Conditions: Kidney Transplantation
Keywords: Donor Specific Antibody Donors, Living Allograft Tolerance
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
The purpose of this research study is to determine whether kidney transplant recipients who receive belimumab (Benlysta®), combined with the standard of care medications for kidney transplant recipients, is safe and effective in helping prevent new donor specific antibodies (DSA) after transplantation. The presence of DSA increases the risk that the kidney transplant recipient's body will reject the new kidney. The investigators are doing this research because it is estimated that greater than 50% of kidney transplant failures are attributed to antibodies produced in the body, that attack the transplanted organ as a foreign object. DSA produced in the body after a kidney transplant, is thought to occur in 20-50% of patients and is associated with a low likelihood that the organ recipient's body will accept the new kidney. A major unmet need in the kidney transplant area are safe and effective therapies to prevent DSA after transplantation.

Detailed description:
Accrual Objective: Kidney transplant recipients (n=5) will receive standard of care (SOC) therapy consisting of alemtuzumab and steroid induction with mycophenolic acid and tacrolimus maintenance immunosuppression, plus induction and treatment for 6 months with belimumab.

Study Design: This is an open-label pilot-study to evaluate the safety and efficacy of belimumab plus standard of care in the prevention of de novo donor specific antibody in adult subjects after kidney transplantation.

The investigators will enroll 5 adult, deceased or living donor kidney transplant recipients who are sensitized, evidenced by: Positive sum Donor Specific Antibody (DSA)\<1000 MFI and/or Panel of Reactive Antibodies (PRA)\>0%. The primary endpoint of this study is de novo DSA production. There are two main reasons for selecting this patient population for the proposed study. 1) Sensitized patients are known to have higher rates of de novo DSA production and 2) Patients with low levels of DSA (sum DSA\<1000 MFI) will enable more fidelity in determining the DSA that is produced de novo.

Kidney transplant recipients will receive the standard of care (alemtuzumab and steroid induction with mycophenolic acid and tacrolimus maintenance immunosuppression), plus six months of therapy with belimumab. Belimumab 10 mg/kg will be administered IV for 6 months at the following intervals: Day of transplant (Day 0), and then at Weeks 2, 4, 8, 12, 16, and 20 post-transplant.

Study Duration: Subjects will be treated for 6 months with belimumab and followed for DSA production for 1 year.

Primary Study Objectives: In this proposal the investigators plan to determine (a) whether the addition of belimumab to the standard of care (SOC: alemtuzumab and steroid induction with mycophenolic acid and tacrolimus maintenance immunosuppression) is safe and effective in preventing de novo DSA production at 1, 3, 6, 9, and 12 months post-transplant.

Secondary efficacy endpoints will be 1) graft survival and function as determined by serum creatinine/eGFR and urine protein at 1, 3, 6, 9, and 12 months 2) rates of acute cellular and antibody mediated rejection, at 1, 3, 6, 9, and 12 months.

Primary Outcomes: To determine whether the addition of belimumab to the standard of care (SOC: alemtuzumab and steroid induction with mycophenolic acid and tacrolimus maintenance immunosuppression) is safe and effective in preventing de novo DSA production 1, 3, 6, 9, and 12 months.

Secondary Outcomes: Secondary endpoints will be 1) graft survival and function as determined by serum creatinine/eGFR and urine protein at 1, 3, 6, 9, and 12 months 2) rates of acute cellular and antibody mediated rejection at 1, 3, 6, 9, and 12 months and 3) the nature, frequency, and severity of serious and non-serious adverse events ≥Grade 2 per Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0.

Arms:
arm 1: Belimumab 10mg/kg will be administered IV at the following intervals: at the time of transplant (Day 0), then post-transplant at 2, 4, 8, 12, 16, and 20 weeks.

Interventions: intervention 1: Belimumab
Intervention descriptions: intervention 1: Kidney transplant recipients (n=5) will receive standard of care (SOC) therapy consisting of alemtuzumab and steroid induction with mycophenolic acid and tacrolimus maintenance immunosuppression, plus induction and treatment for 6 months with belimumab.

Protocol document:
Prot_SAP_000.pdf: 
CAMPath and BELimumab for the Induction of Donor Specific Humoral Transplant Tolerance in 
Sensitized Kidney Transplant Recipients To Improve Long-Term Allograft Survival
NCT03591380
PI: Arjang Djamali, MD
8/17/2020


1  
  
CAMPBEL Trial:  CAMPath and BELimumab for the Induction of Donor Specific Humoral  
Transplant Tolerance in Sensitized Kidney Transplant Recipients To Improve Long-Term  
Allograft Survival  
  
Dated: August 17, 2020  
Version 17.0  
  
  
Principal Investigator:  
 
  
                            Arjang Djamali, MD  
 
  
University of Wisconsin  
                            Department of Medicine 
                            Division of Nephrology   
 
  
1685 Highland Avenue 
                            5142 MCFB   
 
  
Madison, Wisconsin 53705  
 
  
Phone: (608) 262-9306  
 
  
Fax: (608) 262-6743  
 
  
E-mail: axd@medicine.wisc.edu  
  
  
  
 
Co-Investigator:  
 
  
  
  
  
 
  
Dixon B. Kaufman, MD  
 
  
University of Wisconsin  
 
  
Department of Surgery/ Division of Transplant Surgery  
 
  
600 Highland Avenue,   
 
  
Madison, Wisconsin 53792  
 
  
Phone: (608) 265 - 6471  
 
  
E-mail: kaufman@surgery.wisc.edu  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


2  
  
   
  
  
Revision History  
  
  
Version 
Date  
Version  
Number  
  
Detail of Changes  
01/21/2018  13.0  
Initial approved version  
08/02/2018  14.0  
Correction of typographical errors and clarifications of text 
that could be interpreted inconsistently.   
10/14/2019  15.0  
Removal of Kristi Schneider, RN, MS, ANP as Co- 
Investigator;  
Clarification regarding the viral serology tests and the urine 
sample collection.  
03/03/2020  16.0  
Revision of sections 1.1, 1.3, 5.1.2 and 7.3  
08/17/2020  17.0 
Change of Principal Investigator 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


3  
  
  
  
 
  
  
 
Table of Contents  
Synopsis ...........................................................................................................................................4 
1.  
Background Information and Scientific Rationale ...............................................................10 
1.1  Background ......................................................................................................................10 
1.2  Dose Rationale .................................................................................................................12 
1.3  Summary of Known and Potential Risks and Benefits to Human Subjects ....................13 
2.  
Objectives .............................................................................................................................16 
3.  
Study Design .........................................................................................................................16 
3.1  Description .......................................................................................................................16 
3.2  Study Endpoints ...............................................................................................................17 
3.3  Study Population ..............................................................................................................17 
3.4  Screening and Enrollment ................................................................................................17 
3.5  Criteria for Discontinuation .............................................................................................17 
3.6  Criteria for Terminating the Study ...................................................................................19 
4.  
Selection of Subjects .............................................................................................................19 
4.1  Inclusion Criteria .............................................................................................................20 
4.2  Exclusion Criteria ............................................................................................................22 
5.  
Treatment ..............................................................................................................................23 
5.1  Immunosuppression Protocol ...........................................................................................23 
6.  
Study Procedures ..................................................................................................................27 
6.1  Screening Visit .................................................................................................................27 
6.2  Day of Transplant (Day 0) ...............................................................................................28 
6.3 Post-Transplant Study Visits: Week 1, Week 2, Month 1, 2, 3, 4, 5, 6, 9, 12 .....................28 
7.  
Safety Assessments ...............................................................................................................31 
7.1  Adverse Events ................................................................................................................32 
7.2  Serious Adverse Events ...................................................................................................33 
7.3  ICTR Data Monitoring Committee (DMC) .....................................................................34 
8.  
Ethical Considerations and Compliance in Good Clinical Practice .....................................35 
8.1  Statement of Compliance .................................................................................................35 


4  
  
8.2  Informed Consent .............................................................................................................35 
8.3        Recruitment Methods ...................................................................................................35 
8.4  Privacy and Confidentiality .............................................................................................36 
8.5  Records Retention ............................................................................................................36 
9.  
Statistical Section ..................................................................................................................36 
10.  References ..............................................................................................................................37 
11.0 Appendix A (Schedule of Events) .........................................................................................39 
 
  
  
  
  
  
  
Synopsis  
Title  
CAMPBEL Trial:  CAMPath and BELimumab for the Induction of Donor Specific  
Humoral Transplant Tolerance in Sensitized Kidney Transplant Recipients To Improve 
Long-Term Allograft Survival  
Clinical Phase  
Open-label, single-arm, pilot-study  
Sponsor  
University of Wisconsin   
Principal  
Investigator  
Arjang Djamali, MD  
Participating 
Sites  
University of Wisconsin Hospital and Clinics  
Accrual 
Objective  
Kidney transplant recipients (n=5) will receive standard of care (SOC) therapy consisting 
of alemtuzumab and steroid induction with mycophenolic acid and tacrolimus 
maintenance immunosuppression, plus induction and treatment for 6 months with 
belimumab.  


5  
  
Study Design  
This is an open-label pilot-study to evaluate the safety and efficacy of belimumab plus 
standard of care in the prevention of de novo donor specific antibody in adult subjects 
after kidney transplantation.   
We will enroll 5 adult, living donor kidney transplant recipients who are sensitized, 
evidenced by: Positive sum Donor Specific Antibody (DSA) <1000 MFI and/or Panel of 
Reactive Antibodies (PRA)>0%. The primary endpoint of this study is de novo DSA 
production.  There are two main reasons for selecting this patient population for our 
proposed study.  1) Sensitized patients are known to have higher rates of de novo DSA 
production and 2) Patients with low levels of DSA (sum DSA<1000 MFI) will enable more 
fidelity in determining the DSA that is produced de novo.    
 
Kidney transplant recipients will receive the standard of care (alemtuzumab and steroid 
induction with mycophenolic acid and tacrolimus maintenance immunosuppression), plus 
six months of therapy with belimumab. Belimumab 10 mg/kg will be administered IV for 6 
months at the following intervals: Day of transplant (Day 0), and then at Weeks 2, 4, 8, 
12, 16, and 20 post-transplant.   
Study Duration:  Subjects will be treated for 6 months with belimumab and followed for DSA production 
for 1 year post transplant.      
 
Primary Study 
Objectives  
In this proposal we plan to determine (a) whether the addition of belimumab to the 
standard of care (SOC: alemtuzumab and steroid induction with mycophenolic 
acid and tacrolimus maintenance immunosuppression) is safe and effective in 
preventing de novo DSA production at 1, 3, 6, 9, and 12 months post-transplant.   
Secondary efficacy endpoints will be 1) graft survival and function as determined 
by serum creatinine/eGFR and urine protein at 1, 3, 6, 9, and 12 months 2) rates of 
acute cellular and antibody mediated rejection, at 1, 3,  6, 9, and 12 months.  
 
Primary 
Outcomes  
To determine whether the addition of belimumab to the standard of care (SOC:  
alemtuzumab and steroid induction with mycophenolic acid and tacrolimus 
maintenance immunosuppression) is safe and effective in preventing de novo DSA 
production 1, 3, 6, 9, and 12 months.  
Secondary 
Outcomes  
Secondary endpoints will be 1) graft survival and function as determined by serum 
creatinine/eGFR and urine protein at 1, 3, 6, 9, and 12 months 2) rates of acute cellular 
and antibody mediated rejection at 1, 3, 6, 9, and 12 months and 3) the nature, frequency, 
and severity of serious and non-serious adverse events ≥Grade 2 per Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0.  
Eligibility 
Criteria  
Subjects 18-60 years of age receiving a living donor kidney transplant who are sensitized: 
PRA>0 and/or sum DSA<1000 MFI.  
 
 


6  
  
Inclusion  
• 
Male or female subjects 18-60 years of age Criteria  
• 
Planned to receive a living donor kidney transplant   
• 
Sensitized patients: Positive DSA with sum MFI <1000, and/or PRA>0%   
• 
Subjects must be capable of understanding the purpose and risks of the study 
and must sign a statement of informed consent.  
• 
Female subjects must be post-menopausal, surgically sterilized, or she and/or 
sexual partner must be willing to use an acceptable method of birth control with 
a <1% failure rate as stated in the product label from time of study consent, 
during  study participation, and for 16 weeks after the last dose of the study 
agent (i.e., contraceptive subdermal implant of levonorgestrel or etonogestrel, 
intrauterine device or intrauterine system, combined estrogen and progestogen 
oral contraceptive, Injectable progestogen, contraceptive vaginal ring, 
percutaneous contraceptive patches, or abstinence) for the duration of the study.  
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject.  
The documentation of male sterility can come from the site personnel’s: review 
of subject’s medical records, medical examination and/or semen analysis, or 
medical history interview provided by her or her partner.  Note:  Mycophenolate 
mofetil (MMF) affects the metabolism of oral contraceptives and may reduce 
their effectiveness. As such, women receiving MMF who are using oral 
contraceptives for birth control should employ an additional method (e.g., barrier 
method). Mycophenolate can cause fetal harm when administered to a pregnant 
female. Use of mycophenolate during pregnancy is associated with an increased 
risk of first trimester pregnancy loss and an increased risk of congenital 
malformations. Mycophenolate affects the metabolism of oral contraceptives 
and may reduce their effectiveness. As such, women receiving MMF who are 
using oral contraceptives for birth control should employ an additional method 
(e.g., barrier method) resulting in two reliable forms of contraception being used 
simultaneously before starting study treatments, during therapy, and for 6 weeks 
after stopping therapy; unless abstinence is the chosen method of contraception  
• 
Female patients of childbearing potential must have a negative serum 
pregnancy test within 48 hours of transplant.  Must be willing to use 
contraceptives from the time of study consent, during study participation, and for 
16 weeks after the last dose of study agent. For sexually active men, condoms 
should be used during, and for at least 90 days after cessation of mycophenolate 
treatment. No sperm donation should be made during this period of time. For 
female partners of male subjects, it is recommended to use highly effective 
contraception during treatment and for 90 days after the last dose of 
mycophenolate  
• 
No blood donation should be made by the study subjects during mycophenolate 
treatment and for at least 6 weeks after stopping mycophenolate treatment  
• 
If stricter female or male contraception requirements are specified in the 
countryspecific label for any study related therapies, they must be followed.  
  
• 
Male subjects must agree to use an acceptable method for contraception for the 
duration of the study.  


