABMR). 
There was a very significant association of ABMR risk with the presence of DSA 
>100,000 SFI Units at time of transplant (17/29 with DSA >100,000 had ABMR while 
only 5/42 with DSA<100,000 experienced ABMR). There is no significant association 
between DSA >100,000 or <100,000 SFI units with graft loss to ABMR.  The data also 
include 2 patients who developed late ABMR (>12M) due to non-compliance, both 
with graft losses. 
 
Outcomes of Highly-HLA Sensitized Patients Transplanted After Desensitization 
Patient and graft survival, acute rejection episodes, infectious complications, and renal 
function were monitored after transplantation.  A summary of the patient demographics, 
immunologic profiles and infectious complications is shown in (tables 1 and 2). 
Patients who received DD transplants waited 95±46 months on the transplant waitlist 
before receiving desensitization with IVIG + rituximab, but waited only 4.2±4.5 months 
after treatment for transplantation. Patients who received DD transplants did not 
receive additional points toward transplantation for participation in this protocol. 
 
Patient and Graft Survival 
Patient and graft survival (non-death censored) up to 24 months were 95% and 84% 
{LD (100%/90%) vs. DD (91%/80%)} (Figure 3A&B). Graft losses occurred in nine 
patients:  ABMR (6), non-adherence (2), and surgical complications (1). Four deaths 
occurred at 1, 6 and 10 months post-transplant due to donor-transmitted fungal sepsis 
(#1), bacterial sepsis (1), and myocardial infarction (#2).  Data are summarized in table 
2.  No significant differences in outcomes were seen among the three induction 
regimens used. 
 
Acute Rejection Episodes 

Rituximab + IVIG for Desensitization 
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Acute rejection episodes occurred in 37% of transplanted patients. Twenty nine percent 
(22/76) of AR episodes were C4d+ antibody mediated rejections (ABMR) (table 3). 
Most rejection episodes occurred within the first month post-transplant and were 
reversible with treatment.  Seven graft losses were due to ABMR. All but 1 patient 
who lost their allograft to ABMR showed progressive elevations in DSAs. 
 
Renal Function 
Mean serum creatinine values at 1 month, 6 months, 12 months, and 24 months were 
1.9±1.5, 1.3±0.4, 1.5±1.1 and 1.3±0.3 milligrams per deciliter, respectively. 
 
Adverse Events, Serious Adverse Events and Infections 
No patients to date have developed neurological symptoms suggestive of PML. Viral 
infections were seen post-transplant in 6 patients (8%) who were treated with IVIG and 
rituximab for desensitization (table 2). Two CMV, 3 PBK viremia, and 1 CMV/PVB19. 
No patient developed BK nephropathy. One patient died of donor transmitted fungal 
infection at 1 month post-transplant, another patient died of bacterial sepsis after 
prolonged bowel obstruction at one year post transplant.   Minimal infusion-related 
side effects were noted (shortness of breath in several patients requiring additional 
methylprednisolone 125mg x1). Lack of significant infusion-related side-effects is 
likely due to the pre-medication regimen used prior to infusion and the long infusion 
times (2). Tables and figures are shown below: 
 
 
 
Table 1: Demographics for highly sensitized patients desensitized with IVIG and 
rituximab  (N=76) 
 
Total Transplants 
76 
Male/Female (N=76) 
27/49  (64% F) 
Type (DD/LD) (N=76) 
Age Range (Years) 
45/31   (59% DD) 
17-82yrs. 
Mean Follow-Up Post Tx (N=76) 
Percent w.  12-24M Follow-up 
Percent w.  6-12M Follow-up 
Percent w.  <6M Follow-up 
28  (37%) 
15 (20%) 
33 (43%) 
Race: (N=76) 
Caucasian 
African American 
Hispanic 
Other 
31  (41%) 
13  (17%) 
22  (29%) 
10  (13%) 
Etiology of ESRD: (N=76) 
Diabetes/HTN 
26  (34%) 

Rituximab + IVIG for Desensitization 
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FSGS 
SLE 
Other (GN, Alport's, OU, CIN) 
3  (4%) 
 
5  (7%) 
 
42  (55%) 
DD denotes deceased donor. LD denotes living donor, M denotes month. AA denotes 
African-American. ESRD denotes end-stage renal disease. HTN denotes hypertension. 
FSGS denotes focal and segmental glomerulosclerosis. SLE denotes systemic lupus 
erythematosus. GN denotes glomerulonephritis. OU denotes obstructive uropathy. CIN 
denotes chronic interstitial nephritis. 
 
