A Pilot Randomized Controlled Trial of De Novo Belatacept-Based Immunosuppression in Lung Transplantation
Phase: PHASE2
Conditions: Lung Transplant Rejection, Antibody-mediated Rejection
Sponsor: Washington University School of Medicine

	  
1 
A PILOT RANDOMIZED CONTROLLED TRIAL OF DE NOVO BELATACEPT-BASED 
IMMUNOSUPPRESSION IN LUNG TRANSPLANTATION 
 
Howard J. Huang, MD 
Ramsey R. Hachem, MD 
 
Study ID: IM103-387 
 
Draft:  v 6.0 
Date:  8 December 2017 
 
 

	  
2 
TABLE OF CONTENTS 
 
Section 
 
 
 
 
 
 
 
 
         Page 
1.  List of Abbreviations 
 
 
 
 
 
 
 
3 
2.  Protocol Summary  
 
 
 
 
 
 
 
4 
3.  Study Schematic  
 
 
 
 
 
 
 
4 
4.  Key Roles  
 
 
 
 
 
 
 
 
5 
5.  Introduction 
 
 
 
 
 
 
 
 
6 
6.  Objectives and Purpose 
 
 
 
 
 
 
 
7 
7.  Study Design and Endpoints 
 
 
 
 
 
 
7 
8.  Study Enrollment  
 
 
 
 
 
 
 
8 
9.  Study Agent 
 
 
 
 
 
 
 
 
11 
10.  Study Procedures and Schedule 
 
 
 
 
 
11 
11.  Safety Considerations 
 
 
 
 
 
 
 
13 
12.  Statistical Considerations 
 
 
 
 
 
 
18 
13.  References 
 
 
 
 
 
 
 
 
19 
 
 
 
 

	  
3 
LIST OF ABBREVIATIONS 
 
ACR 
Acute Cellular Rejection 
AE 
Adverse Event 
AMR 
Antibody-Mediated Rejection 
ATG 
Anti-Thymocyte Globulin 
ATS 
American Thoracic Society 
BAL 
Bronchoalveolar Lavage 
BELA 
Belatacept 
BMS 
Bristol-Myers Squibb 
BOS 
Bronchiolitis Obliterans Syndrome 
CARV 
Community-Acquired Respiratory Virus/Viral 
CBC 
Complete Blood Counts 
CFR 
Code of Federal Regulations 
CIP 
Cellular Immunophenotyping 
CKD 
Chronic Kidney Disease 
CLAD 
Chronic Lung Allograft Dysfunction 
CMP 
Comprehensive Metabolic Panel 
CMV 
Cytomegalovirus 
CNI 
Calcineurin Inhibitor 
DCC 
Data Coordinating Center 
DSA 
Donor-Specific HLA Antibodies 
DSMB 
Data Safety and Monitoring Board 
EBV 
Epstein-Barr Virus 
ECLS 
Extra-Corporeal Life Support 
ECMO 
Extra-Corporeal Membrane Oxygenation 
FOB 
Fiberoptic Bronchoscopy 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigens 
HSV 
Herpes Simplex Virus 
IgG 
Immunoglobulin G 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IS 
Immunosuppression 
ISHLT 
International Society for Heart and Lung Transplantation 
LB 
Lymphocytic Bronchiolitis 
MMF 
Mycophenolate mofetil 
MPA 
Mycophenolic acid 
PCR 
Polymerase Chain Reaction 
PGD 
Primary Graft Dysfunction 
PTLD 
Post-Transplant Lymphoproliferative Disease 
RAS 
Restrictive Allograft Syndrome 
RCT 
Randomized Controlled Trial 
SAB 
Single Antigen Bead 
SAE 
Serious Adverse Event 
TBBX 
Transbronchial lung Biopsy 
TMP/SMX 
Trimethoprim/sulfamethoxazole 
VZV 
Varicella Zoster Virus 

	  
4 
PROTOCOL SUMMARY 
 
Title 
A Pilot Randomized Controlled Trial Of De Novo Belatacept-Based 
Immunosuppression In Lung Transplantation 
Précis 
This open-label, pilot, randomized controlled trial (RCT) will compare 
the combination of Belatacept, mycophenolate mofetil (MMF) and 
prednisone to tacrolimus, MMF, and prednisone after lung 
transplantation.  The primary endpoint is a composite of the 
development of donor-specific HLA antibodies (DSA), death, or re-
transplantation.  
Objectives 
The primary objective of this pilot study is to assess the feasibility of 
conducting a pivotal RCT examining the efficacy and safety of 
Belatacept-based immunosuppression after lung transplantation. 
Endpoints 
The primary endpoint of this study is a composite of the development 
of DSA, death, or re-transplantation.  
Key secondary endpoints include the individual components of the 
composite endpoint, antibody-mediated rejection, acute cellular 
rejection, chronic lung allograft dysfunction, renal function, and 
infection 1 year after transplantation. 
Population 
40 adult lung transplant recipients  
Phase 
II 
Number of Sites 
2 sites: 
• 
Baylor University Medical Center at Dallas 
• 
Washington University School of Medicine in St. Louis 
Study Agent 
Belatacept 10 mg/kg on days 0, 7, 14, 28, 56, 84, then 5 mg/kg on 
days 112, 140, 168, 196, 224, 252, 280, 308, 336, and 364 
Study Duration 
3 years 
Participant 
Duration 
1 year + 30 day follow-up 
 
 
STUDY SCHEMATIC  
	  
	  
	  
	  
 