7  
  
F e m al e p ati e nt s of c hil d b e ari n g p ot e nti al m u st h a v e a n e g ati v e s er u m pr e g n a n c y t e st 
wit hi n 4 8 h o ur s of tr a n s pl a nt.  M u st b e willi n g t o u s e  c o ntr a c e pti v e s fr o m t h e ti m e of 
st u d y c o n s e nt, d uri n g st u d y p arti ci p ati o n, a n d f or 1 6 w e e k s aft er t h e l a st d o s e of st u d y 
a g e nt.  R e pr o d u cti v e St at u s: D efi niti o n of W o m e n of C hil d -B e ari n g P ot e nti al ( W O C B P). 
W O C B P  c o m pri s e s  w o m e n  w h o  h a v e  e x p eri e n c e d  m e n ar c h e  a n d  w h o  h a v e  n ot  
u n d er g o n e  s u c c e s sf ul  s ur gi c al  st erili z ati o n  ( h y st er e ct o m y,  bil at er al  t u b al  li g ati o n,  or  
bil at er al o o p h or e ct o m y) or w h o ar e n ot p o st -m e n o p a u s al ( s e e d efi niti o n b el o w). P o st -
m e n o p a u s e i s d efi n e d a s :   
• 
W o m e n  w h o  h a v e  h a d  a m e n orr h e a  f or   1 2  c o n s e c uti v e  m o nt h s  ( wit h o ut  
a n ot h er c a u s e) a n d w h o h a v e a d o c u m e nt e d s er u m f olli cl e -sti m ul ati n g h or m o n e 
( F S H) l e v el > 3 5 mI U/ m L.  
• 
W o m e n w h o h a v e irr e g ul ar m e n str u al p eri o d s a n d a d o c u m e nt e d s er u m F S H 
l e v el > 3 5 mI U/ m L.  
• 
W o m e n w h o ar e t a ki n g h or m o n e r e pl a c e m e nt t h er a p y ( H R T). T h e f oll o wi n g 
w o m e n ar e W O C B P:  
• 
W o m e n u si n g t h e f oll o wi n g m et h o d s t o pr e v e nt pr e g n a n c y: Or al c o ntr a c e pti v e s, 
ot h er h or m o n al c o ntr a c e pti v e s ( v a gi n al pr o d u ct s, s ki n p at c h e s, or i m pl a nt e d or 
i nj e ct a bl e  pr o d u ct s),  or  m e c h a ni c al  pr o d u ct s  s u c h  a s  i ntr a ut eri n e  d e vi c e s  or  
b arri er m et h o d s ( di a p hr a g m, c o n d o m s, s p er mi ci d e s).  
• 
W o m e n w h o ar e pr a cti ci n g a b sti n e n c e fr o m i nt er c o ur s e fr o m 2 w e e k s pri or t o 
a d mi ni str ati o n of t h e 1 st d o s e of st u d y a g e nt u ntil 1 6 w e e k s aft er t h e l a st d o s e 
of  st u d y  a g e nt  ( S e x u al  i n a cti vit y  b y  a b sti n e n c e  m u st  b e  c o n si st e nt  wit h  t h e  
pr ef err e d a n d u s u al lif e st yl e of t h e s u bj e ct.  P eri o di c a b sti n e n c e ( e. g. c al e n d ar, 
o v ul ati o n,  s y m pt ot h er m al,  p o st -o v ul ati o n  m et h o d s)  a n d  wit h dr a w al  ar e  n ot  
a c c e pt a bl e m et h o d s of c o ntr a c e pti o n)  W o m e n w h o h a v e a p art n er w h o i s 
st eril e ( e g, d u e t o v a s e ct o m y).    
W O C B P m u st b e u si n g a n a c c e pt a bl e m et h o d of c o ntr a c e pti o n t o a v oi d pr e g n a n c y fr o m 
t h e ti m e of c o n s e nt wit h < 1 % f ail ur e r at e a s st at e d i n t h e pr o d u ct l a b el t hr o u g h o ut 
st u d y p arti ci p ati o n, a n d f or  1 6 w e e k s aft er t h e l a st d o s e of st u d y dr u g i n s u c h a m a n n er 
t h at t h e ri s k of pr e g n a n c y i s mi ni mi z e d. A c c e pt a bl e m et h o d s of c o ntr a c e pti o n i n cl u d e:  
c o m pl et e  a b sti n e n c e,  a n y  f or m  of  i ntr a -ut eri n e  d e vi c e s  ( wit h o ut  h or m o n e s),  t u b al  
st erili z ati o n or y o ur p art n er h a s h a d a v a s e ct o m y.   
Ot h er a c c e pt a bl e f or m s of birt h c o ntr ol i n cl u d e c h o o si n g o n e h or m o n al a n d o n e b arri er 
m et h o d or d o u bl e -b arri er m et h o d s. B arri er m et h o d s i n cl u d e E s s ur e ®, m al e or f e m al e 
c o n d o m, di a p hr a g m wit h s p er mi ci d e, s hi el d, c a p wit h s p er mi ci d e, c o ntr a c e pti v e s p o n g e, 
a n d  s p er mi ci d al s.  H or m o n al  m et h o d s  i n cl u d e  or al  c o ntr a c e pti v e  pill s,  tr a n s d er m al  
p at c h e s,  v a gi n al  ri n g s,  pr o g e st er o n e -o nl y,  a n d  i nj e cti o n s.   P eri o di c  a b sti n e n c e  (f or  
e x a m pl e, c al e n d ar, o v ul ati o n, s y m pt ot h er m al, p o st -o v ul ati o n m et h o d s) a n d wit h dr a w al 
ar e n ot a c c e pt a bl e m et h o d s of c o ntr a c e pti o n.   
• 
T h e s e  all o w e d  m et h o d s  of  c o ntr a c e pti o n  ar e  o nl y  eff e cti v e  w h e n  u s e d  
c o n si st e ntl y, c orr e ctl y a n d i n a c c or d a n c e wit h t h e pr o d u ct l a b el.  T h e i n v e sti g at or 
i s  r e s p o n si bl e  f or  e n s uri n g  s u bj e ct s  u n d er st a n d  h o w  t o  pr o p erl y  us e  t h e s e  
m et h o d s of c o ntr a c e pti o n.  
• 
W O C B P m u st h a v e a n e g ati v e s er u m pr e g n a n c y t e st r e s ult ( mi ni m u m s e n siti vit y 
2 5 I U/ L or e q ui v al e nt u nit s of H C G) wit hi n 4 8 h o ur s pri or t o tr a n s pl a nt ( a n d t h e 
fir st d o s e of st u d y dr u g i ntr a o p er ati v el y).  
• 
W o m e n m u st n ot b e br e a st -f e e di n g  


8  
  
   
E x cl u si o n   
Crit eri a  
S u bj e ct s ar e e x cl u d e d fr o m t h e st u d y f or t h e f oll o wi n g r e a s o n s:   
  
  
A B O i n c o m p ati bl e d o n or ki d n e y D e c e a s e d 
d o n or   
 
  K D PI 8 5 %  
 
  H L A i d e nti c al or m at c h e d ki d n e y    
 
  Tr a n s pl a nt  ot h er  t h a n  ki d n e y:  h a s  pr e vi o u sl y  r e c ei v e d  a  h e m at o p oi eti c  st e m  
c ell/ m arr o w tr a n s pl a nt or a n or g a n tr a n s pl a nt ot h er t h a n a ki d n e y ( wit h t h e e x c e pti o n 
of c or n e al tr a n s pl a nt ati o n)  
 
  T - a n d/ or B -c ell p o siti v e cr o s s m at c h  b y c o m pl e m e nt d e p e n d e nt c yt ot o xi cit y or fl o w 
c yt o m etr y a g ai n st t h e r e ci pi e nt  
 
  C urr e ntl y o n a n y s u p pr e s si v e t h er a p y f or a c hr o ni c i nf e cti o n ( s. u c h  a s t u b er c ul o si s, 
p n e u m o c y sti s, c yt o m e g al o vir u s, h er p e s si m pl e x vir u s, h er p e s z o st er a n d at y pi c al 
m y c o b a ct eri a).  
 
  H o s pit ali z ati o n f or tr e at m e nt of i nf e cti o n wit hi n 6 0 d a y s of D a y 0  
 
  U s e of p ar e nt er al (I V or I M) a nti bi oti c s ( a nti b a ct eri al s, a nti vir al s, a nti -f u n g al s, or a nti 
p ar a siti c a g e nt s) wit hi n 6 0 d a y s of D a y 0  
 
  H a v e a hi st or y of a pri m ar y i m m u n o d efi ci e n c y  
 
  U n c o ntr oll e d i nf e cti o n or a n y ot h er u n st a bl e m e di c al c o n diti o n t h at c o ul d i nt erf er e 
wit h t h e st u d y  
 
  S er o p o siti v e f or HI V, H C V or H B V, e x c e pt f or h e p atiti s B s urf a c e a nti b o d y p o siti v e. 
If  t h e  HI V,  H C V  or  H B V  s cr e e ni n g  vir ol o g y  r e s ult s  ar e  n ot  a v ail a bl e  pri or  t o  
tr a n s pl a nt ati o n t h e n t h e m o st r e c e nt hi st ori c al r e s ult ( wit hi n t h e l a st 6 m o nt h s) will 
b e u s e d.     
 
  H a v e a si g nifi c a nt I g G d efi ci e n c y (I g G l e v el < 4 0 0 m g/ dl) H a v e a n I g A d efi ci e n c y (I g A 
l e v el < 1 0 m g/ d L)  
 
  Pri or t h er a p y at a n y ti m e: h a s e v er r e c ei v e d a n y of t h e f oll o wi n g:   B -c ell t ar g et e d 
t h er a p y ( e. g., rit u xi m a b, ot h er a nti-C D 2 0 a g e nt s, a nti -C D 2 [ e pr at u z u m a b], a nti C D 5 2 
[ al e mt u z u m a b], B L y S-r e c e pt or f u si o n pr ot ei n [ B R 3], T A CI fr a g m e nt, cr y st alli z a bl e 
( F c), b eli m u m a b), or I V c y cl o p h o s p h a mi d e  
• 
Li v e v a c ci n e s wit hi n 3 0 d a y s  
• 
H a v e  a  hi st or y  of  a n  a n a p h yl a cti c  r e a cti o n  t o  p ar e nt er al  a d mi ni str ati o n  of  
c o ntr a st a g e nt s, h u m a n or m uri n e pr ot ei n s or m o n o cl o n al a nti b o di e s  
• 
P ati e nt s wit h a l y m p h o c yt e c o u nt < 5 0 0/ m m 3  
• 
P ati e nt s wit h e vi d e n c e of c urr e nt dr u g or al c o h ol a b u s e or d e p e n d e n c e.  
• 
P ati e nt s wit h v e n o u s a c c e s s li mit ati o n s li k el y t o pr e cl u d e m o nt hl y i nf u si o n s  
• 
P ati e nt s  w h o m  ar e  u nli k el y  t o  c o m pl y  wit h  s c h e d ul e d  st u d y  vi sit s  b a s e d  o n  
i n v e sti g at or j u d g m e nt or h a s a hi st or y of s u b st a n c e a b u s e, p s y c hi atri c di s or d er 
or c o n diti o n t h at m a y c o m pr o mi s e c o m m u ni c ati o n wit h t h e i n v e sti g at or  
• 
M y o c ar di al i nf ar cti o n wit hi n 6 m o nt h s pri or t o e nr oll m e nt or N e w Y or k H e art 
A s s o ci ati o n ( N Y H A) Cl a s s III or I V h e art f ail ur e, u n c o ntr oll e d  a n gi n a, s e v er e 
u n c o ntr oll e d v e ntri c ul ar arr h yt h mi a s, or el e ctr o c ar di o gr a p h y e vi d e n c e of a c ut e 
i s c h e mi a or a cti v e c o n d u cti o n s y st e m a b n or m aliti e s   
• 
Di a g n o si s of li v er cirr h o si s or c hr o ni c vir al h e p atiti s  


9  
  
• 
F e m al e s u bj e ct i s pr e g n a nt or br e a st -f e e di n g. C o nfir m ati o n t h at t h e s u bj e ct i s 
n ot  pr e g n a nt  m u st  b e  e st a bli s h e d  b y  a  n e g ati v e  s er u m  -h u m a n  c h or i o ni c  
g o n a d otr o pi n  ( -h C G)  pr e g n a n c y  t e st  r e s ult  o bt ai n e d  d uri n g  s cr e e ni n g,  a n d  
m u st b e wit hi n 4 8 h o ur s pri or t o tr a n s pl a nt.  Pr e g n a n c y t e sti n g i s n ot r e q uir e d f or  
p o st m e n o p a u s al or s ur gi c all y st erili z e d w o m e n    
• 
P ati e nt  h a s  r e c ei v e d  ot h er  i n v e sti g ati o n al  dr u g s  wit hi n  3 6 5  d a y s  b ef or e  
e nr oll m e nt    
• 
S eri o u s m e di c al or p s y c hi atri c ill n e s s li k el y t o i nt erf er e wit h p arti ci p ati o n i n t hi s 
cli ni c al st u d y   
• 
H a v e e vi d e n c e of s eri o u s s ui ci d e ri s k i n cl u di n g a n y hi st or y of s ui ci d al b e h a vi or 
i n t h e l a st 6 m o nt h s a n d/ or a n y s ui ci d al i d e ati o n i n t h e l a st 2 m o nt h s or w h o i n 
t h e i n v e sti g at or' s j u d g m e nt, p o s e a si g nifi c a nt s ui ci d e ri s k  
• 
Di a g n o s e d  or  tr e at e d  f or  m ali g n a n c y  wit hi n  5  y e ar s  of  e nr oll m e nt,  wit h  t h e  
e x c e pti o n  of  c o m pl et e  r e s e cti o n  of  b a s al  c ell  c ar ci n o m a  or  s q u a m o u s  c ell  
c ar ci n o m a of t h e s ki n, a n i n sit u m ali g n a n c y, or l o w -ri s k pr o st at e c a n c er aft er 
c ur ati v e t h er a p y.   
• 
H a v e a n y ot h er cli ni c all y si g nifi c a nt a b n or m al l a b or at or y  v al u e i n t h e o pi ni o n of 
t h e i n v e sti g at or  
   
  
  
E nr oll m e nt  
  
Tr e at m e nt 
D e s cri pti o n  
Tr e at m e nt r e gi m e n : Al e mt u z u m a b  a n d st er oi d i n d u cti o n wit h m y c o p h e n oli c a ci d a n d 
t a cr oli m u s m ai nt e n a n c e i m m u n o s u p pr e s si o n p er st a n d ar d of c ar e pl u s b eli m u m a b. 
Al e mt u z u m a b:   Al e mt u z u m a b 3 0 m g I V at ti m e of i n d u cti o n ( D a y 0) d uri n g ki d n e y 
tr a n s pl a nt.  
  
St a n d ar d St er oi d T a p er:    o  D e x a m et h a s o n e 1 0 0 m g I V o n D a y 0,  o  
D e x a m et h a s o n e 5 0 m g I V o n D a y 1 o  D e x a m et h a s o n e 1 8 m g I V o n 
D a y 2  o  D e x a m et h a s o n e 1 2 m g I V o n D a y 3 o  Pr e d ni s o n e 3 0 m g 
o n D a y 4, a n d t h e n t a p er p er st a n d ar d of c ar e.  
• 
M y c o p h e n oli c A ci d ( M yf orti c):   M y c o p h e n oli c a ci d 7 2 0 m g a d mi ni st er e d or all y 
t wi c e-d ail y st arti n g p o st o p er ati v el y o n D a y 0.  M y c o p h e n ol at e m of etil m a y b e 
s u b stit ut e d p er S O C.  D o s e m a y b e a dj u st e d a s cli ni c all y i n di c at e d.  
• 
T a cr oli m u s:  T a cr ol i m u s  will  b e  a d mi ni st er e d  or all y  t wi c e-d ail y  st arti n g  p o st  
o p er a ti v el y o n D a y 0.  D o si n g at di s cr eti o n of PI.   
• 
B eli m u m a b t h er a p y. 1 0 m g/ k g/ d o s e will b e a d mi ni st er e d I V f or 6 m o nt h s at t h e 
f ollo wi n g i nt er v al s: at ti m e of tr a n s pl a nt ( D a y 0), t h e n p o st -tr a n s pl a nt at 2, 4, 8, 
1 2, 1 6, a n d 2 0 w e e k s.  
     
St u d y P ot e nti al s u bj e ct s will b e i d e ntifi e d pri or t o ki d n e y tr a n s pl a nt ati o n. P ot e nti al s u bj e ct s will Pr o c e d ur e s 
b e a p pr o a c h e d a b o ut t h e st u d y b y t h e pri n ci p al, c o -i n v e sti g at or s, or r e s e ar c h st aff.   
  
I nf or m e d c o n s e nt will b e o bt ai n e d b ef or e a n y st u d y s p e cifi c pr o c e d ur e s ar e p erf or m e d.  
   
  
   
  
B eli m u m a b : 1 0 m g/ k g/ d o s e will b e a d mi ni st er e d I V f or 6 m o nt h s at t h e f oll o wi n g  
i nt er v al s: at ti m e of tr a n s pl a nt ( D a y 0), t h e n p o st tr a n s pl a nt at 2, 4, 8, 1 2, 1 6, a n d 2 0 
w e e k s.   


1 0  
  
  
A nti -H L A  A nti b o d y  L e v el s:  A nti -H L A  a nti b o d y  l e v el s  will  b e  m o nit or e d  pri or  t o  
tr a n s pl a nt a n d at 1, 3, 6, 9, a n d 1 2 m o nt h s p o st-tr a n s pl a nt p er st a n d ar d of c ar e, u si n g 
L u mi n e x  mi cr o b e a d s t o d et er mi n e if tr e at m e nt i s eff e cti v e i n d o w n -r e g ul ati n g H L A cl a s s 
I a n d II D S A.   
  
  
Ki d n e y Tr a n s pl a nt Bi o p s y: A tr a n s pl a nt ki d n e y bi o p s y will b e p erf or m e d at ti m e of 
tr a n s pl a nt, a n d at 1 y e ar p o st tr a n s pl a nt p er st a n d ar d of c ar e. R e s ult s will b e c oll e ct e d 
a n d r e c or d e d fr o m t h e el e ctr o ni c m e di c al r e c or d.  
  
P eri p h er al bl o o d : will b e c oll e ct e d pri or t o tr a n s pl a nt, a n d at 1, 3, 6, 9 a n d 1 2 m o nt h s 
a n d st or e d f or f ut ur e st u di e s (if c o n s e nt e d t o) a s d e s cri b e d b el o w.   
  
• 
S er u m B A F F/ A P RI L l e v el s: If t h e s u bj e ct a gr e e s, w e will o bt ai n a s a m pl e f or 
f ut ur e B A F F/ A P RI L l e v el s a n al y si s i n t h e s er u m  c oll e ct e d at b a s eli n e, 1, 3, 6, 9, 
1 2 m o nt h s.   
  