 
 
 
Table 2:  Immunologic & infectious profiles for highly sensitized patients receiving 
transplants after desensitization with IVIG and rituximab. (N=76) 
 
Transplant by Flow PRA (Class I or II) 
& Donor Type (N=76) 
Type 
30-79% 
≥80% 
DD (N=45)  LD (N=31) 
7 (16%) 
12 (39%) 
38 (84%)    19 (61%) 
Previous Transplants (N=76) 
0 
1 
≥2 
35  (46%) 
28  (37%) 
13  (17%) 
Infectious Complications (N=8 {11%}) 
Viral (N=6{8%}) 
CMV/PVB19 
CMV 
Polyoma BK 
Fungal (N=1 {1%}) 
Coccidiomycosis from donor 
Bacterial (N=1 {1%}) 
Sepsis post-bowel obstruction 
1  (1%) 
2  (3%) 
3  (4%) 
1(1%)† 
1(1%)† 
Death post transplant (N=4 {5%}) 
Infections (N=2) 
Fungal 
Bacterial 
Myocardial infarction (N=2) 
DD (N=4) 
LD(N=0) 
1 (1%) 
1 (1%) 
2 (3%) 
HLA Matches (N=76) 
0 Ag match 
12  (16%) 

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1 Ag match 
34  (44%) 
2 Ag match 
12  (16%) 
≥3 Ag match 
18  (24%) 
 
Flow PRA denotes panel reactive antibody as determined by flow cytometry assays. DD 
denotes deceased donor. LD denotes living donor.   CMV denotes cytomegalovirus. 
PVB 19 denotes Parvovirus B19. HLA denotes human leukocyte antigen. †= death. 
 
 
 
 
 
Figure 1: This figure shows an analysis of transplantation and outcomes by PRA and 
donor type. 75% of patients had PRA >80%.  There were also more ABMR episodes 
and graft losses to ABMR in this group. 
 
 
 
 
 
 
 
 
 
 
 
Table 3: Shows AR episodes and graft losses in the patients receiving transplants after 
desensitization. Relationship of ABMR to DSA levels at time of transplant is also 
shown. 

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Figure 2A & B: This figure shows T-cell FCMX values for pre-treatment and at time of 
transplant for 31 HS LD (2A) and 45 HS DD (2B) recipients who were desensitized 
with IVIG+ rituximab. A negative T-cell FCMX is <50 MCS. 
 
Figure 2A 
 
 

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Figure 2B 
 
 
 
Figure 3A & B:  This figure shows non-death censored patient and graft survival values 
at 0M, 1M, 6M, 12M and 24M  for 76 HS patients who were desensitized with IVIG + 
rituximab.  (3A) Patient and Graft Survival for all patients up to 24M post transplant. 
(3B) Patient and Graft Survival by donor type LD (N=31) and DD (N=45) for the same 
period. 
 
Figure 3A 
 
 
 

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Figure 3B 
 
 
 
 
 