 
Randomize 
BELA 10 mg/kg 
Tacrolimus  
Prednisone 
BELA 5 mg/kg 
MMF / MPA 
Prednisone 
Tacrolimus 
MMF / MPA 
Prednisone 
Enroll 
N = 40 
BELA 
N = 20 
Control 
N = 20 
ATG 
Induction 
30 day Followup 
Lung Transplant 
BELA 
+ 
ATG 
Induction 
W12 
D0 
D3 
W52 
DSA 
D10 
W12 
W8 
W4 
D0 
W16 
W24 
W36 
W52 
TBBX 
W4 
W16 
W24 
W36 
W52 
W12 

	  
5 
1.  KEY ROLES 
 
Co-Principal Investigator 
Howard J. Huang, MD 
Associate Medical Director, Lung Transplantation	  
Director of Lung Transplant Research  
Annette C. and Harold C. Simmons Transplant Institute  
Baylor University Medical Center at Dallas  
3410 Worth Street, Suite 545  
Dallas, TX 75246  
Phone: 214-820-6856    
Email: Howard.Huang@BSWHealth.org 
 
Co-Principal Investigator 
Ramsey R. Hachem, MD 
Medical Director, Lung Transplantation 
Professor of Medicine 
Washington University School of Medicine in St. Louis 
4523 Clayton Ave., Campus Box 8052 
St. Louis, MO 63110 
Phone: 314-454-7953 
Email: Rhachem@wustl.edu 
 
Co-Principal Investigator and Data Coordinating Center Director 
Kenneth B. Schechtman, PhD 
Associate Professor of Biostatistics and Medicine 
Washington University School of Medicine 
4523 Clayton Ave., Campus Box 8067 
St. Louis, MO 63110-1093 
Phone: 314-362-2271 
Email: Ken@wubios.wustl.edu 
 
Histocompatibility Core Lab Investigator 
Medhat Askar, MD, PhD 
Transplant Immunology Lab Director 
Baylor University Medical Center at Dallas 
3500 Gaston Ave. 4th Floor Y-Wing 
Dallas, TX 75246 
Phone: 214-820-4602 
Email: Medhat.askar@baylorhealth.edu 
 
Pathology Core Lab Investigator 
Joseph P. Gaut, MD, PhD 
Department of Pathology and Immunology 
Washington University School of Medicine 
4523 Clayton Ave., Campus Box 8118 
St. Louis, MO 63110 
Phone: 314-747-2541 
Email: Jpgaut@path.wustl.edu 
 
 
 

	  
6 
2. INTRODUCTION 
 
2.1. BACKGROUND INFORMATION 
Belatacept is a selective costimulation blocker that prevents T-cell activation.  Belatacept is a 
fusion protein consisting of high-affinity receptor for CD80 and CD86 expressed on the surface 
of antigen-presenting cells and the Fc portion of human IgG.  By binding CD80 and CD86, 
Belatacept blocks the second signal of T-cell activation thereby promoting anergy.    
 
2.2. RATIONALE 
Lung transplantation is the ultimate treatment for patients with end-stage lung disease, and 
approximately 2000 patients undergo lung transplantation annually in the United States.  
However, long-term outcomes after transplantation remain disappointing, and the median 
survival after transplantation is approximately 5.5 years (1).  Infection and primary graft 
dysfunction (PGD) are the most common causes of death in the first year after transplantation, 
but chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year 
(1).  Different clinical phenotypes of CLAD have been defined including classic bronchiolitis 
obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), and the incidence of CLAD 
approaches 50% within 3 years of transplantation (2-4).  There is no effective evidence-based 
treatment for CLAD, and it typically follows a progressive clinical course ultimately resulting in 
allograft failure and death (4-6).  Indeed, the median survival after the diagnosis of CLAD is 
approximately 3 years, and studies have consistently shown that patients who develop CLAD 
have a significantly worse quality of life (6, 7).  Clearly, lung transplant recipients urgently need 
strategies to prevent or delay the onset of CLAD to improve survival after transplantation. 
 
The exact pathogenesis of the different phenotypes of CLAD remains unclear.  Studies have 
consistently identified multiple clinical risk factors including primary graft dysfunction (PGD), 
acute cellular rejection (ACR), lymphocytic bronchiolitis (LB), and the development of donor-
specific human leukocyte antigens (HLA) antibodies (DSA) (2, 8-12).  DSA appear to play a 
central role in the development of CLAD.  Studies have consistently identified the development 
of DSA as an independent risk factor for the development of CLAD (11, 12).  Furthermore, DSA 
cause antibody-mediated rejection (AMR) and are associated with an increased risk of high 
grade and recurrent ACR as well as LB (13, 14).  In addition, DSA may mediate the increased 
risk of CLAD associated with PGD (15).  Lastly, experimental data suggest that DSA have a 
direct pathogenic role in the development of CLAD (16-18).  These data are consistent with the 
experience with DSA in kidney transplantation (19).  However, the development of DSA after 
lung transplantation is significantly more frequent than after kidney transplantation.  Indeed, 
single center studies have reported an incidence of DSA after lung transplantation ranging 
between 25-50%, and an incidence of 39% over the first 120 days after transplantation was 
reported in a recent prospective multicenter study (11, 12, 20).  Together, these findings 
demonstrate that DSA are common early after lung transplantation and are associated with an 
increased risk of ACR, LB, AMR and CLAD.  
 
We hypothesize that Belatacept-based immunosuppression (IS) will result in a lower incidence 
of DSA development and improved clinical outcomes after lung transplantation. 
 