• 
I m m u n o gl o b uli n A n al y si s: Q u a ntifi c ati o n of t ot al s er u m l e v el s of 
I m m u n o gl o b uli n l e v el s (I g M, I g A, a n d I g G) will b e p erf or m e d pri or t o tr a n s pl a nt 
a n d at 1, 3, 6, 9 a n d 1 2 m o nt h s p o st tr a n s pl a nt.   
• 
B L y m p h o c yt e  A n al y si s:  B- c ell F A C S p a n el s will b e u s e d t o m e a s ur e 
c h a n g e s o v er t h e c o ur s e of t h er a p y i n t h e tr a n siti o n al, n aï v e, m e m or y a n d 
pl a s m a c ell c o m p art m e nt s. F or t h e s u b s et s of i nt er e st, a b s ol ut e n u m b er s of 
c ell s a n d pr o p orti o n s r el ati v e t o all B c ell s f or t h e i n di vi d u al s u b s et s will b e 
d et er mi n e d, a s will a cti v ati o n st at u s.  S p e cifi c all y w e will a d dr e s s p eri p h er al 
tr a n siti o n al, n ai v e, m e m or y a n d pl a s m a c ell p o p ul ati o n s pri or t o tr a n s pl a nt a n d 
at 1, 3, 6, 9, a n d 1 2 m o nt h s p o st -tr a n s pl a nt.  F urt h er e x pl or at or y a n al y s e s will 
i n cl u d e t h e e x pr e s si o n of B L y S r e c e pt or s ( B R 3, T A CI a n d B C M A) o n B c ell s, 
fr e q u e n c y of all or e a cti v e B c ell s ( u si n g t etr a m er s) a n d a n a n al y si s of t h e eff e ct 
of b eli m u m a b o n I L -1 0 s e cr eti n g B r e g ul at or y c ell s.  A g ai n t h e s e a s s e s s m e nt s 
m a y b e p erf or m e d pri or t o tr a n s pl a nt a n d at 1, 3, 6, 9, a n d 1 2 m o nt h s p o st - 
tr a n s pl a nt.  
• 
T L y m p h o c yt e A n al y si s:  Si mil ar a s s e s s m e nt s will b e m a d e of T c ell s u b s et s 
pri or t o tr a n s pl a nt a n d at 1, 3, 6, 9, a n d 1 2 m o nt h s p o st -tr a n s pl a nt. S p e cifi c all y 
w e will e v al u at e a cti v at e d T c ell a n d T r e g ul at or y c ell p o p ul ati o n s.   
• 
C yt o ki n e A n al y si s:  Q u a ntifi c ati o n of s er u m B L y S a n d A P RI L l e v el s a n d 
c yt o ki n e s/ c h e m o ki n e s a s s o ci at e d wit h T -h el p er s k e wi n g or a cti v ati o n will b e 
p erf or m e d pri or t o tr a n s pl a nt a n d at 1, 3, 6, 9, a n d 1 2 m o nt h s p o st -tr a n s pl a nt  
  
  
 
1.  B ac k gr o u n d I nf or m ati o n a n d Scie ntific R ati o n ale  
 
1. 1  
B a c k gr o u n d  
  


11  
  
Alloantibody directed against graft MHC antigens is a significant barrier to improving 
long-term kidney allograft survival. It is estimated that greater than 50% of kidney 
allograft failures can be attributed to alloantibody 1. The source of alloantibody 
production are B-lymphocytes. BLyS (B lymphocyte stimulator), is a B cell survival 
factor that is required for B cell survival and differentiation.  De novo donor specific 
antibody (DSA) post kidney transplant is thought to occur in 20-50% of patients at 2 
years and are associated with inferior graft survival 2-6. A major unmet need in the 
kidney transplant field are safe and effective therapies to prevent the emergence of de 
novo MHC donor-specific alloantibody.  
  
Belimumab (GSK1550188) is a recombinant, fully human IgG1λ monoclonal antibody 
that binds soluble BLyS with high affinity and inhibits its biological activity. In vivo, 
neutralization of BLyS blocks the differentiation of transitional B cells to naïve B cells 
and the survival of these B cell subsets, thus reducing the number of B cells in the 
mature resting stage 7. Clinical efficacy of belimumab in SLE has been demonstrated 
through improvements in disease activity, steroid use, and risk of severe flare; 
autoantibody levels decreased with treatment 8. Belimumab has been approved under 
the trade name BENLYSTA™ in the United States, Canada, and the European Union. 
We propose a clinical study whereby BLyS is inhibited with belimumab at the time of 
kidney transplantation in order to prevent the production of de novo DSA.  
  
Support for this hypothesis currently exist in the literature.  1) Preclinical studies in 
murine islet and cardiac transplantation have demonstrated efficacy of murine 
antiBLyS antibody in improving graft survival 9, and an increase in transitional B cells 
with BLyS blockade has been postulated as a potential mechanism for this improved 
graft survival 7,10.  2) Additionally, this transitional B-cell signature has been implicated 
in additional clinical tolerance studies 7,11 and 3) elevated BLyS levels have been 
associated with the development of de novo DSA 4) Additionally, BLyS levels were 
greatest in patients with poorly functioning grafts. It has also been reported that BLyS 
staining on kidney allograft biopsies correlates with staining for complement 
deposition,  and that peripheral BLyS levels correlate with HLA-specific antibody levels 
and poor graft outcome. Elevated BLyS levels pre-transplantation have also correlated 
with an increased risk of AMR post-transplantation.2,12,13,15, 16, 17, 18, 19   
  
Post kidney transplant, the incidence of de novo DSA has been estimated to occur in 
20-50% of patients by 2 years 2-6. Thus, while these patients have an induced level of 
relative T cell quiescence on current immunosuppressive regimens, B cell quiescence, 
as measured by the production of DSA, is not achieved in a large number of kidney 
transplant recipients.  This suggests that current therapies are inadequate to control 
the humoral immune response.  The addition of BLyS inhibition at the time of kidney 
transplant may prove to be a paradigm shift for our transplant recipients and the 
prevention of detrimental de novo DSA.   
  
We therefore propose a clinical study where we will inhibit the B cell survival factor 
BLyS at the time of kidney transplantation, which we hypothesize will prevent the 
differentiation of alloreactive B cells, increase the transitional B cell population, and 
thus prevent the generation of de novo DSA.    
Belimumab (GlaxoSmithKline, Inc.) The common name of the investigational product 
is BENLYSTA. The generic United States Adopted Name / International 


12  
  
NonProprietary Name (USAN/INN) is belimumab; the GlaxoSmithKline (GSK) code for 
the drug is GSK1550188.  Belimumab is reconstituted in 4.8 mL sterile water and 
diluted in normal saline (250 mL). After reconstitution and dilution in normal saline, the 
material is stable for up to 8 hours at 2-8°C, or at room temperature.  
The calculated dose (mg) of investigational product to be administered to the subject 
is determined by the subject's body weight (kg) within 24 hours prior to transplant (Day  
-1 or Day 0). If a subject’s weight increases or decreases by more than 5% from their 
baseline (Day -1 or Day 0) weight, the current weight should be used to calculate the 
dose of investigational product administered. The first dose of investigational product 
will be administered on Day 0, intra-operatively. Where possible, the study drug 
infusion should be completed before reperfusion of the allograft. The dose of 
investigational product administered may not be altered. The rate of infusion may be 
slowed or interrupted if the subject appears to develop signs of adverse reactions or 
infusion-related symptoms. At subsequent visits, if a subject’s weight increases or 
decreases by more than 5% from their baseline weight measured at their previous 
visit, the current weight should be used to calculate the dose of investigational product 
administered and it will be used as the subject’s new baseline weight for their next 
visit. At later visits, these subjects may continue to be infused over a longer infusion 
period at the investigator’s clinical discretion. The rate of infusion should not be 
increased above the recommended rate.  
Investigational product should be administered by the investigator/site personnel 
prepared to manage infusion reactions and anaphylaxis. Investigators/site personnel 
should be aware of the risk of hypersensitivity reactions, which may present as an 
infusion reaction, and monitor subjects closely. Subjects will be monitored during and 
after each infusion according to study site guidelines or standard operating procedure 
for 
any 
untoward 
reactions. 
Trained 
rescue 
personnel 
and 
rescue 
medications/equipment should be available for a minimum of the first 3 doses, and 
subjects should be observed for a minimum of 3 hours after the completion of the 
infusion for the first 3 doses.  
Subjects should also be informed of the signs and symptoms of a hypersensitivity 
reaction, the possibility of a delayed reaction, and be instructed to seek medical care 
should a reaction occur. Delayed-type, non-acute hypersensitivity reactions have also 
been observed and included symptoms such as rash, nausea, fatigue, myalgia, 
headache, and facial edema.  
For subjects who have previously received IV immunoglobulin (IVIG) or subjects with 
a history of allergies (allergic responses to food, drugs, insects, or a history of 
urticaria), diphenhydramine (12.5 to 50 mg based on clinical judgment) or equivalent 
and acetaminophen may be administered prophylactically prior to dosing. 
Antihistamine H2-receptor antagonists (e.g., ranitidine) are also permitted. Sites are 
encouraged to follow their standard practices to manage any untoward infusion 
reactions noted during or after the infusion period.  
 
1.2  
Dose Rationale  
In this study, belimumab will be administered as 10 mg/kg IV infusions dosed at the 
same frequency as in the current labeling for SLE.  
  
The selection of belimumab dose was based on review of pooled analyses of safety, 
efficacy and pharmacokinetic (PK) data from Phase 3 SLE studies. In those studies, 


13  
  
not only for the primary endpoint, but also for some disease activity and flare indices, 
and for certain critical biomarkers (anti-double-stranded deoxyribonucleic acid 
(dsDNA) antibodies, complement levels and B-cell subsets), a dose response 
relationship was seen, with greater differences from placebo for the belimumab 10 
mg/kg group than the belimumab 1 mg/kg group. The differences were more marked 
when only data from subjects with low complement and anti-dsDNA at baseline were 
analyzed 14.  
  
In transplantation, unlike SLE or other autoimmune diseases, the event (reperfusion 
of the allograft) that triggers the pathogenic process is easily identified. In this study, 
to maximize BLyS binding at the time of this triggering event, the first dose of 
investigational product will be administered on the day of transplantation 
intraoperatively. Where possible, study drug infusion should be completed before 
reperfusion of the allograft.   
  
This study will focus on examining the impact of belimumab during the first 6 months 
after transplantation, when episodes of rejection are most likely to occur; 
investigational product will be administered at Day 0, Week 2, Week 4 and then every 
4 weeks through Week 20. Subjects will then be observed through the 1-year study 
period with no further belimumab dosing.  
  
For detailed information of the safety and efficacy of belimumab at each of the doses 
studied, refer to the IB GlaxoSmithKline Document Number 2011N128591_01 
(Investigator's Brochure: Belimumab. Version 11: 20-JUN-2013: always refer to the 
most recent version).  
1.3  Summary of Known and Potential Risks and Benefits to Human Subjects  
  
Belimumab: Belimumab has been generally well tolerated in the Phase 2 and Phase 3 
SLE studies.  The majority of subjects in the SLE studies were receiving concomitant 
corticosteroids and/or other immunosuppressants including azathioprine and 
mycophenolate mofetil (MMF). Precautions will be taken to mitigate the risk of 
infections, infusion and hypersensitivity reactions, and the potential risk of malignancy. 
These precautions will include the use of the ICTR Data Monitoring Committee (DMC), 
which will review subject safety and efficacy data.   
  
Common adverse reactions (≥5%) in clinical trials were: nausea, diarrhea, pyrexia, 
nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and 
pharyngitis. Serious adverse reactions have included: infections, Progressive 
Multifocal Leukoencephalopathy (PML), 
Hypersensitivity 
reactions; 
including 
anaphylaxis, depression.  .   
  
PML   
Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, 
including fatal cases, has been reported in SLE patients receiving immunosuppressant 
pharmacotherapy, including belimumab. A diagnosis of PML should be considered in 
any subject presenting with new-onset or deteriorating neurological signs and 
symptoms. The subject should be referred to a neurologist or other appropriate 
specialist for evaluation. If PML is confirmed, study agent should be discontinued and 
consideration should be given to stopping immunosuppressant therapy.  


14  
  
If PML is suspected, this should be immediately reported to the Medical Monitor. The 
appropriateness of continuing study agent, while the case is being assessed, should 
be discussed.  
  
Suicidality  
Some autoimmune diseases have an increased risk of suicidal behavior and/or 
ideation [Bachen, 2009; Timonen, 2003; Stenager, 1992].  For this reason in studies 
of patients with autoimmune disease, patients should be clinically assessed for suicidal 
ideation and/or behavior at each visit, but not for study purposes. If patient exhibits 
suicidal ideations or it is verbally expressed, the PI will enter a note and refer the 
patient to a psychiatrist.  
  
Dosing  
Infusion reactions occurred more frequently on the first two infusion days and tended 
to decrease with subsequent infusions. Delay in the onset of acute hypersensitivity 
reactions has been observed and recurrence of clinically significant reactions after 
initial resolution of symptoms following appropriate treatment, have been observed.  
Therefore, patients should remain under clinical supervision for 3 hours after 
completion of the first 2 IV infusions.  Should symptoms of acute hypersensitivity occur, 
an extended period of monitoring may be appropriate, based on clinical judgment. This 
may include, but is not limited to, monitoring vital signs and observing any untoward 
reactions. Beyond the first 2 IV infusions, subjects should be monitored during and for 
an appropriate period of time after administration according to the study sites’ 
guidelines or standard operating procedure for IV infusions. Patients treated with 
belimumab should be made aware of the potential risk, the signs and symptoms of 
such reactions, and the importance of immediately seeking medical attention. 
Delayed-type, non-acute hypersensitivity reactions have also been observed and 
included symptoms such as rash, nausea, fatigue, myalgia, headache, and facial 
oedema.  
  
For additional information on the risks associated with belimumab, refer to the 
package insert for Benlysta® (GlaskoSmithKlein) at: 
https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing 
_Information/Benlysta/pdf/BENLYSTA-PI-MG.PDF  
  
In this study, belimumab will be administered in combination with standard of care 
immunosuppressants, which will include alemtuzumab, tacrolimus, mycophenolic acid 
and corticosteroids (standard taper) for all study subjects. There has been no 
experience with the use of alemtuzumab or tacrolimus in combination with belimumab, 
while there are data on the use of belimumab in combination with MMF and/or 
corticosteroids. As with all immunosuppressants, each of these agents has the 
potential to be associated with infections and/or malignancy.  
  
  
Alemtuzumab:  The most common adverse events associated with alemtuzumab are:  
• 
Infusion reactions including moderate fever and chills  
• 
Leukopenia  
  


15  
  
As with all immunosuppression, administration of alemtuzumab may be associated 
with an increased risk of infection and the development of malignancy (especially of 
the skin and lymphoid system).  Alemtuzumab (30 mg IV x 1) is standard induction 
immunosuppression for both cadaveric and living-donor renal transplants at many 
centers.  
  
In 251 kidney-transplant recipients receiving alemtuzumab induction (30 mg IV x 1), 
the adverse events did not differ significantly between patients treated with 
alemtuzumab, anti-thymocyte globulin and basiliximab.  The principal side effects were 
leucopenia (57%) and infection (32%).  CMV infection occurred in 13% of the recipients 
and PTLD in two of the recipients.   
  
The carcinogenic effects and the effect of alemtuzumab on fertility have not been 
established. Alemtuzumab is contraindicated in patients who have active acute or 
chronic infections that contraindicate any additional immunosuppression.  
  
For additional information on the risks associated with alemtuzumab, refer to the 
package insert for Campath® (Genzyme Corporation) at the following website:  
http://www.campath.com/pdfs/2009-08-Campath%20US%20PI.pdf  
  
Tacrolimus: The following risks are associated with the administration of tacrolimus:  
• 
Hypertension.  
• 
Hyperkalemia.  
• 
Nephrotoxicity.  
• 
Neurotoxicity.  
• 
Post-transplant insulin-independent diabetes mellitus.  
• 
Myocardial hypertrophy (in most cases reversible upon dose reduction).  
• 
Increased risk of renal insufficiency in patients with hepatic impairment.  
• 
Increased susceptibility to infection.  
For additional information on the risks of tacrolimus, refer to the Prograf® package 
insert at the following website: http://www.astellas.us/docs/prograf.pdf.  
  
Mycophenolic Acid:  The following risks are associated with the use of mycophenolic 
acid are:  
• 
Increased risk of developing lymphomas, lymphoproliferative diseases and other  
malignancies especially of the skin in patients receiving MMF as part of an  
immunosuppressive regimen. The risk appears to be related to the intensity and  
duration of immunosuppression rather than to the use of any specific agent.  
• 
Increased susceptibility to infection, including opportunistic infections, fatal  
infections and sepsis.  
• 
Increased risk of developing latent viral infections including Progressive  Multifocal 
Leukoencephalopathy (PML) and BK virus- associated nephropathy.  
• 
Increased risk of first trimester pregnancy loss and congenital malformations,  
especially of the external ear, face, limbs, heart esophagus and kidneys. • 
Increased risk of neutropenia and leukopenia  
• 
Increased risk of gastrointestinal bleeding.  
  