STUDY DESIGN: 
This single (or multiple)-center, Phase I/II, exploratory study will use an open label 
design. The revision of this protocol is attributed to the failure of the placebo controlled 
protocol which showed a significant increase in SAEs in the IVIG + placebo group (3 
antibody-mediated rejection episodes of 5 transplanted compared with 0 ABMR episodes 
in the IVIG + Rituximab group, p=0.038). The original study was put on hold and this 
iteration represents a redesign of the protocol to investigate the optimal dosing of 
Rituximab for desensitization and for modification of DSA levels post-transplant.   The 
trial will examine the safety and efficacy of human polyclonal IGIV 10%, when given at 
[2.0 gm/kgx2], + Rituximab 1gm to reduce DSA to a level that is permissive for DD 
transplantation in 75 subjects (adults only ages >18 yrs) who are highly-HLA sensitized 
and are awaiting DD kidney transplant. Once transplant offers are entertained, a donor- 
specific crossmatch will be performed to detect anti-HLA antibodies which are 
associated with acute rejection or graft loss.  (These anti-HLA antibodies may result 
naturally or from some previous pregnancy, transfusions, or prior transplants). If 
acceptable crossmatches and DSA levels are seen, the patients will proceed to DD 
transplantation. Patients receiving transplants will receive an additional dose of IVIG at 
transplantation (within 10 days) and will receive additional doses of Rituximab 1g) at 
3M post-transplant if they remain or develop DSAs. OR at 6M if de novo DSAs occur 
(Fig 5 & 6). Patients who are desensitized and not transplanted within 9 
M after desensitization will have completed the study and can be treated as best judged 
by the participating center. The protocol is shown in Figure 4 below. 

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Figure 4: Study Protocol for revised IVIG + Rituximab Study. 
 
 
The decision to accept a DD transplant will rest entirely with the participating transplant 
center. 
 
 
The subjects will be followed to determine the proportion who receive a transplant 
within 9M of completion of the infusions. In addition we will assess the transplanted 
patients to determine the number who sustain a viable and functioning kidney allograft 
for 12 months at which time a repeat study biopsy will be performed.  All subjects will 
be evaluated on an intent-to-treat basis.  The subject accrual rate will be limited to no 
more than five subjects per month in the initial three months to assure safety to all 
subjects. 
 
Figure 5: Pre-Transplant Desensitization Protocol for deceased donor recipients: 

Rituximab + IVIG for Desensitization 
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Figure 6 Shows the Post-Transplant Management Protocol for Patients Receiving DD 
Transplants. 
 
. 
ACCRUAL GOAL: 
75 subjects 
DURATION OF ACCRUAL: 
24 months 

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DURATION OF FOLLOW- 
UP: 
9 months for all desensitized subjects, 12 months for all transplanted subjects 
 
THERAPY STOPPING 
RULES: 
Safety stopping rules for the study include: 
 
 
The study will be put on hold and re-evaluated for safety signals if significant adverse 
events (serious infusion reactions, serious infections or death and or graft loss from early 
ABMR) are seen in three of the first 5 patients.  In addition, if biopsy proven ABMR is 
seen in 4 of the first 10 patients entered, the study will be stopped for re-evaluation. 
Efficacy Stopping Rules: 
The DSMB will review cumulative safety and efficacy data according to a pre-specified 
schedule, not less frequently than quarterly. Based on these data (after the pre-specified 
data reviews, the DSMB may recommend alterations or stopping of the protocol. 
 
 
CONCOMITANT 
MEDICATIONS: 
Concomitant therapy will include a standard immunosuppressive regimen of 
mycophenolate mofetil (CellCept) at 1200 mg/m2/day given in two divided doses, 
Tacrolimus (Prograf) given at 0.05 to 0.15 mg/kg divided twice daily, and prednisone 
loading dose and taper as per center protocol. Induction therapy using Campath 1H 
30mg SQ/IV at the time of transplant OR Thymoglobulin® (total dose not to exceed 
6.0mg/kg) IV per center protocol will be given to subjects on study. The safety and 
efficacy of Campath 1H induction therapy after desensitization with IVIG + Rituximab 
has been previously described for adults (11,12). 
 
Therapy for recurrent biopsy proven rejection will be initiated as standard of care at 
participating institutions. The recommended initial rejection therapy will consist of 
pulse Solumedrol per center protocol. Alternatively, Thymoglobulin will typically be 
given for 5-10 days, depending on the time of return of creatinine levels to baseline. If 
resistant ABMR is seen, the use of IVIG +Rituximab (anti-CD20 monoclonal antibody) 
and/or plasmapheresis will be considered. In addition, the use of monoclonal antibodies 
to the complement component C5 (Eculizumab®, Alexion, Cheshire, CT) may be used at 
the discretion of the investigators. 
 