2.3. POTENTIAL RISKS AND BENEFITS 
 
2.3.1. KNOWN POTENTIAL RISKS 
Some studies in kidney transplantation have demonstrated an increased risk of ACR among 
patients treated with Belatacept in the place of a calcineurin inhibitor (CNI) (21, 22).  There have 
been no controlled studies of Belatacept in lung transplantation, but since the risk of ACR after 

	  
7 
lung transplantation is significantly higher than after kidney transplantation, there may be an 
increased risk of ACR for those randomized to the Belatacept arm of this study.  We have 
designed the study protocol to mitigate this potential risk.  First, all study participants will be 
treated with rabbit anti-thymocyte globulin (ATG, Thymoglobulin®) for induction IS.  This is 
considered a more intensive immunosuppressive induction agent than basiliximab (Simulect®) 
and clearly more intensive IS than no induction therapy.  In addition, participants randomized to 
the Belatacept arm will be treated with the combination of Belatacept and Tacrolimus for the first 
3 months after transplantation.  This time period after transplantation carries the highest risk of 
ACR.  Finally, we have implemented 2 additional bronchoscopies with transbronchial lung 
biopsies at days 120 (week 16) and 270 (week 36) to increase surveillance for ACR. 
 
Another potential risk associated with Belatacept-based immunosuppression is post-transplant 
lymphoproliferative disease (PTLD) (22).  This increased risk has been identified specifically 
among Epstein-Barr Virus (EBV) seronegative recipients of organs from seropositive donors.  
To minimize the risk of PTLD, we will exclude EBV seronegative patients from this study.  
 
2.3.2. KNOWN POTENTIAL BENEFITS 
Belatacept-based IS has been consistently associated with better kidney function than CNI-
based therapy (21-23).  We expect participants in this study to derive a similar benefit in kidney 
function.  Furthermore, Belatacept-treated kidney transplant recipients appear to be less likely to 
develop DSA than CNI-treated recipients (23).  The development of DSA after lung 
transplantation is significantly more frequent than after kidney transplantation, and DSA have 
been linked to all forms of lung allograft rejection.  Thus, this potential benefit of Belatacept-
based IS may result in better outcomes after lung transplantation. 
 
3. OBJECTIVES AND PURPOSE 
The primary objective of this pilot randomized-controlled trial (RCT) is to assess the feasibility of 
conducting a large-scale multicenter RCT examining the efficacy of Belatacept-based 
immunosuppression after lung transplantation.  Objective assessments of feasibility include:  
 
a. Enrollment of 50% of eligible patients at the 2 centers 
b. Randomization of 80% of eligible patients within 4 hours of completion of transplantation 
c. Retention of 75% of randomized patients on the protocol  
d. Adherence to the study drug infusion protocol in 90% of those randomized to the 
Belatacept arm 
 
4. STUDY DESIGN AND ENDPOINTS 
 
4.1. STUDY DESIGN 
This is a pilot 2-center open-label RCT comparing Belatacept-based immunosuppression to 
standard of care immunosuppression consisting of the combination of Tacrolimus, 
Mycophenolate Mofetil (MMF), and Prednisone. 
 
4.2. STUDY ENDPOINTS 
 
4.2.1. PRIMARY ENDPOINT 
The primary endpoint of the study is a composite of the development of DSA, death, or re-
transplantation after transplantation.  Development of DSA has clearly been associated with all 
forms of lung allograft rejection (ACR, LB, AMR, and CLAD).  This is a highly relevant clinical 
event and typically develops early after transplantation, making it an appealing surrogate 
endpoint.   

	  
8 
 
4.2.2. SECONDARY ENDPOINTS  
The following secondary endpoints are chosen because of their impact on outcomes after lung 
transplantation and will be assessed 1 year after transplantation: 
 
a. Individual components of the composite endpoint (DSA, re-transplantation, death). 
b. ACR International Society for Heart and Lung Transplantation (ISHLT) grade A1 or 
higher 
c. LB ISHLT grade B1R or higher 
d. DSA Immunoglobulin G (IgG) subclasses 
e. Complement binding (C1q-positive) and activating (C3-positive) DSA 
f. Definite AMR based on the ISHLT definition 
g. Probable AMR based on the ISHLT definition 
h. CLAD defined as BOS stage 1 or RAS 
i. 
CLAD-free survival 
j. 
Confirmed bacterial infection requiring antibiotic treatment 
k. Cytomegalovirus (CMV) infection requiring antiviral treatment 
l. 
Confirmed community-acquired respiratory viral infection (CARV) 
m. Chronic kidney disease (CKD) stage 3 as estimated by the Cockcroft-Gault equation 
n. Kidney function as estimated by the Cockcroft-Gault equation 
o. Malignancy excluding squamous cell and basal cell skin cancer 
p. Post-transplant Lymphoproliferative Disease (PTLD) 
q. Diabetes mellitus requiring medical treatment 
r. Systemic hypertension requiring medical treatment 
s. Hypercholesterolemia requiring medical treatment 
 
5. STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1. INCLUSION CRITERIA FOR ENROLLMENT 
 
a. Adult between 18 to 70 years of age 
b. On the waiting list for lung transplantation 
c. Willingness to participate in this study and sign informed consent 
d. For women of child bearing potential, willingness to use highly effective contraception 
 