Common side effects associated with use of MMF include diarrhea, abdominal pain, 
nausea and vomiting, headache and drug induced fever.   


16  
  
For additional information about the risks of mycophenolic acid, refer to the Myfortic® 
package insert at the following website:  
http://www.pharma.us.novartis.com/product/pi/pdf/myfortic.pdf  
  
Dexamethasone: Side effects of dexamethasone include convulsions, headache, 
vertigo, mood swings, psychosis, congestive heart failure (CHF), hypertension, salt 
and water retention, increased potassium excretion, Cushing syndrome, menstrual 
irregularities, hyperglycemia, GI irritation, peptic ulcer, weight gain.  Dermatologic 
effects may include thin skin, petechiae, ecchymosis, facial erythema, poor wound 
healing, hirsutism and urticaria.  Muscle weakness, loss of muscle mass and 
osteoporosis may also occur.  Ophthalmologic complications may include increased 
intraocular pressure, glaucoma, exophthalmos and cataracts.  Other complications 
may include immunosuppression and increased susceptibility to infection.  
For further information about the risks associated with dexamethasone, please refer to 
the package insert at the following website:  
http://www.americanregent.com/documents/Product15PrescribingInformation.pdf  
  
 
2.  Objectives  
  
We propose an open-label, single-arm, pilot study to test whether the addition of 
belimumab, to inhibit the B cell survival factor BLyS at the time of kidney 
transplantation, to standard or care therapy (alemtuzumab and steroid induction with 
mycophenolic acid and tacrolimus maintenance immunosuppression) will prevent the 
prevent the generation of de novo DSA.  
  
 
3.  Study Design  
 
3.1  
Description  
We propose an open-label, single-arm pilot study to examine the addition of 
belimumab at induction to our standard of care regimen of alemtuzumab and steroid 
induction 
followed 
by 
tacrolimus 
and 
mycophenolic 
acid 
maintenance 
immunosuppression in adult living donor kidney transplant recipients to assess its 
ability to induce functional B-cell transplant tolerance: prevent the generation of de 
novo DSA.  Significant support for this hypothesis exists in the literature including 1) 
the successful induction of transplant tolerance in a preclinical model [9], 2) the 
transitional B cell tolerance signature [11] 3) the association of elevated BLyS levels 
with the development of de novo DSA post kidney transplant [2, 12, 13].   Our study 
population will consist of sensitized adult kidney transplant recipients: PRA>0 and/or 
sum DSA<1000 MFI. The primary endpoint of this study is de novo DSA production.    
  
There are two main reasons for selecting this patient population for our proposed 
study.  1) Sensitized patients are known to have higher rates of de novo DSA 
production and 2) excluding patients with lower levels of DSA (sum DSA<1000 MFI) 
will enable more fidelity in determining the DSA that is produced de novo.  
  
Additionally, we contend that alemtuzumab should be the induction agent of choice for 
this study instead of Thymoglobulin for three reasons. 1) In the United States it is 
provided at no cost and is easy to administer (a single 30mg dose is given 


17  
  
intravenously with no central venous access required).  This cuts down significantly on 
cost as opposed to Thymoglobulin.  2) Mechanistically, more support exists in the 
literature for the use of alemtuzumab rather than Thymoglobulin.  BLyS levels have 
been shown to significantly increase after alemtuzumab induction as opposed to 
Thymoglobulin induction, and lastly, 3) de novo DSA production appears to be ~50% 
at 2 years with alemtuzumab (potentially due to the increase BLyS levels).  Therefore, 
we are potentially more likely to show a reduction in DSA levels (the primary endpoint) 
compared to our control cohort.  
  
We will collect blood samples prior to transplant, then 1, 3, 6, 9 and 12 months to 
measure anti-HLA antibodies and BAFF/APRIL levels. In addition, we will collect 
protocol kidney biopsies at time of transplant and at 1-year post transplant.  
 
3.2  
Study Endpoints  
  
 
   
3.2.1 Primary Endpoints  
The primary endpoint of this study is de novo DSA production at 1, 3, 6, 9, and 12 months.  
  
3.2.2 Secondary Endpoints  
  
Secondary endpoints will be 1) graft survival and function as determined by serum 
creatinine/eGFR and urine protein at 1, 3, 6, 9, and 12 months 2) rates of acute cellular 
and antibody mediated rejection at 1, 3, 6, 9, and 12 months and 3) the nature, frequency, 
and severity of serious and non-serious adverse events ≥Grade 2.  
 
3.3  
Study Population  
Subjects 18-60 years of age receiving a living donor kidney transplant who are 
sensitized by pregnancy, transfusions, or prior transplant: PRA>0% and/or sum 
DSA<1000 MFI.    
 
3.4  
Screening and Enrollment  
This research study will be explained in lay language to each potential research 
participant. The participant will sign an informed consent prior to any screening study 
procedures. After written consent is obtained, subjects who are deemed to qualify for the 
study will be enrolled. Potential subjects will be invited to participate initially via phone or 
in person by study personnel to briefly explain the study. If the potential subject agrees, 
the study personnel will go through the consent form and answer questions. The study 
personnel will ask the potential subject if they would like to be in the study.  If the subject 
agrees to participate, they will be informed about signing the consent and setting up 
study visits.  
 
3.5  
Criteria for Discontinuation   
It is understood by all concerned that an excessive rate of withdrawals can render the 
study uninterpretable; therefore, unnecessary withdrawal of subjects should be 
avoided.  
In addition to the reasons for withdrawal provided below, subjects are free to withdraw 
from treatment or from the study at any time for any reason or may be withdrawn if 
necessary to protect their health.  


18  
  
Subjects who withdraw from the study or study treatment after receiving at least one 
dose of investigational product will continue to be followed up until the end of the study.  
Reasons for withdrawal may include the following:  
• 
Prohibited concurrent medication or therapy  
• 
Prior therapy at any time: has ever received any of the following:   B-cell targeted 
therapy (e.g., rituximab, other anti-CD20 agents, anti-CD2 [epratuzumab], anti-
CD52 [alemtuzumab], BLyS-receptor fusion protein [BR3], TACI fragment, 
crystallizable (Fc), or belimumab)  
• 
Live vaccines within 30 days  
• 
Unacceptable toxicity as assessed by the PI  
Study drug must be discontinued if the investigator determines that continuing it would 
result in a significant safety risk for that patient.  Subjects MUST discontinue 
investigational product for any of the following reasons:  
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason).  
• 
Any clinical adverse event, clinically stignificant laboratory abnormality, or 
concurrent illness, which, in the opinion of the investigator, indicates that continued 
participation in the study is not in the best interest of the subject.  
• 
Pregnancy - Instruct WOCBP (Women of Child Bearing Potential) to contact the 
investigator or study staff immediately if they suspect they might be pregnant (e.g., 
missed or late menstrual period) at any time during study participation. The 
investigator must immediately notify GlaxoSmithKline if a study subject becomes 
pregnant. The pregnancy must be followed up to determine outcome (including 
premature termination) and status of mother and child.  Pregnancy complications 
and elective terminations for medical reasons must be reported as an AE or SAE.  
Spontaneous abortions must be reported as an SAE. Any SAE occurring in 
association with a pregnancy brought to the investigator’s attention after the 
subject has completed the study and considered by the investigator as possibly 
related to the study treatment, must be reported to GSK within 24 hours.  
• 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious 
disease) illness.  
• 
AE(s) (including infections, abnormal laboratory value(s), abnormal test procedure 
result(s) including ECG abnormalities, unsatisfactory death, significant protocol 
deviation, withdrawal of consent, or lost to follow-up, according to the criteria 
specified above.  
• 
Malignancy (except non-melanoma skin cancer)  
  
In addition to these requirements for study drug discontinuation, the investigator should 
discontinue study drug for a given patient if, in his/her professional judgment, it is felt 
that continuation would be detrimental to the patient’s well-being.  
  
Patients may withdraw from the study for any reason at any time.  
All subjects who discontinue should comply with any protocol-specified follow-up 
procedures. The only exception to this requirement is when a subject withdraws 
consent for all study procedures or loses the ability to consent freely (i.e., is imprisoned 


19  
  
or involuntarily incarcerated for the treatment of either a psychiatric or physical illness). 
If a subject withdraws before completing the study, the reason for withdrawal must be 
documented appropriately.   
3.5.1 Discontinuation of study treatment and premature patient withdrawal  
  
Patients may voluntarily withdraw from the study treatment or from the study for any 
reason at any time.  They may be considered withdrawn from the study if they state 
an intention to withdraw, fail to return for visits, or become lost to follow-up for any 
other reason.  If premature withdrawal occurs for any reason, the investigator must 
make every effort to determine the primary reason for a patient’s premature withdrawal 
from the study.  The investigator should discontinue study treatment for a given patient 
or withdraw the patient from study if, on balance, he/she believes that continuation 
would be detrimental to the patient’s well-being.  Patients who discontinue study 
treatment should NOT be considered withdrawn from the study and should continue 
to be followed until the end of the study, unless consent is withdrawn.  Patients who 
are prematurely withdrawn from the study will not be replaced by an equal number of 
newly enrolled patients.  
 
3.6  
Criteria for Terminating the Study  
The Principal Investigator will review safety and efficacy criteria on an ongoing basis. 
The study enrollment will be halted and data reviewed by the Data Safety Monitoring 
Committee and the University of Wisconsin Health Sciences Institutional Review 
Board for any of the following:  
   
1) If greater than two patients are discontinued from study treatment due to 
elevated liver function tests as described in the protocol.  
2) If greater than two patients develop hypogammaglobulinermia and infectious 
complications resulting in discontinuation of study treatment  3)  Death of one 
or more patients.  
  
 After this review, the Investigator, Data Safety Monitoring Committee and the IRB will 
jointly make a final determination regarding continuation, modification, or termination 
of the study. The study can be terminated at any time for any reason by the Principle 
Investigator or GlaxoSmithKline, Inc.  Should this be necessary, the patient should be 
seen as soon as possible.  The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection 
of the patient’s interests.  The investigator will be responsible for informing the DMC, 
IRB and the FDA of the early termination of the trial.  
  
See Section 7.3 for information on the ICTR Data Monitoring Committee (DMC) for this 
study.  
  
 
4.  Selection of Subjects  
Potential subjects will be identified prior to kidney transplant based on the following 
inclusion and exclusion criteria.   


20  
  
 
4.1  
Inclusion Criteria  
• 
Male or female subjects 18-60 years of age  
• 
Planned to receive a living donor kidney transplant   
• 
Sensitized patients: Positive sum DSA <1000, and/or PRA>0%.  
• 
Subjects must be capable of understanding the purpose and risks of the study and 
must sign a statement of informed consent.  
• 
Female subjects must be post-menopausal, surgically sterilized, or she and/or 
sexual partner must be willing to use an acceptable method of birth control with a 
<1% failure rate as stated in the product label from time of study consent, during  
study participation, and for 16 weeks after the last dose of the study agent (i.e., 
contraceptive subdermal implant of levonorgestrel or etonogestrel, intrauterine 
device or intrauterine system, combined estrogen and progestogen oral 
contraceptive, Injectable progestogen, contraceptive vaginal ring, percutaneous 
contraceptive patches, or abstinence) for the duration of the study.  Male partner 
sterilization with documentation of azoospermia prior to the female subject's entry 
into the study, and this male is the sole partner for that subject.  The documentation 
of male sterility can come from the site personnel’s: review of subject’s medical 
records, medical examination and/or semen analysis, or medical history interview 
provided by her or her partner.  Note:  Mycophenolate mofetil (MMF) affects the 
metabolism of oral contraceptives and may reduce their effectiveness. As such, 
women receiving MMF who are using oral contraceptives for birth control should 
employ an additional method (e.g., barrier method). Mycophenolate can cause 
fetal harm when administered to a pregnant female. Use of mycophenolate during 
pregnancy is associated with an increased risk of first trimester pregnancy loss and 
an increased risk of congenital malformations. Mycophenolate affects the 
metabolism of oral contraceptives and may reduce their effectiveness. As such, 
women receiving MMF who are using oral contraceptives for birth control should 
employ an additional method (e.g., barrier method) resulting in two reliable forms 
of contraception being used simultaneously before starting study treatments, 
during therapy, and for 6 weeks after stopping therapy; unless abstinence is the 
chosen method of contraception  
• 
Female patients of childbearing potential must have a negative serum pregnancy 
test within 48 hours of transplant.  Must be willing to use contraceptives from the 
time of study consent, during study participation, and for 16 weeks after the last 
dose of study agent. For sexually active men, condoms should be used during, and 
for at least 90 days after cessation of mycophenolate treatment. No sperm donation 
should be made during this period of time. For female partners of male subjects, it 
is recommended to use highly effective contraception during treatment and for 90 
days after the last dose of mycophenolate  
• 
No blood donation should be made by the study subjects during mycophenolate 
treatment and for at least 6 weeks after stopping mycophenolate treatment  
• 
If stricter female or male contraception requirements are specified in the 
countryspecific label for any study related therapies, they must be followed.  
  
• 
Male subjects must agree to use an acceptable method for contraception for the 
duration of the study.  
  


2 1  
  
F e m al e p ati e nt s of c hil d b e ari n g p ot e nti al m u st h a v e a n e g ati v e s er u m pr e g n a n c y t e st 
wit hi n 4 8 h o ur s of tr a n s pl a nt.  M u st b e willi n g t o u s e c o ntr a c e pti v e s fr o m t h e ti m e of 
st u d y c o n s e nt, d uri n g st u d y p arti ci p ati o n, a n d f or 1 6 w e e k s aft er t h e l a st d o s e of st u d y 
a g e nt.  R e pr o d u cti v e St at u s: D efi niti o n of W o m e n of C hil d -B e ari n g P ot e nti al ( W O C B P). 
W O C B P  c o m pri s e s  w o m e n  w h o  h a v e  e x p eri e n c e d  m e n ar c h e  a n d  w h o  h a v e  n ot  
u n d er g o n e s u c c e s sf ul s ur gi c al st erili z ati o n ( h y st er e ct o m y, bil at er al t u b al li g ati o n, or 
bil at er al o o p h or e ct o m y) or w h o ar e n ot p o st -m e n o p a u s al ( s e e d efi niti o n b el o w).  
  
P o st- m e n o p a u s e i s d efi n e d a s:   
• 
W o m e n w h o h a v e h a d a m e n orr h e a f or  1 2 c o n s e c uti v e m o nt h s ( wit h o ut a n ot h er 
c a u s e)  a n d  w h o  h a v e  a  d o c u m e nt e d  s er u m  f olli cl e -sti m ul ati n g  h or m o n e  ( F S H)  
l e v el > 3 5 mI U/ m L.  
• 
W o m e n w h o h a v e irr e g ul ar m e n str u al p eri o d s a n d a d o c u m e nt e d s er u m F S H l e v el 
> 3 5 mI U/ m L.  
• 
W o m e n w h o ar e t a ki n g h or m o n e r e pl a c e m e nt t h er a p y ( H R T).  
  