DATA SAFETY 
MONITORING 
A major component of this study will be to determine the safety of this combination of 
drugs for desensitization and subsequent transplantation. In order to insure this is done, a 
Data Safety Monitoring Board (Drs. Jordan, Dr. Lill (Bone Marrow Transplantation) & 
Vo) will be created to monitor AEs and SAEs that occur during the study. Cedars-Sinai 
will maintain the database for all patients entered into the study and will be responsible 
for accumulation of safety data and reporting to participating centers and Genentech with 
each occurrence. 
 
RECIPIENT INCLUSION 
CRITERIA: 
1. 
End-stage renal disease. 
2. 
No known contraindications for therapy with IGIV10%/Rituximab. 
3. 
Age 18-70 years at the time of screening. 
4. 
CPRA> 30% demonstrated on 3 consecutive samples, UNOS wait time sufficient to 
allow DD offers, history of sensitizing events, positive crossmatch with the intended 
donor. 
5. 
Subject/Parent/Guardian must be able to understand and provide informed consent. 
 
RECIPIENT EXCLUSION 
CRITERIA: 
1. 
Lactating or pregnant females. 
2. 
Pediatric patients <18 years of age 
3. 
Women of child-bearing age who are not willing or able to practice FDA-approved 
forms of contraception. 
4. 
HIV-positive subjects. 
5. 
Subjects who test positive for HBV infection [positive HBVsAg, HBVcAg, or 

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HBVeAg/DNA] or HCV infection [positive Anti-HCV (EIA) and confirmatory 
HCV RIBA]. 
6. 
Subjects with active TB. 
7. 
Subjects with selective IgA deficiency, those who have known anti-IgA antibodies, 
and those with a history of anaphylaxis or severe systemic responses to any part of 
the clinical trial material. 
8. 
Subjects for whom multiple organ transplants are planned. 
9. 
Recent recipients of any licensed or investigational live attenuated vaccine(s) within 
two months of the screening visit (including but not limited to any of the following: 
 
Adenovirus [Adenovirus vaccine live oral type 7] 
 
Varicella [Varivax] 
 
Hepatitis A [VAQTA] 
 
Rotavirus [Rotashield] 
 
Yellow fever [Y-F-Vax] 
 
Measles and mumps [Measles and mumps virus vaccine live] 
 
Measles, mumps, and rubella vaccine [M-M-R-II] 
 
Sabin oral polio vaccine 
 
Rabies vaccines [IMOVAX Rabies I.D., RabAvert]) 
10.  A significantly abnormal general serum screening lab result defined as a WBC < 3.0 
X 103/ml, a Hgb < 8.0 g/dL, a platelet count < 100 X 103/ml, , an SGOT > 5X upper 
limit of normal, and an SGPT >5X upper limit of normal range. 
11.  Individuals deemed unable to comply with the protocol. 
12.  Subjects with active CMV or EBV infection as defined by CMV-specific serology 
(IgG or IgM) and EBV-specific serology (IgG or IgM) and confirmed by 
quantitative PCR with or without a compatible illness. 
13.  Subjects with a known history of previous myocardial infarction within one year of 
screening. 
14.  Subjects with a history of clinically significant thrombotic episodes, and subjects 
with active peripheral vascular disease. 
15.  Use of investigational agents within 4 weeks of participation. 
 
 
References 
 
1.  Jordan SC, Tyan D, Stablein D, McIntosh M, Rose S, Vo A, Toyoda M, Davis C, 
Shapiro R, Adey D, Milliner D, Graff R, Steiner R, Ciancio G, Sahney S, Light 
J.Evaluation of intravenous immunoglobulin as an agent to lower allosensitization 
and improve transplantation in highly sensitized adult patients with end-stage renal 
disease: report of the NIH IG02 trial .J Am Soc Nephrol. 2004 Dec;15(12):3256-62. 
 
 
2.   Vo AA, Lukovsky M, Toyoda M, Wang J, Reinsmoen NL, Lai CH, Peng A, 
Villicana R, Jordan SC. Rituximab and intravenous immune globulin for 
desensitization during renal transplantation. N Engl J Med. 2008 Jul 17;359(3):242- 
51. 
 