5.2. EXCLUSION CRITERIA FOR ENROLLMENT 
Individuals who meet any of the following exclusion criteria will be excluded from study 
participation: 
 
a. Requiring invasive mechanical ventilation immediately before transplantation 
b. Requiring extracorporeal life support (ECLS) (i.e., ECMO) immediately before 
transplantation 
c. Received treatment to deplete HLA antibodies before transplantation 
d. Having DSA immediately before transplantation (i.e., positive virtual crossmatch) 
e. Multi-organ transplant recipient (e.g., heart-lung, lung-liver, lung-kidney) 
f. Pregnant or breast-feeding 
g. Active infection with Hepatitis B virus 
h. Active infection with Hepatitis C virus 
i. 
Active infection with human immunodeficiency virus (HIV) 
j. 
Chronic infection with Burkholderia cepacia complex before transplantation 
k. EBV seronegative status 

	  
9 
l. 
Participation in another interventional clinical trial 
m. Any condition that in the opinion of the site PI introduces undue risk by participating in 
this study  
 
5.3. STRATEGIES FOR RECRUITMENT AND RETENTION 
We will recruit study participants from the 2 sites’ lung transplant clinics or inpatient services (if 
appropriate candidates are hospitalized at the time of listing).  We will screen and approach 
potential participants at the time of listing for transplantation.  We will explain the study and the 
potential benefits and risks involved in participation to patients during the informed consent 
process.  The study will not enroll children (< 18 years of age) and will not enroll vulnerable 
participants (i.e., those who lack the capacity to consent or those who may perceive coercion to 
participate).  We recognize the importance of minorities and women in clinical research, and we 
will not exclude participants from this study based on race or gender.  Race and gender 
characteristics of patients being listed for transplantation are proportionate to the underlying 
diagnoses and referral patterns.  A targeted/planned enrollment table is shown below: 
 
 
Ethnic categories 
 
Racial 
categories 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Unknown 
Female 
Male 
Unknown 
Total 
American  
Indian 
0 
0 
0 
0 
0 
0 
0 
Asian 
1 
1 
0 
0 
0 
0 
2 
Pacific 
Islander 
0 
0 
0 
0 
0 
0 
0 
Black 
2 
3 
0 
0 
0 
0 
5 
White 
11 
14 
0 
3 
4 
0 
32 
More than 
1 race 
0 
0 
0 
0 
1 
0 
1 
Unknown 
0 
0 
0 
0 
0 
0 
0 
Total 
14 
18 
0 
3 
5 
0 
40 
 
      
We plan to randomize 40 patients at the 2 sites over 15 months. Over the past 3 years, a mean 
108 patients have undergone lung transplantation annually at the 2 sites, and in 2016, 123 

	  
10
patients underwent lung transplantation at the 2 sites.  Based on these data, we expect that 
approximately 135 patients will undergo transplantation at the 2 sites over the 15-months study 
enrollment period.  We have planned to enroll a conservative number of patients because we 
expect that some patients may be ineligible and others may not consent to participate.  
Nonetheless, we plan to screen all patients listed for transplantation at the 2 sites and approach 
those who are eligible to consent. 
 
5.4. PARTICIPANT WITHDRAWAL OR TERMINATION 
Participants are free to withdraw from study participation at any time upon request.  The 
investigators may terminate study participation if a participant has an adverse event (AE), a 
serious adverse event (SAE), or any medical condition such that continued participation in the 
study would not be in the best interest of the participant.  The investigators may withdraw 
participants randomized to the Belatacept arm from the study for any of the indications outlined 
in 5.4.1.: 
 
5.4.1. INDIVIDUAL PATIENT-SPECIFIC STOPPING RULES 
 
a. Three episodes of ACR grade A2 or higher 
b. Three episodes of LB grade B1R or higher 
c. Development of CLAD 
d. Development of AMR 
e. Serious infectious complication that in the opinion of investigator warrants changing the 
maintenance immunosuppressive regimen 
f. 
Malignancy including PTLD, but excluding skin cancer 
 
Upon withdrawal from the study protocol, these participants will be treated with a regimen 
deemed most appropriate by the patient’s primary transplant physician. 
 
5.5. STUDY-WIDE STOPPING RULES 
Circumstances that may warrant termination or suspension of the study include determination of 
unexpected, significant, or unacceptable risk to participants.  Study-wide stopping rules will be 
based on the comparison of rates of the following clinical outcomes between the 2 treatment 
groups: 
 
a. Incidence of DSA 
b. Incidence of CLAD 
c. Incidence of AMR 
d. Incidence of serious infection that in the opinion of the investigator warrants changing 
the maintenance immunosuppressive regimen 
 
Safety assessments will be made every 12 months after initiation of randomization, and the 
investigators will terminate or suspend the study if the Belatacept group has a significantly 
higher incidence of any of the above outcomes (5.5.a.-d.) than the standard of care 
immunosuppression group.  In addition, the Data Safety and Monitoring Board (DSMB) may 
develop additional stopping rules for safety concerns.  Safety data including AEs, SAEs, 
laboratory test abnormalities, and treatment failures will be presented by treatment group at 
each DSMB meeting.  Summary statistics and/or plots of the key outcomes will be provided to 
the DSMB at each meeting to allow appropriate assessment of the relative risks and benefits.  
We do not plan to include a futility monitoring plan or an efficacy-stopping rule because this is a 
phase II trial with the potential for collecting valuable information for designing the subsequent 
clinical trial or identifying potential subgroups of interest..  The investigators will promptly inform 

	  
11
the IRB, Bristol-Myers Squibb (BMS), and the NIH and provide the reasons for temporary 
suspension or termination.  If suspended, the study may resume once concerns about safety, 
protocol compliance, or data quality are addressed and satisfy the necessary regulatory 
agencies.   
 