T h e f oll o wi n g w o m e n ar e W O C B P:  
• 
W o m e n u si n g t h e f oll o wi n g m et h o d s t o pr e v e nt pr e g n a n c y: Or al c o ntr a c e pti v e s, 
ot h er h or m o n al c o ntr a c e pti v e s ( v a gi n al pr o d u ct s, s ki n p at c h e s, or i m pl a nt e d or 
i nj e ct a bl e pr o d u ct s), or m e c h a ni c al pr o d u ct s s u c h a s i ntr a ut eri n e d e vi c e s or b arri er 
m et h o d s ( di a p hr a g m, c o n d o m s, s p er mi ci d e s).  
• 
W o m e n  w h o  ar e  pr a cti ci n g  a b sti n e n c e  fr o m  i nt er c o ur s e  fr o m  2  w e e k s  pri or  t o  
a d mi ni str ati o n of t h e 1 st d o s e of st u d y a g e nt u ntil 1 6 w e e k s aft er t h e l a st d o s e of 
st u d y a g e nt ( S e x u al i n a cti vit y b y a b sti n e n c e m u st b e c o n si st e nt wit h t h e pr ef err e d 
a n d u s u al lif e st yl e of t h e s u bj e ct.  P eri o di c a b sti n e n c e ( e. g. c al e n d ar, o v ul ati o n, 
s y m pt ot h er m al,  p o st -o v ul ati o n  m et h o d s)  a n d  wit h dr a w al  ar e  n ot  a c c e pt a bl e 
m et h o d s of c o ntr a c e pti o n)  W o m e n w h o h a v e a p art n er w h o i s st eril e ( e. g., d u e 
t o v a s e ct o m y).   
W O C B P m u st b e u si n g a n a c c e pt a bl e m et h o d of c o ntr a c e pti o n t o a v oi d pr e g n a n c y 
fr o m t h e ti m e of c o n s e nt wit h < 1 % f ail ur e r at e a s st at e d i n t h e pr o d u ct l a b el t hr o u g h o ut 
st u d y p arti ci p ati o n, a n d f or  1 6 w e e k s aft er t h e l a st d o s e of st u d y dr u g i n s u c h a m a n n er 
t h at t h e ri s k of pr e g n a n c y i s mi ni mi z e d. A c c e pt a bl e m et h o d s of c o ntr a c e pti o n i n cl u d e:  
c o m pl et e  a b sti n e n c e,  a n y  f or m  of  i ntr a -ut eri n e  d e vi c e s  ( wit h o ut  h or m o n e s),  t u b al  
st erili z ati o n or y o ur p art n er h a s h a d a v a s e ct o m y.   
Ot h er a c c e pt a bl e f or m s of birt h c o ntr ol i n cl u d e c h o o si n g o n e h or m o n al a n d o n e b arri er 
m et h o d or d o u bl e -b arri er m et h o d s. B arri er m et h o d s i n cl u d e E s s ur e ®, m al e or f e m al e 
c o n d o m,  di a p hr a g m  wit h  s p er mi ci d e,  s hi el d,  c a p  wit h  s p er mi ci d e,  c o ntr a c e pti v e  
s p o n g e,  a n d  s p er mi ci d al s.  H or m o n al  m et h o d s  i n cl u d e  or al  c o ntr a c e pti v e  pill s,  
tr a n s d er m al  p at c h e s,  v a gi n al  ri n g s,  pr o g e st er o n e-o nl y,  a n d  i nj e cti o n s.   P eri o di c  
a b sti n e n c e (f or e x a m pl e, c al e n d ar, o v ul ati o n, s y m pt ot h er m al, p o st -o v ul ati o n m et h o d s) 
a n d wit h dr a w al ar e n ot a c c e pt a bl e m et h o d s of c o ntr a c e pti o n.   
• 
T h e s e all o w e d m et h o d s of c o ntr a c e pti o n ar e o nl y eff e cti v e w h e n u s e d c o n si st e ntl y, 
c orr e ctl y a n d i n a c c or d a n c e wit h t h e pr o d u ct l a b el.  T h e i n v e sti g at or i s r e s p o n si bl e 
f or  e n s uri n g  s u bj e ct s  u n d er st a n d  h o w  t o  pr o p erl y  u s e  t h e s e  m et h o d s  of  
c o ntr a c e pti o n.  


2 2  
  
• 
W O C B P m u st h a v e a n e g ati v e s er u m pr e g n a n c y t e st r e s ult ( mi ni m u m s e n siti vit y 
2 5 I U/ L or e q ui v al e nt u nit s of H C G) wit hi n 4 8 h o ur s pri or t o tr a n s pl a nt ( a n d t h e fir st 
d o s e of st u d y dr u g i ntr a o p er ati v el y). W o m e n m u st n ot b e br e a st -f e e di n g  
 
4. 2  
E x cl u si o n Crit e ri a  
• 
A B O i n c o m p ati bl e d o n or ki d n e y  
• 
D e c e a s e d d o n or   
•  
K D PI8 5 %  
• 
H L A i d e nti c al or m at c h e d ki d n e y    
• 
Tr a n s pl a nt  ot h er  t h a n  ki d n e y:  h a s  pr e vi o u sl y  r e c ei v e d  a  h e m at o p oi eti c  st e m  
c ell/ m arr o w  tr a n s pl a nt  or  a n  or g a n  tr a n s pl a nt  ot h er  t h a n  a  ki d n e y  ( wit h  t h e  
e x c e pti o n of c or n e al tr a n s pl a nt ati o n)  
•  
T- a n d/ or B -c ell p o siti v e cr o s s m at c h b y c o m pl e m e nt d e p e n d e nt c yt ot o xi cit y or fl o w 
c yt o m etr y a g ai n st t h e r e ci pi e nt  
• 
C urr e ntl y o n a n y s u p pr e s si v e t h er a p y f or a c hr o ni c i nf e cti o n ( s u c h a s t u b er c ul o si s, 
p n e u m o c y sti s, c yt o m e g al o vir u s, h er p e s si m pl e x vir u s, h er p e s z o st er a n d at y pi c al 
m y c o b a ct eri a).  
• 
H o s pit ali z ati o n f or tr e at m e nt of i nf e cti o n wit hi n 6 0 d a y s of D a y 0  
• 
U s e of p ar e nt er al (I V or I M) a nti bi oti c s ( a nti b a ct eri al s, a nti vir al s, a nti -f u n g al s, or 
a nti p ar a siti c a g e nt s) wit hi n 6 0 d a y s of D a y 0  
• 
H a v e a hi st or y of a pri m ar y i m m u n o d efi ci e n c y  
• 
U n c o ntr oll e d i nf e cti o n or a n y ot h er u n st a bl e m e di c al c o n diti o n t h at c o ul d i nt erf er e  
wit h t h e st u d y  
• 
S er o p o siti v e f or HI V, H C V or H B V, e x c e pt f or h e p atiti s B s urf a c e a nti b o d y p o siti v e 
If  t h e  HI V,  H C V  or  H B V  s cr e e ni n g  vir ol o g y  r e s ult s  ar e  n ot  a v ail a bl e  pri or  t o  
tr a n s pl a nt ati o n t h e n t h e m o st r e c e nt hi st ori c al r e s ult ( wit hi n t h e l a st 6 m o nt hs) will 
b e u s e d.   
• 
H a v e a si g nifi c a nt I g G d efi ci e n c y (I g G l e v el < 4 0 0 m g/ dl) H a v e a n I g A d efi ci e n c y 
(I g A l e v el < 1 0 m g/ d L)  
• 
Pri or t h er a p y at a n y ti m e: h a s e v er r e c ei v e d a n y of t h e f oll o wi n g: a) B -c ell t ar g et e d 
t h er a p y  ( e. g.,  rit u xi m a b,  ot h er  a nti-C D 2 0  a g e nt s,  a nti -C D 2  [ e pr at u z u m a b],  
a nti C D 5 2 [ al e mt u z u m a b], B L y S -r e c e pt or f u si o n pr ot ei n [ B R 3], T A CI fr a g m e nt,  
cr y st alli z a bl e ( F c), b eli m u m a b), or I V c y cl o p h o s p h a mi d e  
• 
Li v e v a c ci n e s wit hi n 3 0 d a y s  
• 
H a v e a hi st or y of a n a n a p h yl a cti c r e a cti o n t o p ar e nt er al a d mi ni str ati o n of c o ntr a st 
a g e nt s, h u m a n or m uri n e pr ot ei n s or m o n o cl o n al a nti b o di e s  
• 
P ati e nt s wit h a l y m p h o c yt e c o u nt < 5 0 0/ m m 3  
• 
P ati e nt s wit h e vi d e n c e of c urr e nt dr u g or al c o h ol a b u s e or d e p e n d e n c e.   
• 
P ati e nt s wit h v e n o u s a c c e s s li mit ati o n s li k el y t o pr e cl u d e m o nt hl y i nf u si o n s  
• 
P ati e nt s  w h o m  ar e  u nli k el y  t o  c o m pl y  wit h  s c h e d ul e d  st u d y  vi sit s  b a s e d  o n  
i n v e sti g at or j u d g m e nt or h a s a hi st or y of s u b st a n c e a b u s e, p s y c hi atri c di s or d er or 
c o n diti o n t h at m a y c o m pr o mi s e c o m m u ni c ati o n wit h t h e i n v e sti g at or  
• 
M y o c ar di al i nf ar cti o n wit hi n 6 m o nt h s pri or t o e nr oll m e nt or N e w Y or k H e art  
A s s o ci ati o n ( N Y H A) Cl a s s III or I V h e art f ail ur e, u n c o ntr oll e d a n gi n a, s e v er e  
u n c o ntr oll e d  v e ntri c ul ar  arr h yt h mi a s,  or  el e ctr o c ar di o gr a p h y  e vi d e n c e  of  a c ut e  
i s c h e mi a or a cti v e c o n d u cti o n s y st e m a b n or m aliti e s   
• 
Di a g n o si s of li v er cirr h o si s or c hr o ni c vir al h e p atiti s  


2 3  
  
• 
F e m al e s u bj e ct i s pr e g n a nt or br e a st -f e e di n g. C o nfir m ati o n t h at t h e s u bj e ct i s n ot 
pr e g n a nt  m u st  b e  e st a bli s h e d  b y  a  n e g ati v e  s er u m  -h u m a n  c h ori o ni c  
g o n a d otr o pi n  ( -h C G )  pr e g n a n c y  t e st  r e s ult  o bt ai n e d  d uri n g  s cr e e ni n g.   
Pr e g n a n c y  t e sti n g  i s  n ot  r e q uir e d  f or  p o st -m e n o p a u s al  or  s ur gi c all y  st erili z e d  
w o m e n    
• 
P ati e nt h a s r e c ei v e d ot h er i n v e sti g ati o n al dr u g s wit hi n 3 6 5 d a y s b ef or e e nr oll m e nt    
• 
S eri o u s m e di c al or p s y c hi atri c ill n e s s li k el y t o i nt erf er e wit h p arti ci p ati o n i n t hi s 
cli ni c al st u d y  
• 
H a v e e vi d e n c e of s eri o u s s ui ci d e ri s k i n cl u di n g a n y hi st or y of s ui ci d al b e h a vi or i n 
t h e l a st 6 m o nt h s a n d/ or a n y s ui ci d al i d e ati o n i n t h e l a st 2 m o nt h s or w h o i n t h e 
i n v e sti g at or' s j u d g m e nt, p o s e a si g nifi c a nt s ui ci d e ri s k  
• 
Di a g n o s e d  or  tr e at e d  f or  m ali g n a n c y  wit hi n  5  y e ar s  of  e nr oll m e nt,  wit h  t h e  
e x c e pti o n  of  c o m pl et e  r e s e cti o n  of  b a s al  c ell  c ar ci n o m a  or  s q u a m o u s  c ell  
c ar ci n o m a  of  t h e  s ki n,  a n  i n  sit u  m ali g n a n c y,  or  l o w -ri s k  pr o st at e  c a n c er  aft er  
c ur ati v e t h er a p y.  
• 
H a v e a n y ot h er cli ni c all y si g nifi c a nt a b n or m al l a b or at or y v al u e i n t h e o pi ni o n of t h e 
i n v e sti g at or  
  
 
5.  Tre at me nt  
 
5. 1  
I m m u n o s u p pr e s si o n Pr ot o c ol  
T h e  i m m u n o s u p pr e s si v e  t h er a p y  will  c o n si st  of  t h e  st a n d ar d  of  c ar e  ( S O C)  
al e mt u z u m a b  a n d  st er oi d  i n d u cti o n  wit h  m y c o p h e n oli c  a ci d  a n d  t a cr oli m u s  
m ai nt e n a n c e  i m m u n o s u p pr e s si o n  a n d  b eli m u m a b  1 0  m g/ k g  I V  a d mi ni st er e d  f or  6  
m o nt h s at t h e f oll o wi n g i nt er v al s: at ti m e of tr a n s pl a nt ( D a y 0), t h e n p o st -tr a n s pl a nt at 
2, 4, 8, 1 2, 1 6, a n d 2 0 w e e k s.  
  
 
5. 1. 1  
A nti b a ct eri al, a nti vir al, a n d a ntif u n g al pr o p h yl a xi s   
A nti b a ct eri al, a nti vir al f or C M V pr o p h yl a xi s, a n d a ntif u n g al pr o p h yl a xi s t h er a p y will b e 
a d mi ni st er e d  a n d  a dj u st e d  p er  i n stit uti o n al  st a n d ar d  of  c ar e.  R e c o m m e n d e d  
pr o p h yl a xi s p er c urr e nt i n stit uti o n al st a n d ar d of c ar e i n cl u d e s:  
• 
A nti b a ct eri al pr o p h yl a xi s: S ulf a -Tri m et h o pri m D o u bl e Str e n gt h ( B a ctri m D S)  
8 0 0 -1 6 0 M G p er t a bl et d ail y f or o n e y e ar  
• 
A nti vir al C M V pr o p h yl a xi s p er d o n or/r e ci pi e nt C M V ri s k pr ofil e:    
o  Hi g h or m o d er at e C M V ri s k: D o n or s er o p o siti v e/ R e ci pi e nt s er o n e g ati v e 
[ D +/ R-], D o n or s er o p o siti v e/ R e ci pi e nt s er o p o siti v e [ D +/ R +], or D o n or 
s er o n e g ati v e/ R e ci pi e nt s er o p o siti v e [ D -/ R +]:   
 V al g a n ci cl o vir 9 0 0 m g or all y d ail y f or 6 m o nt h s. D o si n g a dj u st e d 
f or r e n al f u n cti o n.  
o  L o w C M V ri s k: D o n or s er o n e g ati v e/ R e ci pi e nt s er o n e g ati v e [ D -/ R-]:   
 A c y cl o vi r 4 0 0 m g t wi c e d ail y or all y f or 3 m o nt h s. D o si n g a dj u st e d 
f or r e n al f u n cti o n.  
• 
A ntif u n g al pr o p h yl a xi s:   
o  N y st ati n 5 m L s wi s h a n d s w all o w f or o n e m o nt h  
  


2 4  
  
 
5. 1. 2  
Tr e at m e nt m o nit ori n g a n d d o s e m o dif yi n g str at e gi e s   
T h e  f oll o wi n g  A E s,  l a b or at or y  a s s e s s m e nt  r e s ult s  or  c h a n g e s  i n  c o n c urr e nt  
m e di c ati o n s r e q uir e e v al u ati o n a n d di s c u s si o n wit h t h e G S K m e di c al m o nit or wit hi n 2 4 
h o ur s of t h e i n v e sti g at or b e c o mi n g a w ar e of t h e e v e nt.  
D o s e A dj u st m e nt a n d Di s c o nti n u ati o n  
If a s u bj e ct e x p eri e n c e s a cli ni c all y si g nifi c a nt A E a n d t hi s A E c o nti n u e s at t h e n e xt 
s c h e d ul e d d o s e, or c o ul d p ot e nti all y b e e x a c er b at e d b y t h e n e xt d o s e, t h e i n v e sti g at or 
m a y d el a y t h e n e xt d o s e b y u p t o 2 w e e k s or wit h h ol d 1 d o s e, p er p h y si ci a n di s cr eti o n.  
A s a r e s ult, a n y s u b s e q u e nt st u d y vi sit s will b e a dj u st e d. If a si mil ar c o n c er n i s pr e s e nt 
at t h e ti m e of t h e n e xt s c h e d ul e d d o s e, a n y d e ci si o n m a d e t o di s c o nti n u e tr e at m e nt 
will b e dri v e n b y t h e I n v e sti g at or’ s cli ni c al j u d g m e nt. L a b or at or y t e st s will b e r e p e at e d 
p er I n v e sti g at or’ s di s cr eti o n.    
If  it  i s  d et er mi n e d  t h at  i n v e sti g ati o n al  pr o d u ct  s h o ul d  b e  di s c o nti n u e d,  t h e  s u bj e ct  
s h o ul d  b e  f oll o w e d  at  r e g ul arl y  s c h e d ul e d  m o nt hl y  st u d y  vi sit s  a s  r e q uir e d  u ntil  
r e s ol uti o n of t h e A E, a n d r et ur n f or f oll o w-u p vi sit s a s d e s cri b e d i n S u bj e ct Wit h dr a w al 
Crit eri a.  
F or a f ull li sti n g of t h e di s c o nti n u ati o n crit eri a, pl e a s e s e e s e cti o n 3. 5 of t h e pr ot o c ol.   
      H y p o g a m m a gl o b uli n e mi a  
B e nl y st a s h o ul d b e di s c o nti n u e d i n s u bj e ct s wit h I g G l e v el s < 2 5 0 m g/ d L a s s o ci at e d 
wit h a s e v er e or s eri o u s i nf e cti o n. F or I g G c o n c e ntr ati o n s < 2 5 0 m g/ dl t h at ar e n ot 
a s s o ci at e d  wit h  a  s e v er e  or  s eri o u s  i nf e cti o n,  i n cr e a s e d  vi gil a n c e  f or  i nf e cti o n  i s  
r e q uir e d. Cli ni c al j u d g m e nt s h o ul d b e a p pli e d wit h r e s p e ct t o t h e a p pr o pri at e n e s s of 
c o nti n ui n g st u d y t h er a p y i n t h e s e s u bj e ct s. If a s u bj e ct e x p eri e n c e s a n y I g G l e v el s < 
2 5 0 m g/ d L, t h e d o s e of st u d y a g e nt m u st b e wit h h el d a n d t h e M e di c al M o nit or a n d 
Gl a x o S mit h Kl ei n  m u st  b e  c o n s ult e d  b ef or e  a d mi ni st eri n g  a n y  s u b s e q u e nt  d o s e  of  
st u d y a g e nt. If a s u bj e ct e x p eri e n c e s a cli ni c all y si g nifi c a nt, p ot e nti all y lif e -t hr e at e ni n g 
( Gr a d e 4) A E t h at t h e i n v e sti g at or b eli e v e s m a y b e d efi nit el y, p o s si bl y or pr o b a bl y 
r el at e d  t o  st u d y  a g e nt,  t h e n  tr e at m e nt  wit h  st u d y  a g e nt  will  b e  di s c o nti n u e d.  T h e  
s u bj e ct s h o ul d b e wit h dr a w n fr o m st u d y a g e nt, a n d f oll o w e d at r e g ul arl y s c h e d ul e d 
st u d y vi sit s a s s p e cifi e d b y pr ot o c ol a n d al s o u ntil r e s ol uti o n of t h e A E( s) ( w hi c h e v er 
i s l o n g er).  
Li v er C h e mi str y St o p pi n g Crit eri a  
Li v er  c h e mi str y  t hr e s h ol d  st o p pi n g  crit eri a  h a v e  b e e n  d e si g n e d  t o  a s s ur e  s u bj e ct  
s af et y a n d t o e v al u at e li v er e v e nt eti ol o g y (i n ali g n m e nt wit h t h e U S F o o d a n d Dr u g 
A d mi ni str ati o n pr e m ar k eti n g cli ni c al li v er s af et y g ui d a n c e).  
St u d y tr e at m e nt will b e st o p p e d  if a n y of t h e f oll o wi n g li v er c h e mi str y st o p pi n g crit eri a 
i s m et:  
1.  Al a ni n e a mi n otr a n sf er a s e ( A L T)  3 x u p p er li mit of n or m al ( U L N) a n d t ot al bilir u bi n  
 2 x U L N ( > 3 5 % dir e ct bilir u bi n); or A L T  3 x U L N a n d i nt er n ati o n al n or m ali z e d r ati o  