3. Shapiro R. Reducing antibody levels in patients undergoing transplantation. N Engl J 
Med. 2008 Jul 17;359(3):305-6. 
 
4.   Reinsmoen NL, Lai CH, Vo A, Cao K, Ong G, Naim M, Wang Q, Jordan SC. 
Acceptable donor-specific antibody levels allowing for successful deceased and 
living donor kidney transplantation after   desensitization therapy. 
Transplantation 2009; 27:86(6):820-5. 
 
5.   Vo AA, Peng A, Toyoda M, Kahwaji J, Cao K, Lai CH, Reinsmoen NL, Villicana 
R, Jordan SC. Use of intravenous immune globulin and rituximab for desensitization 

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of highly HLA-sensitized patients awaiting kidney transplantation. 
Transplantation. 2010 May 15;89(9):1095-102. 
 
6.  Lai CH, Cao K, Ong G, Naim M, Wang Q, Mirocha J, Vo A, Jordan SC, Reinsmoen 
NL.  Antibody testing strategies for deceased donor kidney transplantation after 
immunomodulatory therapy. Transplantation. 2011 Jul 15;92(1):48-53. 
 
7.   Reinsmoen NL, Lai CH, Vo A, Jordan SC. Evolving paradigms for desensitization 
in managing broadly HLA sensitized transplant candidates. Discov Med. 2012 
Apr;13(71):267-73. 
 
8.  Jordan SC, Reinsmoen N, Lai CH, Vo A.  Novel immunotherapeutic approaches to 
improve rates and outcomes of transplantation in sensitized renal allograft 
recipients. Discov Med. 2012 Mar;13(70):235-45. 
 
 
9. Solez  K, Colvin R B, Racusen LC,  Sis B, Halloran PF,  Birk PE, 
Campbell PM, Cascalho M, Collins AB,  Demetris AJ,  Drachenberg CB, Gibson IW, 
Grimm PC,  Haas M,  Lerut E, Liapis H,  Mannon RB,  Marcus PB,  Mengel M, 
Mihatsch MJ,   Nankivell BJ,  Nickeleit V, Papadimitriou  JC, Platt JL,  Randhawa 
P,  Roberts I, Salinas-Madriga L,  Salomon DR, Seron  D, Sheaff M, Weening JJ. 
Banff '05 Meeting Report: Differential Diagnosis of Chronic Allograft Injury and 
Elimination of Chronic Allograft Nephropathy ('CAN'). American Journal of 
Transplantation. 2007; 7(3):518-526. 
 
10. Gebel H, Bray R, and Nickerson P. Pre-transplant assessment of donor-reactive, 
HLA-specific antibodies in renal transplantation: Contraindication vs. risk. Am. J. 
Transp. 2003; 3: 1488-1500. 
 
11. Vo, AA., Weschler, EA., Wang, J., Peng, A., Toyoda, M., Lukovsky, M., 
Reinsmoen, N., and Jordan, SC.  Analysis of Subcutaneous (SQ) Alemtuzumab 
Induction Therapy in Highly Sensitized Patients Desensitized with IVIG and 
Rituximab.  American Journal of Transplantation.  2008; 8: 144-149. 
 
12. Shapiro R. et al. Alemtezumab preconditioning with tacrolimus monotherapy 
in pediatric renal transplantation. American J. Transplantation 2007; 12: 2736-38. 

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1.0 
STATISTICAL CONSIDERATIONS 
 
 
 
1.1 
IVIG + Rituximab for Desensitization 
 
Primary Objective: 
 
This trial is designed to determine if Rituximab + IVIG is effective in improving rates of 
transplantation for highly-HLA sensitized DD candidates on the UNOS waiting list over a 9M 
period of time after completion of treatment. Results will be compared to transplant rates in a 
group of age and anti-HLA antibody matched patients who remain on the UNOS wait list during 
the study period. This is the PRIMARY END POINT. Secondary end points include and will be 
evaluated based on time line in appendix A: 
 
 
Transplantation rate assumptions: 
 
 
60-65% in the IVIG + Rituximab group 
 
 
~15% in the non-desensitized patients on UNOS wait list 
 
 
 
1.2 
Target Sample Size 
 
 
The target sample size is based on the statistical estimates of adequate sample size to 
power the study at 95% confidence. 95% Confidence Intervals for the 12-month 
Transplant Rate Assumes a 50% transplant rate (Expected proportion = 0.50) at 12 
months for IVIG + Rituximab 