5.6. ETHICAL CONSIDERATIONS 
The study will be conducted in the following manner: 
 
a. In accordance with Good Clinical Practice (GCP), as defined by the International 
Conference on Harmonization (ICH), World Health Organization (WHO) and any local 
directives. 
b. In compliance with the protocol. 
c. The protocol, any amendments, and the subject informed consent will receive 
Institutional Review Board / Independent Ethics Committee (IRB/IEC) approval / 
favorable opinion before initiation of the study. 
d. With personnel who are qualified by education, training, and experience to perform their 
respective tasks and that the study will not use the services of study personnel for whom 
sanctions have been invoked or where there has been scientific misconduct or fraud. 
e. With signed, dated informed consent from each of the participants. 
f. 
Investigators must ensure that subjects are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer 
to participate. The approved informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.  
g. Inclusion of relevant safety information regarding dose / schedule of IP and any other 
drugs / procedures.  
h. BMS and health authorities will have direct access to study records. 
i. 
Inclusion of information outlining BMS support of the study (study drug, funding, etc.) 
 
 
6. STUDY AGENT 
Belatacept (Nulojix) will be provided by BMS for use in this study and will be stored and 
dispensed by the 2 sites’ investigational drug service pharmacies.  Based on experience in 
kidney transplantation, Belatacept will be dosed at 10 mg/kg on days 0, 7, 14, 28, 56, 84, then 
at 5 mg/kg on days 112, 140, 168, 196, 224, 252, 280, 308, 336 and 364, where day 0 is the 
day of transplant. After the initial 4 doses on days 0, 7, 14 and 28, subsequent doses may be 
given ± 3 days. 
 
7. STUDY PROCEDURES AND SCHEDULE 
 
7.1. RANDOMIZATION 
Participant eligibility for randomization will be determined within 4 hours of completion of 
transplantation (transfer to the intensive care unit from the operating room). 
 
7.1.1. INCLUSION CRITERIA FOR RANDOMIZATION 
 
a. Provided written informed consent for participation in this study 
b. Underwent single or bilateral lung transplant 
c. Negative urine pregnancy test for women of child bearing potential 
 
7.1.2. EXCLUSION CRITERIA FOR RANDOMIZATION 
 

	  
12
a. Allograft dysfunction requiring ECMO support 
b. Delayed chest closure (i.e., primary chest closure not yet performed) 
c. Severe coagulopathy and clinically significant bleeding in the opinion of the site PI 
d. Any condition that in the opinion of the site PI introduces undue risk by participating in 
this study 
  
7.1.3. RANDOMIZATION PROCEDURE AND GROUPS 
Enrolled participants will be assessed within 4 hours of arriving in the ICU after transplant. 
Eligible participants will be randomized, within center, and blocked to prevent temporal bias 
using a computer-generated method with a 1:1 ratio to on one of 2 treatment assignments: 
 
a. Belatacept-based immunosuppression 
i. Belatacept + Tacrolimus + Prednisone from day 0 through day 89, then 
ii. Belatacept + Mycophenolate Mofetil + Prednisone from day 90 through day 365 
b. Tacrolimus + Mycophenolate Mofetil + Prednisone 
 
7.1.4. BELATACEPT DOSING AND DIAGNOSTIC TESTING SCHEDULE 
 
 
 
7.2. STUDY AND STANDARD OF CARE PROCEDURES 
Routine clinical assessment of study participants will be performed according to the sites’ 
clinical protocols.  After discharge from the transplant hospitalization, patients are seen in the 
lung transplant clinic every 1-2 weeks for the first 3 months after transplantation then every 4 
weeks through the 1st year after transplantation at both sites.  These clinic visits include a 
medical history, medication history, physical examination, routine lab work, chest x-ray, and 
spirometry.  Certified and trained respiratory therapists will conduct spirometry measurements 
according to American Thoracic Society (ATS) guidelines.  Unscheduled visits are arranged on 
an as-needed basis if patients develop signs or symptoms of allograft dysfunction or another 
complicating condition.  Participants will undergo fiberoptic bronchoscopy (FOB) with 
bronchoalveolar lavage (BAL) and transbronchial lung biopsies (TTBX) on days 28, 84, 112, 
168, 252, and 365 (± 14 days).  In addition, patients will undergo bronchoscopy with BAL and 
lung biopsies for clinical indications (i.e., if they develop signs or symptoms of allograft 
dysfunction).   
 
7.3. LABORATORY PROCEDURES AND EVALUATIONS  
Routine blood work including complete blood counts (CBC), comprehensive metabolic panels 
(CMP), blood CMV polymerase chain reaction (PCR), and trough levels of tacrolimus will be 
done according to the sites’ clinical protocols twice weekly during the first 3 months after 
transplantation then monthly through the 1st year after transplantation.  In between these time 
BELA 10 mg/kg 
Tacrolimus  
Prednisone 
BELA 5 mg/kg 
MMF / MPA 
Prednisone 
TBBX 
W4 
W16 
W24 
W36 
W52 
W12 
BELA 
W4 
D14 
D7 
D0 
W8 
W12 
W24 
W20 
W28 
W32 
W36 
W40 
W44 
W48 
W16 
CIP 
W52 
W36 
W24 
W16 
W12 
W4 
D10 
D0 
W8 
D10 
W8 
W4 
D0 
W12 
W24 
W36 
W52 
W16 
DSA 
W52 

	  
13
points, patients may require unscheduled lab evaluations on an as needed basis.  A urine 
pregnancy test will be performed on all women of child bearing potential at enrollment, at 
randomization, and before conversion from Tacrolimus to mycophenolate mofetil on day 90 for 
study participants randomized to Belatacept therapy.   
 