2 5  
  
(I N R) > 1. 5. N O T E: s er u m bilir u bi n fr a cti o n ati o n s h o ul d b e p erf or m e d if t e sti n g i s 
a v ail a bl e. If fr a cti o n ati o n i s u n a v ail a bl e, uri n ar y bilir u bi n i s t o b e m e a s ur e d vi a 
di p sti c k ( a m e a s ur e m e nt of dir e ct bilir u bi n, w hi c h w o ul d s u g g e st li v er i nj ur y).  
2.  A L T  5 x U L N.  
3.  A L T  3 x U L N i f a s s o ci at e d wit h s y m pt o m s ( n e w or w or s e ni n g) b eli e v e d t o b e r el at e d 
t o  h e p atiti s  ( s u c h  a s  f ati g u e,  n a u s e a,  v o miti n g,  ri g ht  u p p er  q u a dr a nt  p ai n  or  
t e n d er n e s s or j a u n di c e) or b eli e v e d t o b e r el at e d t o h y p er s e n siti vit y ( s u c h a s f e v er, 
r a s h or e o si n o p hili a).  
4.  A L T  3 x U L N p er si st s f or  4 w e e k s.  
5.  A L T  3 x U L N a n d c a n n ot b e m o nit or e d w e e kl y f or 4 w e e k s.   
6.  A L T  5 x U L N b ut < 8 x U L N a n d l a b s c a n n ot b e m o nit or e d w e e kl y f or  2 w e e k s  
S u bj e ct s wit h A L T  3 x U L N a n d < 5 x U L N a n d bilir u bi n < 2 x U L N, w h o d o n ot e x hi bit 
h e p atiti s s y m pt o m s or r a s h, c a n c o nti n u e st u d y tr e at m e nt a s l o n g a s t h e y c a n b e 
m o nit or e d w e e kl y f or 4 w e e k s.   
C o n c urr e nt M e di c ati o n - Pr o hi bit e d  
S u bj e ct s w h o r e c ei v e c o n c urr e nt m e di c ati o n or tr e at m e nt t h at i s pr o hi bit e d f or s af et y 
r e a s o n s ( e. g. li v e v a c ci n e s, c y cl o p h o s p h a mi d e or B-c ell a g e nt s s u c h a s rit u xi m a b) 
s h o ul d  b e  wit h dr a w n  fr o m  st u d y  tr e at m e nt  a n d  s h o ul d  n ot  r e c ei v e  a d diti o n al  
i n v e sti g ati o n al pr o d u ct wit h o ut t h e e x pli cit a p pr o v al of t h e M e di c al M o nit or ( F u n di n g 
S p o n s or).  
  
R e q uir e d A cti o n s, M o nit ori n g, a n d F oll o w u p A s s e s s m e nt s f oll o wi n g A N Y Li v er   
St o p pi n g E v e nt   
  
A cti o n s:   
• 
I m m e di at el y di s c o nti n u e st u d y tr e at m e nt   
• 
R e p ort t h e e v e nt t o G S K wit hi n 2 4 h o ur s  
• 
C o m pl et e t h e li v er e v e nt C R F a n d c o m pl et e S A E d at a c oll e cti o n t o ol if t h e e v e nt 
al s o m e et s t h e crit eri a f or a n S A E ( All e v e nt s of A L T  3 x U L N a n d bilir u bi n  
2 x U L N ( > 3 5 % dir e ct bilir u bi n) or A L T  3 x U L N a n d I N R > 1. 5,  if I N R m e a s ur e d 
w hi c h m a y i n di c at e s e v er e li v er i nj ur y ( p o s si bl e ‘ H y’ s L a w’), m u st b e r e p ort e d a s 
a n S A E ( e x cl u di n g st u di e s of h e p ati c i m p air m e nt or cirr h o si s); I N R m e a s ur e m e nt 
i s n ot r e q uir e d a n d t h e t hr e s h ol d v al u e st at e d will n ot a p pl y t o s u bj e ct s r e c ei vi n g 
a nti c o a g ul a nt s)  
• 
P erf or m li v er e v e nt f oll o w u p a s s e s s m e nt s   
• 
M o nit or t h e s u bj e ct u ntil li v er c h e mi stri e s r e s ol v e , st a bili z e, or r et ur n t o wit hi n 
b a s eli n e ( s e e M O NI T O RI N G b el o w)  
• 
D o n ot r e st art/r e c h all e n g e s u bj e ct wit h st u d y tr e at m e nt u nl e s s all o w e d p er pr ot o c ol 
a n d G S K M e di c al G o v er n a n c e a p pr o v al i s gr a nt e d M o nit ori n g:   
F or bilir u bi n or I N R crit eri a:   
• 
R e p e at li v er c h e mi stri e s (i n cl u d e A L T, A S T, al k ali n e p h o s p h at a s e, bilir u bi n) a n d 
p erf or m li v er e v e nt f oll o w u p a s s e s s m e nt s wit hi n  2 4 hr s  


2 6  
  
• 
M o nit or s u bj e ct s t wi c e w e e kl y u ntil li v er c h e mi stri e s r e s ol v e, st a bili z e or r et ur n t o 
wit hi n b a s eli n e  
• 
A s p e ci ali st or h e p at ol o g y c o n s ult ati o n i s r e c o m m e n d e d   
F or
 Al l
 ot h er
 
crit eri a:    
• 
R e p e at li v er c h e mi stri e s (i n cl u d e A L T, A S T, al k ali n e p h o s p h at a s e, bilir u bi n) a n d  
p erf or m li v er e v e nt f oll o w u p a s s e s s m e nt s wit hi n 2 4 -7 2 hr s   
• 
M o nit or s u bj e ct s w e e kl y u ntil li v er c h e mi stri e s r e s ol v e, st a bili z e or r et ur n t o wit hi n 
b a s eli n e  
  
F oll o w U p A s s e s s m e nt s:   
• 
Vir al h e p atiti s s er ol o g y (I n cl u d e s: H e p atiti s A I g M a nti b o d y; H e p atiti s B s urf a c e 
a nti g e n a n d H e p atiti s B C or e A nti b o d y (I g M); H e p atiti s C R N A; C yt o m e g al o vir u s 
I g M a nti b o d y;  E p st ei n-B arr vir al c a p si d a nti g e n I g M a nti b o d y ( or if u n a v ail a bl e, 
o bt ai n h et er o p hil e a nti b o d y or m o n o s p ot t e sti n g);  H e p atiti s E I g M a nti b o d y)  
 
S er u m c r e ati n e p h o s p h o ki n a s e ( C P K) a n d l a ct at e d e h y dr o g e n a s e ( L D H).  
• 
Fr a cti o n at e bilir u bi n, if t ot al bilir u bi n 2 x U L N  
• 
O bt ai n c o m pl et e bl o o d c o u nt wit h diff er e nti al t o a s s e s s e o si n o p hili a  
• 
R e c or d  t h e  a p p e ar a n c e  or  w or s e ni n g  of  cli ni c al  s y m pt o m s  of  li v er  i nj ur y,  or  
h y p er s e n siti vit y, o n t h e A E r e p ort f or m  
• 
R e c or d u s e of c o n c o mit a nt m e di c ati o n s o n t h e c o n c o mit a nt m e di c ati o n s r e p ort 
f or m  i n cl u di n g  a c et a mi n o p h e n,  h er b al  r e m e di e s,  ot h er  o v er  t h e  co u nt er 
m e di c ati o n s  
• 
R e c or d al c o h ol u s e o n t h e li v er e v e nt c a s e r e p ort f or m   
F or  bili r u bi n  or  
I N R crit eri a:  
• 
A nti -n u cl e ar  a nti b o d y,  a nti -s m o ot h  m u s cl e  a nti b o d y,  T y p e  1  a nti -li v er  ki d n e y  
mi cr o s o m al a nti b o di e s, a n d q u a ntit ati v e t ot al i m m u n o gl o b uli n G (I g G o r g a m m a 
gl o b uli n s).  
• 
S er u m a c et a mi n o p h e n a d d u ct H P L C a s s a y ( q u a ntifi e s p ot e nti al a c et a mi n o p h e n 
c o ntri b uti o n t o li v er i nj ur y i n s u bj e ct s wit h d efi nit e or li k el y a c et a mi n o p h e n u s e i n 
t h e pr e c e di n g w e e k [ J a m e s, 2 0 0 9]). N O T E: n ot r e q uir e d i n C hi n a   
• 
Li v er i m a gi n g ( ultr a s o u n d, m a g n eti c r e s o n a n c e, or c o m p ut eri s e d t o m o gr a p h y) a n d 
/ or li v er bi o p s y t o e v al u at e li v er di s e a s e; c o m pl et e Li v er e v e nt c a s e r e p ort  f or m  
  
I n cr e a s e d M o nit ori n g Crit eri a wit h C o nti n u e d T h er a p y  
Crit eri a   
• 
If A L T 5 x U L N a n d < 8 x U L N a n d bilir u bi n < 2 x U L N wit h o ut s y m pt o m s b eli e v e d t o 
b e r el at e d t o li v er i nj ur y or h y p er s e n siti vit y, a n d w h o c a n b e m o nit or e d w e e kl y f or 
2 w e e k s O R   
• 
A L T 3 x U L N a n d < 5 x U L N  a n d bilir u bi n < 2 x U L N wit h o ut s y m pt o m s b eli e v e d t o b e 
r el at e d t o li v er i nj ur y or h y p er s e n siti vit y, a n d w h o c a n b e m o nit or e d w e e kl y f or 4 
w e e k s  
R e q uir e d A cti o n s   
• 
N otif y t h e G S K m e di c al m o nit or wit hi n 2 4 h o ur s of l e ar ni n g of t h e a b n or m alit y t o 
di s c u s s s u bj e ct s af et y.   
• 
S u bj e ct c a n c o nti n u e st u d y tr e at m e nt  
• 
S u bj e ct  m u st  r et ur n  w e e kl y  f or  r e p e at  li v er  c h e mi stri e s  ( A L T,  A S T,  al k ali n e  
p h o s p h at a s e, bilir u bi n) u ntil t h e y r e s ol v e, st a bili z e or r et ur n t o wit hi n b a s eli n e   


2 7  
  
• 
If at a n y ti m e s u bj e ct m e et s t h e li v er c h e mi str y st o p pi n g crit eri a, pr o c e e d a s 
d e s cri b e d a b o v e f or R e q uir e d A cti o n s a n d F oll o w u p A s s e s s m e nt s f oll o wi n g 
A N Y Li v er St o p pi n g E v e nt  
• 
If A L T d e cr e a s e s fr o m A L T 5 x U L N a n d < 8 x U L N t o ≥3 x U L N b ut < 5 x U L N, 
c o nti n u e t o m o nit or li v er c h e mi stri e s w e e kl y.   
• 
If, aft er 4 w e e k s of m o nit ori n g, A L T < 3 x U L N a n d bilir u bi n < 2 x U L N, m o nit or s u bj e ct s 
t wi c e m o nt hl y u ntil li v er c h e mi stri e s n or m ali z e or r et ur n t o wit hi n b a s eli n e.  
  
 
5. 1. 3  
D ur ati o n of Tr e at m e nt a n d F oll o w -u p.   
T h e a b o v e  tr e at m e nt pr ot o c ol i s i n v e sti g ati o n al.  H o w e v er all p ati e nt s will b e tr e at e d 
a n d m o nit or e d a c c or di n g t o o ur st a n d ar d of c ar e f or ki d n e y tr a n s pl a nt p ati e nt s.  D S A 
will b e m o nit or e d pr e -tr a n s pl a nt a n d at 1, 3, 6, 9, a n d 1 2 m o nt h s. W e will p erf or m a 
pr ot o c ol  bi o p s y at 1 y e ar p o st -tr a n s pl a nt p er st a n d ar d of c ar e.  
D at a f or t h e st u d y will b e c oll e ct e d f or 1 y e ar p o st tr a n s pl a nt vi a R E D C a p. W e will 
c oll e ct m e di c al h e alt h i nf or m ati o n g e n er at e d a s p art of p o st -tr a n s pl a nt st a n d ar d of c ar e 
cli ni c vi sit s, l a b a n al y si s a n d pr o c e d ur e s d o n e wit hi n t h e y e ar.  If t h e ki d n e y f ail s a n d 
p ati e nt r et ur n s t o di al y si s t h e st u d y c o or di n at or or t h e PI will c o nt a ct t h e p ati e nt’ s 
di al y si s u nit a n d l o c al n e p hr ol o gi st s e v er y t hr e e m o nt h s f or o n e y e ar p o st tr a n s pl a nt t o 
c oll e ct  t h e  n e c e s s ar y  s af et y  m o nit ori n g  i nf or m ati o n  i n cl u di n g  i nf e cti o u s  ( s u c h  a s  
h er p e s si m pl e x vir u s) a n d h e m at ol o gi c al c o m pli c ati o n s, a n d l a b r e s ult s.  
  
 
6.  St u d y Pr oce d ures  
T h e f oll o wi n g a s s e s s m e nt s will b e o bt ai n e d  f or all s u bj e ct s, a s o utli n e d i n t h e St u d y 
Vi sit S c h e d ul e of E v e nt s ( A p p e n di x A).  
  