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Confidence interval for proportion using normal approximation (n large) 
1 
2 
3 
Confidence level, 1- 
0.95 
0.95 
0.95 
1 or 2 sided interval? 
2 
2 
2 
Expected proportion,  
0.50 
0.50 
0.50 
Distance from proportion to limit,  
0.127 
0.117 
0.113 
n 
60 
70 
75 
 
 
 
We do not have a good estimate of the IVIG + Rituximab transplant rate at 12 months in 
this patient population. We expect the rate to be at least 50%, hopefully as high as 60 to 
65%. This is based on our experience over the past 7 years where 67% of deceased donor 
recipients were transplanted after desensitization (Vo et al. Transplantation 2013;65:1-7). 
This article is included. Thus these estimates are reliable in our hands. 
For estimation using a 95% confidence interval, the assumed 50% transplant rate is 
conservative in that the width of the 95% confidence interval will be maximum when the 
assumed rate is 50%, i.e. the estimate will be least precise when the assumed rate is 50%. 
 
Table 3 shows the upper limit of the 95% confidence interval estimates of the historical 
transplant rate at 3 years to be about 32% (highest at 38% in 2006). 
Column 3 (Distance from proportion to limit) in the above power and sample size table 
shows that the lower limit of the 95% confidence interval for the IVIG + Rituximab 
transplant rate at 12 months (assuming the rate = 50%) is about 39% [50% – 11.3% = 
38.7%], which is higher than the upper limit of the 95% confidence interval for the 
historical rate at 3 years (even in 2006). 
If the observed IVIG + Rituximab transplant rate is > 50%, then the lower level of the 
95% confidence interval will be > 39% and the evidence for the effectiveness of IVIG + 
Rituximab will be stronger. 
For example, if the observed transplant rate is 60%, then the 95% confidence interval 
(based on n = 75) is approximately 49% to 71%. 
[As I wrote in the document: “If the observed 12-month IVIG + Rituximab transplant rate 
is > 50%, then the effectiveness evidence is even stronger (the lower limit of the CI will 
be higher).”] 
 
If the 9-month transplant rate is 50% (or 60 to 65%) then the 12-month rate should be 
even higher. During the placebo controlled phase of this study, the 13/15 patients were 
transplanted at a mean of 7 months post treatment. (7 IVIG + Placebo v. 6 IVIG + 
Rituximab). The mean wait time on dialysis for this group was > 11 years prior to being 
entered into the study and transplanted. Our original time of assessment of transplantation 

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was 6M. However, with this preliminary data, we felt it better to look at 9M since this 
would likely be more reasonable and would give a fair assessment of the efficacy of the 
therapy. We feel we are being conservative with these estimates. Hopefully, this clarifies 
the sample size calculation issues. 
Column 1: the lower limit of the CI is 0.373 or about 37% when the sample size is 60. 
Column 2: the lower limit of the CI is 0.383 or about 38% when the sample size is 70. 
 
Column 3: the lower limit of the CI is 0.387 or about 39% when the sample size is 75. 
 
If the upper limit of the UNOS CI (historical data) is below the lower limit of the above CI, then 
the CI do not overlap and there is evidence that IVIG + Rituximab is more effective re the 12- 
month transplant rate. 
 
Given the UNOS data for transplant rates (Table 4 & 5),  60 should be sufficient as a sample size 
to show benefit of the IVIG + Rituximab treatment. However, 75 patients gives a better and more 
robust distinction. Since we will be looking at transplant rates at 9M post-treatment, and given the 
vagueries of organ allocation and patient readiness issues, we feel the choice of 75 patients will 
provide more security for an accurate and definitive study. 
 
If the observed 12-month IVIG + Rituximab transplant rate is > 50%, then the effectiveness 
evidence is even stronger (the lower limit of the CI will be higher). 
 