Blood will be drawn for DSA testing on days 0 and 10 (± 3 days), and days 28, 56, 84, 112, 168, 
252, and 365 (± 14 days).  Samples will be tested for DSA using Luminex Single Antigen Bead 
(SAB) assay (One Lambda, Canoga Park, CA). If a sample tests positive for DSA, follow up 
testing will be performed for IgG subclasses (IgG 1, 2, 3 and 4), and markers of complement 
binding and activation (C1q and C3). The BUMC Transplant Immunology Lab will serve as the 
study core lab for antibody testing. Specimens from WUSM participants will shipped to the 
BUMC core lab for processing and analysis. Blood samples will be drawn at the same time 
points for cellular immunophenotyping (CIP) assays to be performed at both centers using pre-
validated DuraClone IM flow cytometry panels (Beckman Coulter, Brea, CA) (24).  
 
7.4. CONCOMITANT AND PROPHYLACTIC MEDICATIONS 
All study participants will be treated with ATG (3 mg/kg divided into 3 daily doses starting on day 
0) for induction immunosuppression.  Tacrolimus will be initiated enterally or sublingually within 
the first 48 hours after transplantation and dosed to target a trough blood level of 8-15 ng/mL.  
On day 90, mycophenolate mofetil (MMF) will be substituted for tacrolimus in the Belatacept 
arm and will be dosed at 1 g twice daily (or converted to enteric coated mycophenolic acid 
(Myfortic) 720 mg twice daily in the event of gastrointestinal toxicity).  In the control arm, MMF 
will be initiated intravenously at 1 g twice daily on day 0 and will be converted to enteral dosing 
at 1 g twice daily once the patient can take oral medications or enteric coated mycophenolic 
acid (Myfortic) 720 mg twice daily in the event of gastrointestinal toxicity.  All study participants 
will be treated with methylprednisolone 500 mg intravenously before perfusion of the allograft 
during the transplant procedure, then methylprednisolone 0.5 mg/kg intravenously twice daily for 
6 doses, then prednisone 0.5 mg/kg orally daily through day 14, then 0.2 mg/kg daily through 
day 30, then 0.1 mg/kg daily through day 180, then 5 mg daily through day 365. 
 
All study participants will be treated with trimethoprim/sulfamethoxazole (Bactrim), dapsone, 
inhaled pentamidine, or atovaquone for Pneumocystis jirovecii prophylaxis throughout the study 
period.  Recipients at risk for CMV infection (i.e., seronegative recipients of seropositive donors 
or seropositive recipients) will be treated with valganciclovir for CMV prophylaxis through day 
365.  Recipients who are not at risk for CMV infection (i.e., seronegative recipients of 
seronegative donors) will be treated with acyclovir or valacyclovir for herpes simplex virus (HSV) 
and varicella zoster virus (VZV) prophylaxis throughout the study period.  Antifungal prophylaxis 
will be tailored to culture results from bronchoscopy specimens and pre-transplant cultures.   
 
7.5. SCHEDULE OF EVENTS TABLE 
Below is a table illustrating the schedule of study and clinical events.  Time windows for each 
time point are listed above.  Unscheduled visits may occur at any time point after randomization, 
and data from these unscheduled visits will be included in the study analyses as appropriate.   
 
TIME POINTS 
 
Week 
 
0 
 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Day 
 
0 
10 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
365 
EVENTS 
 
Screening 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 

	  
14
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
CBC, CMP 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug level 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMV blood PCR 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-ray 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometry 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DSA  
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
CIP 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
X 
TBBX 
 
 
 
X 
 
X 
X 
 
X 
 
 
X 
 
 
 
X 
AE evaluation 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
8. SAFETY CONSIDERATIONS 
 
8.1 SERIOUS ADVERSE EVENT DEFINITION 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 
a. Results in death 
b. Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
c. Requires inpatient hospitalization or causes prolongation of existing hospitalization 
d. Results in persistent or significant disability or incapacity 
e. Results in a congenital anomaly or birth defect 
f. 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the other serious outcomes listed in the 
definitions above. Examples of such events include, but are not limited to, intensive 
treatment in an emergency department or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization.    
g. Results in potential Drug Induced Liver Injury (DILI) 
h. Results in suspected transmission of an infectious agent (pathogenic or nonpathogenic) 
via the study drug 
i. 
Although pregnancy, overdose and cancer are not always considered serious by 
regulatory definition, these events must be handled as SAEs.  
 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
 
a. A visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
b. Elective surgery, planned prior to signing consent 
c. Admissions as per protocol for planned medical or surgical procedure 
d. Routine health assessment requiring admission for baseline/trending of health status 
(e.g. routine colonoscopy) 
e. Medical / surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases. 
f. 
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical or surgical intervention (e.g. lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason.  
 