 
6. 1  
S cr e e ni n g Vi sit   
Pri or t o a n y s cr e e ni n g pr o c e d ur e s, i nf or m e d c o n s e nt will b e o bt ai n e d. O n c e c o n s e nt 
i s o bt ai n e d, t h e f oll o wi n g a s s e s s m e nt s will b e c o m pl et e d a n d i nf or m ati o n c oll e ct e d f or 
st u d y p arti ci p a nt s wit hi n 3 0 d a y s of tr a n s pl a nt.  If a n y s cr e e ni n g pr o c e d ur e h a s b e e n 
p erf or m e d wit hi n t h e 3 0 -d a y s cr e e ni n g wi n d o w p er st a n d ar d of c ar e, r e s ult s c a n b e 
u s e d f or t h e  s cr e e ni n g vi sit a n d pr o c e d ur e d o e s n ot n e e d t o b e r e p e at e d.   
• 
D o c u m e nt i nf or m e d C o n s e nt  
• 
D e m o gr a p hi c s  
• 
M e di c al hi st or y    
• 
P h y si c al e x a m i n cl u di n g vit al si g n s a n d w ei g ht  
• 
M e di c ati o n s   
• 
O bt ai n st a n d ar d of c ar e l a b r e s ult s, i n cl u di n g:  
• 
H e m at ol o g y p a n el -C B C a n d diff er e nti al  
• 
Li v er F u n cti o n -A S T, A L T, t ot al bilir u bi n  
• 
El e ctr ol yt e s  
• 
B U N/ Cr e ati ni n e  
• 
c P R A ( H L A all o a nti b o di e s)  
• 
S er u m pr e g n a n c y t e st f or w o m e n of c hil d b e ari n g p ot e nti al  


2 8  
  
• 
Uri n e pr ot ei n/ cr e ati ni n e e x c e pt w h e n t h e st u d y s u bj e ct i s a n uri c or oli g uri c, 
a n d/ or u n a bl e t o pr o vi d e a uri n e s a m pl e .   
• 
P erf or m E C G, a b n or m aliti e s m u st b e d o c u m e nt e d a s n ot m e di c all y r el e v a nt  
• 
R e v i e w  of  m e di c al  hi st or y  c oll e ct e d  at  m o st  r e c e nt  st a n d ar d  of c ar e 
pr etr a n s pl a nt cli ni c vi sit a n d pri m ar y c ar e/ s p e ci ali st s c ar e vi sit s.     D et er m i n e 
eli gi bilit y b a s e d o n i n cl u si o n/ e x cl u si o n crit eri a  
  
 
6. 2  
D a y of Tr a n s pl a nt ( D a y 0)  
T h e fir st d o s e of i n v e sti g ati o n al pr o d u ct will b e a d mi ni st er e d o n D a y 0 i ntr a -o p er ati v el y. 
T h e  d o s e  of  i n v e sti g ati o n al  pr o d u ct  a d mi ni st er e d  m a y  n ot  b e  alt er e d.  T h e  r at e  of  
i nf u si o n  m a y  b e  sl o w e d  or  i nt err u pt e d  if  t h e  s u bj e ct  a p p e ar s  t o  d e v el o p  si g n s  of  
a d v er s e r e a cti o n s or i nf u si o n -r el at e d s y m pt o m s. At l at er vi sit s, t h e s e s u bj e ct s m a y 
c o nti n u e  t o  b e  i nf u s e d  o v er  a  l o n g er  i nf u si o n  p eri o d  at  t h e  i n v e sti g at or’ s  cli ni c al  
di s cr eti o n. T h e r at e of i nf u si o n s h o ul d n ot b e i n cr e a s e d a b o v e t h e r e c o m m e n d e d r at e.  
Bl o o d pr e s s ur e a n d h e art r at e will b e r e c or d e d wit hi n 1 5 mi n ut e s pri or t o b eli m u m a b 
inf u si o n,  at  1 5 ± 5  mi n ut e s  aft er  t h e  b e gi n ni n g  of  t h e  i nf u si o n,  a n d  1 5 ± 5  mi n ut e s  
f oll o wi n g c o m pl eti o n of t h e i nf u si o n.  
Bi o p s y will b e o bt ai n e d at tr a n s pl a nt p er st a n d ar d of c ar e.  
  
6. 3 P o st -Tr a n s pl a nt St u d y Vi sit s: W e e k 1, W e e k 2, M o nt h 1, 2, 3, 4, 5, 6,  9, 1 2  
St u d y vi sit s will o c c ur at W e e k 1 +/ - 3 d a y s ( w hil e i n t h e h o s pit al r e c o v eri n g fr o m 
s ur g er y), W e e k 2, a n d M o nt h s 1, 2, 3, 4, 5, 6, 9, a n d 1 2, aft er tr a n s pl a nt i n c o nj u n cti o n 
wit h st a n d ar d of c ar e. Wit h t h e e x c e pti o n of t h e W e e k 2 vi sit t h at will t a k e 3 h o ur s, 
vi sit s t h at i n cl u d e a b eli m u m a b i nf u si o n ( M o nt h s 1, 2, 3, 4, 5) will t a k e a b o ut 2 h o ur s 
t o c o m pl et e. T h e r e m ai n d er of st u d y vi sit s will o nl y t a k e a b o ut a n h o ur. M a n y of t h e 
pr o c e d ur e s r e q uir e d f or t h e st u d y ar e t h e s a m e a s t h o s e d o n e at st a n d ar d of c ar e cli ni c 
vi sit s a n d will n ot r e q uir e a d diti o n al pr o c e d ur e s/t e st s.  At t h e s e vi sit s, t h e f oll o wi n g 
pr o c e d ur e s a n d t e st s will o c c ur:  
• 
C oll e cti o n  of  vit al  si g n s  (i n cl u di n g  t e m p er at ur e,  bl o o d  pr e s s ur e,  h e art  a n d  
br e at hi n g r at e, a n d w ei g ht), at all vi si t s  
• 
A bri ef p h y si c al e x a m   
• 
Bl o o d a n d uri n e s a m pl e c oll e cti o n s f or st a n d ar d l a b or at or y t e st s ( all vi sit s), e x c e pt 
w h e n  t h e  st u d y  s u bj e ct  i s  a n uri c  or  oli g uri c,  a n d/ or  u n a bl e  t o  pr o vi d e  a  uri n e  
s a m pl e.  
• 
R e vi e w of m e di c ati o n s ( o n d a y of st u d y vi sit.)  
• 
R e s e ar c h bl o o d s a m pl e c oll e cti o n at M o nt h s 1, 3, 6, 9, 1 2 (if c o n s e nt e d)  
• 
A n y c h a n g e s t o h e alt h or m e di c al hi st or y will b e r e c or d e d a n d a s s e s s e d  
  
 
6. 3. 1  
St u d y Tr e at m e nt   
 B el i m u m a b:  1 0 m g/ k g/ d o s e will b e a d mi ni st er e d I V f or 6 m o nt h s at t h e f oll o wi n g 
i nt er v al s: at ti m e of tr a n s pl a nt ( D a y 0), t h e n p o st -tr a n s pl a nt at W e e k s 2, 4, 8, 1 2, 
1 6, a n d 2 0.  
 
    


29  
  
 
6.3.2  
Study Related Clinical Assessments   
• 
Physical examination to include patient weight and vital signs prior to each infusion 
and at each study visit .  Physical exam will include standard neurologic 
assessments to monitor for the presence of any drug related toxicities as outlined 
in section 5.1.2.  
• 
Adverse events recorded prior to each belimumab dose.  Subjects will be asked to 
report any changes in sleep patterns, anxiety or mental status, suicidal ideation.  
• 
Concomitant medications collected and reviewed at each visit  
 
6.3.3  
Laboratory Assessments   
Laboratory assessments will be performed according to the schedule of events in 
Appendix A.  
  
Post-transplant follow-up standard of care labs results will be collected via the 
Transplant Data System every month for the first year post-transplant for safety 
monitoring.    
Subjects who do not receive a transplant, following belimumab injection, will have their 
labs and clinical care monitored quarterly by the study coordinators, or the PI who will 
collect the data from UWHC electronic records or request records from the subject’s 
provider if not within the UWHC system.   
  
Subjects will also have a kidney biopsy at 1 year post-transplant per standard of care.  
  
 
6.3.4  
Mechanistic Assessments  
  
We will measure anti-HLA antibodies using the Single Antigen Bead Luminex assay 
(One Lambda, Inc., CA, USA) prior to treatment and 1, 3, 6, 9, and 12 months.   
  
The following standard of care assays will be done and data analyzed as part of this 
protocol:  
  
Single antigen Bead Luminex Antibody screening. This state of the art flow 
cytometry based assay is performed routinely in our HLA laboratory at the UWHC. It 
allows us to determine both anti HLA antibody and PRA measurements. Blood 
samples are analyzed for HLA antibodies by LabScreen® Single Antigen Class I and 
II beads LXFC kits from One Lambda, Inc (OLI, Canoga Park, CA, USA). The method 
is followed as described in the package insert, using 3μL of HLA antigen coated beads.   
  
Kidney Transplant Biopsy:  A donor biopsy will be collected intra-operatively per 
standard of care at the time of transplant, and percutaneously with ultrasound 
guidance as per standard protocol at 1 year post-transplant. Results will be collected 
and recorded from the electronic medical record.  
  
 
6.3.5   
Banking of Samples for Future Studies  
If the subject agrees to allow their blood cells/plasma to be used for future research 
related to kidney transplantation by indicating such on the informed consent, the 
samples and all the coded data associated including standard of care kidney function 


30  
  
and study related lab results, medication and adverse event logs, and physical exam 
notes will be maintained by key personnel.  Samples will be coded with a subject 
number and stored a -80° C freezer or in liquid nitrogen storage in Dr. Djamali’s 
Research Laboratory at the University of Wisconsin Hospital and Clinics, 600 Highland 
Ave Madison, Wisconsin.  Subjects will not be re-consented and the results of any 
future testing will not be provided to the subjects nor will they be used in making any 
clinical decisions regarding their care.  The risks to the subjects are limited to breach 
of confidentiality and release of information to individuals not involved in this research.  
We will do everything possible to keep the subjects information confidential.  No 
identifiable information will be shared.  Any electronic files pertaining to health 
information and samples will only be accessible to the investigators and study 
personnel.  Computers are password protected and the files will be stored on a 
Department of Surgery secure password protected network server.   No portable 
electronic devices will be used for data collection or storage.  No future research (with 
the exception of mechanistic assays identified in this protocol) or sharing of samples 
will be done without an IRB approved protocol.  
  
If the subject agrees peripheral blood will be collected prior to transplant and at 1, 
3, 6, 9, and 12 months and stored for the below future studies.   
  
  
• 
BAFF and APRIL measurements: Serum BAFF and APRIL levels will 
be measured as described previously using the Quantikine ELISA 
Immunoassay (R&D Systems, Minneapolis, MN) (17). Briefly, samples are 
collected in tubes without anticoagulant and spun at 2000 rpm for 10 min. 
Serum is collected and frozen in liquid nitrogen for long term. Standards 
and sera are assayed in duplicate wells.  This will occur on samples prior 
to treatment and 1, 3, 6, 9, and 12 months.   
  
• 
B Lymphocyte Analysis:  B-cell FACS panels will be used to measure 
changes over the course of therapy in the transitional, naïve, memory 
and plasma cell compartments. For the subsets of interest, absolute 
numbers of cells and proportions relative to all B cells for the individual 
subsets will be determined, as will activation status.  Specifically we will 
address peripheral transitional, naive, memory and plasma cell 
populations prior to transplant and at 1, 3, 6, 9, and 12 months post- 
transplant. Further exploratory analyses will include the expression of 
BLyS receptors (BR3, TACI and BCMA) on B cells, frequency of 
alloreactive B cells (using tetramers) and an analysis of the effect of 
belimumab on IL-10 secreting B regulatory cells.  Again these 
assessments will be performed prior to transplant and at 1, 3, 6, 9, and 
12 months post transplant  
  
• 
T Lymphocyte Analysis:  Similar assessments will be made of T cell 
subsets prior to transplant and at 1, 3, 6, 9, and 12 months post- 
transplant.  Specifically we will evaluate activated T cell and T regulatory 
cell populations.  
  


31  
  
• 
Cytokine Analysis:  Quantification of serum BLyS and APRIL levels and 
cytokines/chemokines associated with T-helper skewing or activation will 
be performed prior to transplant and at 1, 3, 6, 9, and 12, months 
posttransplant  
  
• 
Immunoglobulin Analysis:  Quantification of total serum levels of 
Immunoglobulin levels (IgM, IgA, and IgG) will be performed prior to 
transplant and at 1, 3, 6, 9, and 12 months post-transplant.  
  
 
7.  Safety Assessments  
The patient will be evaluated for safety, and adverse events will be documented 
according to the procedures of the investigational site. The investigator will determine 
the relationship of the events to the administration of belimumab.  
Patients will be clinically assessed for suicidal ideation and/or behavior at each visit. If 
patient exhibits suicidal ideations or it is verbally expressed, the PI will enter a note 
and refer the patient to a psychiatrist.  
Expected Adverse Events (AEs) ≥ Grade 2, and all unexpected adverse events will be 
documented, graded, and assessed for causality to belimumab by the Principal 
Investigator.   
All Serious Adverse Events (SAEs) will be reported to GlaxoSmithKline within 24 
hours. SAEs that meet the FDA and IRB reporting criteria will be reported within the 
specified timeframe. Serious Adverse Events will be documented, graded, and 
assessed for causality to belimumab by the Sponsor-Investigator.  
If the patient is a WOCBP, pregnancy tests (blood; minimum sensitivity 25 IU/L of 
HCG) must be performed within 48 hours before the first dose and the beginning of 
each cycle. If the patient becomes pregnant, she must be discontinued from treatment.  
Laboratory tests may be performed as part of routine standard of care as directed by 
subject’s nephrologist. Results of these standard of care tests will be monitored as part 
of this study. Additional tests including a hematology profile will be done prior to each 
study drug cycle and hepatic function labs will be done prior to each treatment cycle 
for monitoring the subject’s for potential drug related toxicities.  
Physical exams will be performed prior to each cycle, and will include the monitoring 
of specific known study drug related toxicities including neuropathy and edema.    
Subjects will continue to have health information collected from standard of care clinic 
visits, or nephrology/dialysis unit visits, and monitored for safety for 12 months from 
the time of discontinuation of study treatment. If subjects transplant fails prior to the 6 
month time point, they will continue to have health information collected from standard 
of care post-transplant follow up clinic visits, or nephrology/dialysis unit visits, and 
monitored for safety for 12 months from the time of transplant.  
    
MMF  


32  
  
Mycophenolate can cause fetal harm when administered to a pregnant female. Use of 
mycophenolate during pregnancy is associated with an increased risk of first trimester 
pregnancy loss and an increased risk of congenital malformations.   
Mycophenolate affects the metabolism of oral contraceptives and may reduce their 
effectiveness. As such, women receiving MMF who are using oral contraceptives for 
birth control should employ an additional method (e.g., barrier method) resulting in two 
reliable forms of contraception being used simultaneously before starting study 
treatments, during therapy, and for 6 weeks after stopping therapy; unless abstinence 
is the chosen method of contraception  
• For women of childbearing potential, a serum pregnancy test is required within 48 
hours prior to transplant.   
• For sexually active men, condoms should be used during, and for at least 90 days 
after cessation of mycophenolate treatment. No sperm donation should be made 
during this period of time. For female partners of male subjects, it is recommended to 
use highly effective contraception during treatment and for 90 days after the last dose 
of mycophenolate  
• No blood donation should be made by the study subjects during mycophenolate 
treatment and for at least 6 weeks after stopping mycophenolate treatment  
If stricter female or male contraception requirements are specified in the countryspecific 
label for any study related therapies, they must be followed.  
 
7.1  
Adverse Events  
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a pre-existing medical condition in a patient or clinical investigation 
subject administered an investigational (medicinal) product and that does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of investigational 
product, whether or not considered related to the investigational product.  
Adverse events are defined as any signs (including abnormal diagnostic test result) or 
medical diagnoses noted by medical personnel, or symptoms reported by the subject, 
regardless of relationship to study drug, that:  
1. 
have onset anytime after the start of study drug treatment, or   
2. 
increase in severity during drug treatment or procedures (pre-existing 
signs, symptoms or diagnoses).   
  
Subjects will be interviewed in a non-directed manner to identify potential adverse 
events.  This occurrence of an adverse event will be based on changes in the subject’s 
physical examination, laboratory results, and/or signs and symptoms. Only those 
abnormal laboratory results that are considered clinically significant will be evaluated 
as a potential adverse event.  All adverse events ≥Grade 2 per CTCAE, including 
observed or volunteered problems, complaints, or symptoms are to be recorded, if 
they are thought to be related to the study drug or study procedures.  All documented 
adverse events will be monitored until they are resolved or are clearly determined to 


33  
  
be due to a subject’s stable or chronic disease condition or intercurrent illness(es).  
Each adverse event is to be evaluated for duration, intensity and causal relationship 
with the study medication or other factors.  
  
Adverse events will be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0.    
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with 
unique clinical descriptions of severity for each AE based on this  general guideline:   
  
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.   
  
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
ageappropriate instrumental ADL.   
  
Grade 3 Severe or medically significant but not immediately life-threatening;   
hospitalization or prolongation of hospitalization indicated; disabling; limiting self 
care ADL  
  
Grade 4 Life-threatening consequences; urgent intervention indicated.   
  
Grade 5 Death related to AE.  
 
7.2  
Serious Adverse Events  
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:   
  
• Is fatal  
• Is life-threatening  
• Requires or prolongs inpatient hospitalization  
• Results in persistent or significant disability/incapacity  
• Is a congenital anomaly/birth defect  
  
The inpatient stay following the transplantation procedure will be considered SAE only 
if prolonged for more than 14 days.   
  
A medical event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to prevent a 
serious outcome, may also be considered serious (e.g. intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug dependency 
or drug abuse).  Medical and scientific judgment must be exercised when classifying 
events as serious.  The Investigator must determine both the intensity of the serious 
adverse event and the relationship of the event to the administration of study 
medications.    
  