 
1.3 
Planned Efficacy Evaluations 
 
The efficacy end points will be evaluated after all 75 patients have been enrolled into the trial. We 
plan to evaluate rates of deceased donor transplantation as well as conversion rate of DSA and 
rates of ABMR in those transplanted. The efficacy of the proposed combination of IVIG + 
Rituximab will be determined by the statistical methods. These evaluations will be carried out in 
concert with our safety monitoring that is outlined in section 9.0. The appropriate stopping points 
and re-evaluation points are described there as well. 
 
 
1.3.1   Primary Efficacy Variables 
 
The primary efficacy variable is the number of highly-HLA sensitized patients receiving a 
deceased donor transplant within 9 months after completion of the treatment. From our previous 
experience, the anticipated transplant rates for patients receiving IVIG + Rituximab 
desensitization is ~70% (49,112, 131). The rates for DD transplantation in non-treated patients 
based on sensitization levels is shown in Figure 15 below. Briefly, the rates of transplantation for 
all sensitized patients are <12% per year for the past decade. This indicates that desensitization 

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with IVIG + Rituximab is likely to benefit this high risk group who are otherwise unlikely to 
receive a life-saving transplant. 
 
 
 
 
 
 
 
 
Figure 15: Data shown in figure 14 represent an analysis of 95,083 deceased donor transplants 
performed over the 10 year period 2000-2009.  When analyzed by PRA status, one can see that 
<20% of all transplants performed are in highly-HLA sensitized patients. Data from the United 
States Renal Data Systems (usrds.gov) for 2009 also show that the wait time for a deceased donor 
kidney for patients with PRAs <10% is 4 years but increases to 8 years for patients with PRAs 
>10%. These trends have not changed over the past decade. 
 
 
 
1.3.2   Secondary Efficacy Variables 
 
In addition to the primary efficacy variables, we will evaluate a number of secondary efficacy 
variables. These include donor-specific antibody testing, patient and graft survival, infectious 
complications, immunologic testing, protocol biopsies and rates of allograft rejection. These end 
points are outlined in section 2.0 and Appendix A. Data will be analyzed in the treatment group. 
 
 
1.3.3   Methods of Analysis 

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We aim to recruit 75 HS patients on the basis of a clinically relevant increase in the absolute rate 
of transplantation for highly-HLA sensitized deceased donor recipients of approximately 50 
percentage points between the two groups during 9 months of follow-up, with an estimated event 
rate of 15% in the control UNOS study group. We determined that this number of patients would 
provide the study with a power of 95%, with a two-sided type I error of 5% and a nonadherence 
or loss to follow up rate of 5(or 10)%. A transplant rate of 60-70% in the intervention limb is 
based on our experience with desensitization in the recent years (49, 113, 131). All analyses shall 
be performed on the basis of the intention-to-treat principle. Patients that were transplanted 
outside of the study will be included in the analysis.  
 
 
We shall compare the proportions of patients in the treatment group compared to the UNOS 
control group using time-to-event analysis with respect to outcomes such as the primary outcome 
(rate of transplantation) and certain secondary outcomes (such as recipient and graft survival, 
occurrence of rejection in the treatment group only). These outcomes shall be analyzed with the 
use of the log-rank test. Cox proportional-hazards regression shall be used to obtain unadjusted 
hazard ratios and to adjust for significant stratifying variables and to test for effect modification 
in all secondary analyses. Data from patients who are lost to follow-up shall be regarded as 
censored at the time of the last contact. Data from patients who do not receive transplantation 
shall be censored at end of 9 months post desensitization. We shall use Kaplan–Meier estimates 
of the proportion of patients with the above listed outcomes. We shall calculate the number of 
patients who would need to be desensitized to allow one deceased donor renal transplant from the 
hazard ratio and its 95% confidence interval. 
For other outcomes, the Chi square or Fischer exact test shall be used if the variable is 
categorical, and the t-test or signed rank test if it is continuous variable. 
 
 
To determine whether the treatment effect varies according to the patients’ PRA status, a priori 
subgroup analysis shall be planned with patients stratified according to the titer of PRA (>80% or 
<80%), and a test of interaction shall be performed in a Cox model. Post hoc subgroup analyses 
shall be conducted with the use of other stratifying variables. Treatment effects shall be described 
in terms of hazard ratios and absolute risk differences with 95% confidence intervals. All P values 
reported shall be two-sided and adjudged significant if <0.05.