8.2. SERIOUS ADVERSE EVENT REPORTING – Sponsor  

	  
15
Procedures for safety reporting to BMS (Sponsor) are described below: 
 
a. All Serious Adverse Events (SAEs) that occur following a study subject’s written consent 
in the study through 30 days of discontinuation of study drug dosing will be reported to 
BMS Worldwide Safety: Worldwide.Safety@BMS.com.  
b. A MedWatch Form 3500A (Food & Drug Administration) reviewed and approved by BMS 
will be used to report all SAEs. The BMS protocol ID number will be included on all Form 
3500A submitted by the Sponsor or Investigators. 
c. Following the study subject’s written consent to participate in the study, all SAEs, 
whether related or not related to the study drug, are collected, including those thought to 
be associated with protocol-specified procedures. The Investigators will report any SAE 
occurring after these time periods that is believed to be related to study drug or protocol-
specified procedure. For drugs with potential for delayed SAEs (e.g. delayed excretion of 
the parent or active metabolites), a longer follow-up period may be warranted to allow 
collection of these SAEs, laboratory tests and other assessments.  
d. The Sponsor will reconcile the clinical database SAE cases (case level only) transmitted 
to 
BMS 
Global 
Pharmacovigilance 
& 
Epidemiology 
(GPV&E): 
Worldwide.Safety@BMS.com. Reconciliation will be performed every 3 months and prior 
to database lock or final data summary. BMS GPV&E will email, upon request from the 
Investigators, the GPV&E reconciliation report. Requests for reconciliation should be 
sent to aebusinessprocess@bms.com. The data elements listed on the GPV&E 
reconciliation report will be used for case identification purposes. If the Investigators 
determine a case was not transmitted to BMS GPV&E, the case will be sent immediately 
to BMS. 
e. In accordance with local regulations, BMS will notify Investigators of all reported SAEs 
that are suspected (related to the investigational product) and unexpected (i.e., not 
previously described in the investigator brochure). An event meeting these criteria is 
termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). Investigator 
notification of these events will be in the form of a SUSAR report.  
f. 
Other important findings which may be reported by BMS as an Expedited Safety Report 
(ESR) include: increased frequency of a clinically significant expected SAE, an SAE 
considered associated with study procedures that could modify the conduct of the study, 
lack of efficacy that poses significant hazard to study subjects, clinically significant safety 
finding from a nonclinical (e.g. animal) study, important safety recommendations from a 
study data monitoring committee, or Sponsor decision to end or temporarily halt a 
clinical study for safety reasons.  
g. Upon receiving an ESR from BMS, the Investigators must review and retain the ESR 
with the investigator brochure (IB). Where required by local regulations or when there is 
a central IRB/IEC for the study, the Sponsor will submit the ESR to the appropriate 
IRB/IEC. The Investigators and IRB/IEC will determine if the informed consent requires 
revision. The Investigators should also comply with the IRB/IEC procedures for reporting 
any other safety information.  
h. Suspected SAEs (whether expected or unexpected) shall be reported by BMS to the 
relevant local health authorities (either as expedited and/or in aggregate reports).  
i. 
SAEs, whether related or not related to study drug, and pregnancies will be reported to 
BMS within 24 hours. SAEs will be recorded on a BMS approved MedWatch Form 
3500A; pregnancies will be reported on a Pregnancy Surveillance Form.  
 
SAE Email Address: Worldwide.Safety@BMS.com 
 
 
SAE FAX Number: 609-818-3804 

	  
16
 
j. 
If only limited information is initially available, follow-up reports will be submitted. 
(Follow-up SAE reports will include the same Investigator term(s) initially reported.) 
k. If an ongoing SAE changes in its intensity or relationship to the study drug or if new 
information becomes available, a follow-up SAE report will be sent within 24 hours to 
BMS (or designee) using the same procedures used for transmitting the initial SAE 
report.  
l. 
All SAEs will be followed to resolution or stabilization.  
 
8.3 SERIOUS ADVERSE EVENT REPORTING – FOOD & DRUG ADMINISTRATION (FDA) 
Procedures for safety reporting to the FDA are described below: 
 
a. Any event that is both serious and unexpected will be reported to the FDA as soon as 
possible and no later than 7 days (for a death or life-threatening event) or 15 days (for all 
other SAEs) after the Investigator or Institution’s receipt of the information. BMS will be 
provided with a simultaneous copy of all adverse events filed with the FDA.  
b. SAEs will be reported on MedWatch Form 3500A via electronic submission 
(http://www.accessdata.fda.gov/scripts/medwatch/). Alternatively, Form 3500A can be 
sent to the FDA at: 
 
MEDWATCH 
6500 Fishers Lane 
Rockville, MD 20852-9787 
FAX: 1-800-FDA-0178 (1-800-332-0178)  
 
8.4 ADVERSE EVENT DEFINITION 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a 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 (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of investigational product, 
whether or not considered related to the investigational product.  
 
Causal relationship to the study drug is determined by a physician and will be used to assess all 
adverse events. The causal relationship can be one of the following: 
 
a. Related: There is a reasonable causal relationship between study drug administration 
and the AE.  
b. Not Related:  There is not a reasonable causal relationship between study drug 
administration and the AE.  
 
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship. 
 
Adverse effects can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. In order to prevent reporting bias, subjects should not 
be questioned regarding the specific occurrence of one or more AEs.  
 
8.5 NONSERIOUS ADVERSE EVENT REPORTING  
A nonserious adverse event is defined as an AE not classified as serious 
 

	  
17
a. Nonserious adverse events will be provided to BMS in aggregate via interim or final 
study reports as specified in the agreement or as part of an annual reporting requirement 
(FDA IND).  
b. The collection of nonserious AE information will begin at the initiation of the study drug. 
All nonserious AE (not only those deemed to be treatment-related) will be collected 
continuously during the treatment period and for a minimum of 30 days after the last 
dose of study drug.  
c. Nonserious AEs will be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up will also be conducted for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study 
treatment as appropriate. 
 