 
7.2.1  
Reporting  
  


34  
  
It is the responsibility of the Investigator to promptly notify the Institutional Review 
Board of all unanticipated problems involving risk to human research subjects.  All 
serious adverse events including fatal or life-threatening events experienced by study 
participants in the study will be reported to GlaxoSmithKline, Inc., to ICTR DMC, the 
FDA per applicable regulations, and the UW IRB according to current IRB guidelines.  
  
Adverse Events that are:   
Notify:  
Serious  
  
      Suspected/Related*          
Unexpected   
GSK Medical Monitor: Within 24 hours  
DMC: Within 14 business days  
HSIRB: Within 14 business days  
FDA and all participating institutions as soon as 
possible, but no later than 15 calendar days after 
learning of the event  
Life threatening or Fatal  
  
Suspected/Related*  
Unexpected   
GSK Medical Monitor: Within 24 hours  
DMC: Within 24 hours   
HSIRB: Within 1 business day of learning of the 
event.  
FDA: Within 7 calendar days of learning of the 
event  
*Events that are possibly, probably, or definitely related meet the criteria for  
“Suspected/Related”  
  
 
7.3  
ICTR Data Monitoring Committee (DMC)  
  
We plan to utilize the UW ICTR Data Monitoring Committee (DMC) to oversee the study. 
The UW ICTR DMC is comprised of experienced members (core plus ad hoc) with 
expertise required to oversee this study. The DMC members will review protocol-specific 
reports created by statisticians using data pulled from the ICTR OnCore clinical research 
management system and Research Electronic Data Capture (REDCap) data 
management tool. These standard reports will include an overview of study objectives, a 
review of actual and projected accrual rates, an evaluation of patient demographics for 
balance of randomization, and a summary of the number and seriousness of adverse 
events. An interim analysis of study results may be performed and source documents 
may be reviewed to allow the DMC to independently judge whether the overall integrity 
and conduct of the protocol remain acceptable based on data provided and reported by 
the Principal Investigator. The DMC will make recommendations to the Principal 
Investigator that could include actions of continuation, modification, suspension, or 
termination.  


35  
  
  
In providing oversight for the conduct of this study, the ICTR DMC will meet biannually 
during the study to review all adverse events. Additional meetings may be scheduled as 
determined by the DMC or as requested by the PI. The predefined stopping points for 
this study are described in section 3.6 of this protocol. We will submit all reportable 
events to the DMC and the Health Sciences IRB in accordance with their reporting 
guidelines.  
  
 
8.  Ethical Considerations and Compliance in Good Clinical Practice  
 
8.1  
Statement of Compliance  
This trial will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCP), adopting the principles of the Declaration of Helsinki, and all 
applicable regulatory requirements.  
  
Prior to study initiation, the protocol and the informed consent documents will be 
reviewed and approved by an appropriate ethics review committee or Institutional 
Review Board (IRB). Any amendments to the protocol or consent materials must also 
be approved before they are implemented.  
 
8.2  
Informed Consent  
The informed consent form is a means of providing information regarding the trial to a 
prospective participant and allows for an informed decision about participation in the 
study. All participants must read, sign and date a consent form prior to participation in 
the study, taking study drug and/or undergoing any study-specific procedures.   
  
The informed consent form must be updated or revised whenever important new safety 
information is available, whenever the protocol is amended, and/or whenever any new 
information becomes available that may affect a patients’ participation in the trial.  
A copy of the informed consent will be given to a prospective participant for review. 
The Study Investigator or a designee of the Investigator will review the consent and 
answer any questions that the potential participant may have. The participant will be 
informed that their participation is voluntary and they may withdraw from the study at 
any time, for any reason.  
  
8.3        Recruitment Methods  
  
Patients being evaluated for a living donor kidney transplant who meet the selection 
criteria will be contacted by study personnel.  The potential subjects will be contacted 
to briefly explain the study and ask if they would mind to review a consent form.  If the 
potential subject agrees, the study personnel go through the consent form and answer 
questions. At the end, the study personnel will ask the potential subject if they would 
like to be in the study. If a potential subject replies yes, study personnel will have them 
review and sign the consent form. Study personnel will meet them prior to any study 
related procedures to obtain consent.  


36  
  
 
8.4  
Privacy and Confidentiality  
A patient’s privacy and confidentiality will be respected throughout the study. Each 
study participant will be assigned a sequential identification number and these 
numbers rather than names will be used to collect, store and report participant 
information.  
  
All data collected for this study from subjects will be done in a private patient exam 
room.  Data may be extracted from the subject’s medical record (paper/electronic) by 
the Publications and Clinical Research Service (PACRS), study coordinators and the 
PIs.  Data necessary to achieve the aims of the research will be the only data collected 
from the subjects or the medical records.  Source documents for data, including signed 
ICF and Research Authorization forms, will be maintained in subject study specific 
binders. Subjects are identified on all documents and samples by a study specific 
identifier and study assigned number. These binders are stored in the locked office of 
the Office of Clinical Trials coordinator.  
  
All paper files and computers are located in an office that is staffed during the day, and 
locked when staff is not present. Electronic source documents and data analysis will 
be created and stored on the Department of Surgery secure password protected 
network server.  
  
Study personnel will have access to the OnCore registration log that links identifiable 
subject information to the assigned subject study code. Only key personnel assigned 
to the study will have access to this information.  
  
Data including treatments, eGFR, AEs, deaths, infections (bacterial/viral/fungal), or 
sepsis may be included in REDCap for Data Safety Monitoring.  
  
No data or subject information will be released to the funding institution as this is an 
investigator initiated study and all data belongs solely to the investigator. No data will 
be stored on laptops or portable devices.  
 
8.5  
Records Retention  
The investigator will retain, in a confidential manner, all data pertinent to the study for 
all treated subjects. The investigator will retain source documents and accurate case 
histories that record all observations and other data pertinent to the investigation (e.g., 
the medical record) for the maximum period (7 years) or 2 years after 
completion/termination of the IND with the FDA, as required by applicable regulations 
and guidelines or following institutional procedures.  
  
 
9.  Statistical Section  
  
A biostatistician in the UW Madison Department of Surgery or the Division of 
Nephrology will perform the statistical analyses. The primary outcome and secondary 
outcomes will be assessed using descriptive statistics.  Specifically, we will describe 
the rate of de novo DSA development, graft survival and function as determined by 
serum creatinine/eGFR and urine protein, rates of acute cellular and antibody 


37  
  
mediated rejection, and the nature, frequency, and severity of serious and non-serious 
adverse events ≥Grade 2.    
  
  
10.  References  
  
1. 
Sellares J, de Freitas DG, Mengel M, et al. Understanding the causes of 
kidney transplant failure: the dominant role of antibody-mediated rejection 
and nonadherence. American Journal of Transplantation. 
2012;12(2):388399.  
2. 
Todeschini M, Cortinovis M, Perico N, et al. In kidney transplant patients, 
alemtuzumab but not basiliximab/low-dose rabbit anti-thymocyte globulin 
induces B cell depletion and regeneration, which associates with a high 
incidence of de novo donor-specific anti-HLA antibody development. 
Journal of Immunology. 2013;191(5):2818-2828.  
3. 
DeVos JM, Patel SJ, Burns KM, et al. De novo donor specific antibodies 
and patient outcomes in renal transplantation. Clinical Transplants. 
2011:351-358.  
4. 
DeVos JM, Gaber AO, Knight RJ, et al. Donor-specific HLA-DQ antibodies 
may contribute to poor graft outcome after renal transplantation. Kidney 
International. 2012;82(5):598-604.  
5. 
Terasaki PI, Cai J. Humoral theory of transplantation: further evidence. 
Current Opinion in Immunology. 2005;17(5):541-545.  
6. 
Mihaylova A, Baltadjieva D, Boneva P, et al. Clinical relevance of anti-HLA 
antibodies detected by flow-cytometry bead-based assays--single-center 
experience. Human Immunology. 2006;67(10):787-794.  
7. 
Redfield RR, 3rd, Rodriguez E, Parsons R, et al. Essential role for B cells 
in transplantation tolerance. Current Opinion in Immunology. 
2011;23(5):685-691.  
8. 
Hahn BH. Belimumab for systemic lupus erythematosus. The New 
England Journal of Medicine. 2013;368(16):1528-1535.  
9. 
Parsons RF, Yu M, Vivek K, et al. Murine islet allograft tolerance upon 
blockade of the B-lymphocyte stimulator, BLyS/BAFF. Transplantation. 
2012;93(7):676-685.  
10. 
Parsons RF, Vivek K, Rostami SY, et al. Acquisition of humoral 
transplantation tolerance upon de novo emergence of B lymphocytes. 
Journal of Immunology. 2011;186(1):614-620.  
11. 
Newell KA, Asare A, Kirk AD, et al. Identification of a B cell signature 
associated with renal transplant tolerance in humans. The Journal of 
Clinical Investigation. 2010;120(6):1836-1847.  
12. 
Zarkhin V, Li L, Sarwal MM. BAFF may modulate the rate of B-cell 
repopulation after rituximab therapy for acute renal transplant rejection. 
Transplantation. 2009;88(10):1229-1230.  
13. 
Thibault-Espitia A, Foucher Y, Danger R, et al. BAFF and BAFF-R levels 
are associated with risk of long-term kidney graft dysfunction and 


38  
  
development of donor-specific antibodies. American Journal of 
Transplantation. 2012;12(10):2754-2762.  
14. 
van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the 
treatment of systemic lupus erythematosus: high disease activity 
predictors of response. Annals of the Rheumatic Diseases. 
2012;71(8):1343-1349.  
15. 
Parsons RF, Yu M, Vivek K, Zekavat G, Rostami SY, Ziaie AS, Luo Y, 
Koeberlein B,Redfield RR, Ward CD, Migone TS, Cancro MP, Naji A, 
Noorchashm H. Murine islet allograft tolerance upon blockade of the 
Blymphocyte stimulator, BLyS/BAFF.Transplantation 2012;93(7):676-85.  
16. 
Lehnhardt A, Dunst F, Koch M, Kemper MJ. BAFF/BAFF-R axis is 
dysregulated in patients after pediatric renal transplantation. Pediatr 
Nephrol 2011. 26;9:1613-1614.  
17. 
Xu H, He X, Liu Q, Shi D, Chen Y, Zhu Y, Zhang X. Abnormal High 
Expression of BCell Activating Factor Belonging to the TNF Superfamily 
(BAFF) Associated With Long-Term Outcome in Kidney Transplant 
Recipients. Transplant Proc 2009a.41;5:1552-1556.  
18. 
Xu H, He X, Sun J, Shi D, Zhu Y, Zhang X. The Expression of B-Cell 
Activating Factor Belonging to Tumor Necrosis Factor Superfamily (BAFF) 
Significantly Correlated With C4D in Kidney Allograft Rejection. Transplant 
Proc 2009b. 41;1:112-116.  
19. 
Banham G, Prezzi D, Harford S, Taylor CJ, Hamer R, Higgins R, Bradley 
JA, ClatworthyMR. Elevated pretransplantation soluble BAFF is associated 
with an increased risk of acute antibody-mediated rejection. 
Transplantation. 2013 Aug 27;96(4):413-20  
  
  
  
  
 


3 9  
  
1 1. 0 A p pe n di x A ( Sc he d ule of E ve nts)  
   
C A M P B E L Trial  
 
 
   
H os pitalizati o n  
O ut patie nt Visit   
 
   
 
Da y of  
Tra ns pla nt   
( Da y 0)  
 
 
 
 
 
 
 
 
 
 
  
≤3 0 da ys 
pri or t o 
tra ns pla nt  
Ma y be sa me d a y as 
scree ni n g  
 3 d  
 3 d  
 3 d  
 3 d  
 3 d  
 3 d  
 3 d  
 7 d  
 7 d  
 7 d  
I nf or me d C o nse nt  
X  
  
  
  
  
  
  
  
  
  
  
  
De m o gra p hics  
X  
   
   
   
   
   
   
   
   
   
   
   
Me dical Hist or y  
X  
  
  
  
  
  
  
  
  
  
  
  
P h ysical E xa m  
X  
  
X  
X  
X  
X  
X  
R  
R  
X  
X  
X  
Vital Si g ns ( + wei g ht) 1  
X  
X ∆  
X  
X  
X  
X  
X  
R  
R  
X  
X  
X  
He mat ol o g y 2 *  
X  
X  
X  
X  
X  
X  
X  
R  
R  
X  
X  
X  
C o m pre he nsi ve Meta b olic Pa nel *  
X  
X  
X  
X  
X  
X  
X  
R  
R  
X  
X  
X  
Uri ne Pr otei n/ Creati ni ne *  
X  
X  
X  
X  
X  
X  
X  
R  
R  
X  
X  
X  
Ser u m pre g na nc y test 8*  
X  
X  
   
 R 8  
 R 8  
 R 8   R 8  
 R 8  R 8   
   
   
   
P R A *  
X  
X  
   
   
X  
   
X  
   
   
X  
 X  
X  
A nti H L A a nti b o dies b y L u mi ne x *   
X  
X  
   
   
X  
   
X  
   
   
X  
 X  
X  
E C G *  
X  
  
   
   
   
   
   
   
   
   
   
   
Viral Ser ol o g y 3 *  
X   
X  
   
   
   
   
   
   
   
   
   
   
I m m u n o gl o b uli n Pa nel: I g G, I g A, 
I g M b y cli nical la b *  
X  
  
  
  
X  
X  
X  
X  
X  
X  
X  
X  
Tacr oli m us Tr o u g h   
   
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ster oi d Ta per  
   
X  
   
   
   
   
   
   
   
   
   
   
Ale mt uz u ma b  
   
X  
   
   
   
   
   
   
   
   
   
   
Tacr oli m us/ M yc o p he n olic Aci d 9  
   
X  
X  
X  
X  
X  
X  
X  
X  
X   
 X  
X  
Beli m u ma b 4  
   
R 4  
   
R 4  
R 4  
R 4  
R 4  
R 4  
R 4  
   
   
   
Ki d ne y bi o ps y 5  
         
X   
   
   
   
   
   
   
   
   
   
X  
A d verse E ve nts 6  
   
R 6  
R 6  
R 6  
R 6  
R 6  
R 6  
R 6  
R 6  
R 6  
R 6  
R 6  
C o n Me ds  
R   
  
R  
R  
R  
R  
R  
R  
R  
R  
R  
R  
C yt o ki ne A nal ysis 7  
 R  
R  
   
   
R  
   
R  
   
   
R  
 R  
R  
T L y m p h oc yte A nal ysis 7  
 R  
R  
   
   
R  
   
R  
   
   
R  
R  
R  
B L y m p h oc yte A nal ysis 7  
 R  
R  
   
   
R  
   
R  
   
   
R  
 R  
R  
I m m u n o gl o b uli n A nal ysis (I g M,  
I g A, I g G) 7  
 R  
R  
   
   
R  
   
R  
   
   
R  
 R  
R  
B A F F/ A P RI L A nal ysis 7   
  R  
R  
   
   
R  
   
R  
   
   
R  
 R  
R  
1 Vital si g ns i ncl u de te m perat ure, bl o o d press ure, p ulse a n d res pirat or y rate rec or de d pri or t o eac h st u d y dr u g d ose. 
  
2 He mat ol o g y: C B C a n d differe ntial   
3 HI V, H Bs A g, a nti -H Bc, a nti -H Bs a nti b o dies, he patitis C a nti b o d y, her pes si m ple x vir us, C M V, E pstei n Barr  vir us, a n d varicella z oster vir us per sta n dar d of care. F or 
eli gi bilit y assess me nt, if t he scree ni n g vir ol o g y res ults f or HI V, H C V a n d H B V are n ot a vaila ble pri or t o tra ns pla ntati o n t he n t he m ost rece nt hist orical res ult ( wit hi n t he 
last 6 m o nt hs) will be use d. Per sta n dar d of care, t he viral ser ol o g y tests f or C M V, E pstei n Barr Vir us, a n d varicella are n ot t o be re peate d o nce f o u n d p ositi ve.   


40  
  
4 Belimumab infusion  5 Kidney biopsy will be performed at time of transplant per standard of care, and at 1 year to assess histologic response per standard of care.  
6 Adverse events recorded prior to each study drug dose and will include subject reports of changes in sleep patterns, anxiety and suicidality 
7   If subject consents: Blood collected for future research lab processing and analysis by transplant research lab 8 For Women of Child-
bearing potential, within 48 hours prior to transplant and prior to each dose of belimumab. 9 Tacrolimus and Mycophenolic Acid start date 
and dosing may be adjusted per physician discretion  
*Clinical labs drawn on the day prior to transplant (day -1) do not need to be repeated unless clinically indicated  
X=Standard of Care  
R= Procedure for Research Purposes  
∆ Blood pressure and Heart rate will be recorded within 15 minutes prior to infusion, 15±5 minutes after beginning infusion and 15±5 after completion of infusion