8.6 LABORATORY TEST ABNORMALITIES 
All laboratory test results captured as part of this study will be recorded following institutional 
procedures and stored in a database maintained by the DCC. Test results that constitute SAEs 
will be documented and reported.  
 
The following laboratory abnormalities will be documented and reported appropriately: 
 
a. Any laboratory test result that is clinically significant or meets the definition of an SAE 
b. Any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 
c. Any laboratory abnormality that required the subject to receive specific corrective 
therapy 
d. Potential Drug Induced Liver Injury (DILI) 
Whenever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs meeting the defined criteria will be reported as SAEs. Potential Drug Induced Liver 
Injury is defined as: 
 
1. ALT or AST elevation > 3 times upper limit of normal (ULN) AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) 
3. No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to be 
hepatotoxic.  
 
8.7 PREGNANCY 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half lives (~ 49 days) after product administration, the investigational 
product will be permanently discontinued. 
 
Investigators will immediately notify BMS Worldwide Safety: Worldwide.Safety@BMS.com of 
the event using the Pregnancy Surveillance Form in accordance with SAE reporting procedures 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information will be reported on the Pregnancy 
Surveillance Form.  
 

	  
18
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on the pregnancy will be collected on the Pregnancy Surveillance Form.  
 
8.8 OVERDOSE 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose will be 
reported as an SAE.  
 
8.9 OTHER SAFETY CONSIDERATIONS 
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious 
AE, as appropriate and reported accordingly.   
 
8.10 DATA AND SAFETY MONITORING BOARD 
The primary role of the Data and Safety Monitoring Board (DSMB) is to advise on scientific, 
safety, ethical and other policy issues relating to the study. DSMB members will:  
a. Familiarize themselves with the study protocol, communicate by teleconference or email 
and develop a charter.  
b. Propose appropriate analyses and meet periodically to review developing outcome and 
safety data. 
c. Designate a board member to record and maintain minutes for all meetings.  
d.  
 
9. STATISTICAL CONSIDERATIONS 
 
9.1. SAMPLE SIZE CALCULATION 
All power computations are based on two sided tests with p value ≤ 0.05 considered statistically 
significant.  They reflect a dichotomous composite primary endpoint:  the development of DSA, 
death, or re-transplantation 1 year of transplantation.  Power computations are based on various 
rates of development of the composite primary endpoint in the control group and in the 
Belatacept group.  The incidence of DSA within 1 year of lung transplantation has been shown 
to be 50-60% in recent studies, and 15% of patients die or undergo re-transplantation within 1 
year.  However, no data currently exist on the incidence of DSA or survival in lung transplant 
recipients treated with Belatacept.  Data in kidney transplantation suggest that the incidence of 
DSA among Belatacept-treated patients is approximately 5%. The table below provides sample 
size estimates for different DSA incidences in the 2 groups.  For example, if the incidence of 
DSA in the Belatacept group is 20% and the incidence in the control group is 50%, the study will 
have 90% power to detect this difference if 58 subjects are enrolled in each study arm. 
 
 
Power Primary endpoint in control group 
Primary endpoint in Belatacept group  
 
35% 
40% 
45% 
50% 
60% 
10% 
90% 
65 
48 
38 
30 
21 
80% 
51 
38 
30 
24 
17 
15% 
90% 
106 
73 
54 
41 
27 
80% 
82 
57 
42 
33 
21 
20% 
90% 
198 
115 
80 
58 
34 
80% 
151 
91 
62 
45 
27 
25% 
90% 
459 
216 
127 
85 
46 
80% 
349 
165 
98 
66 
36 

	  
19
 
We plan to randomize 40 patients in a 1:1 fashion (20 per group); thus, we do not anticipate that 
this pilot study will be sufficiently powered to detect a statistically significant difference in the 
incidence of DSA between the 2 groups.  However, the primary objective of the pilot study is to 
assess the feasibility of conducting a large scale pivotal RCT.  Nonetheless, this pilot study will 
generate an estimate and 95% confidence intervals of the incidence of DSA development, 
death, and re-transplantation among lung transplant recipients treated with Belatacept-based 
immunosuppression.  This will be important in making appropriate power computations and 
sample size calculations for the pivotal RCT. 
 
9.2. STATISTICAL ANALYSES 
We will compare baseline characteristics across groups using t-tests (or Wilcoxon-Rank sum 
tests if the data are not normally distributed) and chi-square tests.  We will use survival models 
(Kaplan-Meier method using the log rank test and Cox proportional hazards models) to compare 
freedom from the composite primary endpoint between the 2 groups to enhance the power of 
the analyses.  We will use Cox proportional hazards models to adjust for covariates that include 
age, gender, race, primary diagnosis, HLA mismatch status, PGD grade, episodes of acute 
rejection, and CARV infection.  Because of the relatively small sample size in this pilot study, we 
will adjust for only one covariate at a time and will use separate Cox models for each covariate.  
Thus, we do not plan to develop risk models for the outcome.  However, in the larger pivotal 
trial, we would have an opportunity to use more complex statistical models.  Similarly, we will 
analyze secondary outcomes using the Kaplan-Meier method and the log rank test and Cox 
models.  All of the analyses will be conducted on an intention-to-treat basis that includes all 
subjects who are randomized.  However, we will also conduct secondary analyses on a per 
protocol basis, recognizing that these can be potentially biased.   
 
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