Clinical trial NCT00421174
Conditions: Pneumonia Idiopathic Pneumonia Syndrome
Keywords: Etanercept IPS
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Start date: 2007-08-01; Completion date: 2013-07-01
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is designed as a Phase III, multi-center randomized, double-blind, placebo-controlled trial investigating the use of etanercept for the treatment of acute, non-infectious pulmonary dysfunction (IPS) occurring after allogeneic hematopoietic cell transplantation (HCT).

Detailed description:
BACKGROUND:

Over the last two decades, allogeneic hematopoietic cell transplantation (HCT) has emerged as an important treatment for a number of malignant and non-malignant disorders. Unfortunately, several complications, including graft-versus-host disease (GVHD) and pulmonary dysfunction, limit the utility of this aggressive form of therapy. Infectious and non-infectious lung complications occur in 25% to 55% of HCT recipients and account for up to 50% of transplant-related mortality. In about half of affected patients, no infectious organisms are identified in the lungs. Two major types of non-infectious pulmonary injury are recognized: acute idiopathic pneumonia syndrome (IPS) and sub-acute lung injury (obstructive airway disease or bronchiolitis obliterans \[BrOb\] and restrictive lung disease). The current study will examine the use of etanercept in patients with IPS.

DESIGN NARRATIVE:

Eligible patients will be randomized to receive one of two arms of therapy: (A) etanercept plus corticosteroids, or (B) placebo plus corticosteroids. Patients will receive a total of eight doses of etanercept (or placebo) over a 4-week period. The initial dose of etanercept (or placebo) will be administered intravenously on Day 0, with subsequent doses administered subcutaneously (SQ). Dosing will be administered twice weekly over 4 consecutive weeks. The placebo will be the inert diluent used for the etanercept formulation.

Additionally, patients in both arms will receive corticosteroids (2 mg/kg/day) Day 0 through Day 7, with subsequent taper as clinically indicated. Chest radiographs shall be obtained weekly through Day 28. Plasma cytokine profiles will be obtained on Days 0, 7, and 28.

For patients \< 30 days post-transplant: If the patient's clinical condition is such that a broncho-alveolar lavage (BAL) is deemed "not possible to be performed" by the treating physician (or pulmonologist), then the "on study" BAL may be waived. In such circumstances, the patient may register and be randomized to study therapy without the BAL being undertaken.

For patients not on mechanical ventilation: If a BAL is not done, appropriate virology studies on a nasal swab (or nasal washing) are required as a minimum procedure to study entry.

For patients on mechanical ventilation: Microbiologic studies of a deep endotracheal aspirate are allowed in lieu of a formal bronchoscopy procedure. However, no protocol-specified biologic studies (see Section 4.4) will be done on these specimens.

For patients 31-180 days post-transplant: An "on study" bronchoscopy is required in all cases.

If, at any point following initiation of study drug therapy, previously obtained BAL fluid cultures or other BAL fluid analysis become positive for an infectious pathogen, study drug therapy shall be discontinued at that point, and not re-instituted. The patient will discontinue study drug therapy, but will still be followed for outcome.

The primary study endpoint is response at Day 28. Patients who discontinue study drug therapy for any reason will still be followed for primary and secondary study endpoints.

Arms: arm 1: Etanercept plus corticosteroids arm 2: Placebo plus Corticosteroids
Interventions: intervention 1: Etanercept intervention 2: Placebo plus corticosteroid
Intervention descriptions: intervention 1: Etanercept will be given eight doses of study drug over a 4-week period. The initial dose of etanercept will be administered intravenously on Day 0, with subsequent doses administered subcutaneously (SQ). Dosing will be administered twice weekly over 4 consecutive weeks. Additionally, patients in both arms will receive corticosteroids (2 mg/kg/day) Day 0 through Day 7, with subsequent taper as clinically indicated. intervention 2: Patients will receive a total of eight doses of placebo over a 4-week period. The initial dose of placebo will be administered intravenously on Day 0, with subsequent doses administered subcutaneously (SQ). Dosing will be administered twice weekly over 4 consecutive weeks. The placebo will be the inert diluent used for the etanercept formulation.

Additionally, patients in both arms will receive corticosteroids (2 mg/kg/day) Day 0 through Day 7, with subsequent taper as clinically indicated.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
 
 
A Randomized Double-Blind, Placebo-Controlled Trial of Soluble 
Tumor Necrosis Factor Receptor: Enbrel (Etanercept) for the 
Treatment of Acute Non-Infectious Pulmonary Dysfunction 
(Idiopathic Pneumonia Syndrome) Following  
Allogeneic Cell Transplantation 
 
 
BMT CTN PROTOCOL 0403 
VERSION 5.0 
 
Study Chairpersons 
Gregory Yanik, M.D.1 
Kenneth Cooke, M.D.1 
 
Protocol Team 
Jennierose D’Elia 3 
Becky Drexler 4 
James Ferrara, M.D. 1 
Sergio Giralt, M.D. 5 
Vincent Ho, M.D. 6 
Mary Horowitz, M.D., M.S. 4 
 
Brent Logan Ph.D. 4 
David Madtes, M.D. 7 
Robert Soiffer, M.D. 6 
Daniel Weisdorf, M.D. 8 
Eric White, M.D. 1 
 
 
Sponsored by the National Institutes of Health 
National Heart, Lung and Blood Institute 
National Cancer Institute 
 
 
 
1 University of Michigan Medical Center 
2 University Hospitals of Cleveland 
3 The EMMES Corporation 
4 Center for International Blood and Marrow 
Transplant Research, National Marrow 
Donor Program 
5 Memorial Sloan-Kettering Cancer Center  
6 Dana Farber Cancer Institutes 
7 Fred Hutchinson Cancer Research Center 
8 University of Minnesota 
 


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Core Study Participants: 
 Affiliate Study Participants: 
Dana Farber/Partners Cancer Center 
Duke University Medical Center-Adult  
Fred Hutchinson Cancer Research Center 
Johns Hopkins University 
Memorial Sloan-Kettering Canter Center 
Oregon Health Sciences University  
University Hospitals of Cleveland/Case Western 
University of Florida College of Medicine (Shands) 
University of Michigan Medical Center 
University of Minnesota 
University of Pennsylvania Cancer Center 
University of Texas, MD Anderson Cancer Center 
 
 Indiana BMT at Beech Grove 
Indiana University Medical Center 
Mayo Clinic 
 
 
 


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PROTOCOL SYNOPSIS – BMT CTN PROTOCOL 0403 
 
A Randomized Double-Blind, Placebo-Controlled Trial of Soluble Tumor Necrosis Factor 
Receptor: Enbrel (Etanercept) for the Treatment of Acute Non-Infectious Pulmonary 
Dysfunction (Idiopathic Pneumonia Syndrome) Following Allogeneic Cell Transplantation 
 
 
Co-Principal Investigators: Gregory Yanik, M.D., Kenneth Cooke, M.D. 
 
Study Design: 
The study is designed as a Phase III, multi-center randomized, 
double-blind, placebo-controlled trial investigating the use of 
etanercept for the treatment of acute, non-infectious pulmonary 
dysfunction (IPS) occurring after allogeneic hematopoietic cell 
transplantation (HCT).   
 
Primary Objective: 
To determine the Day 28 response rate following treatment with 
etanercept plus corticosteroids compared to placebo plus 
corticosteroids for patients with IPS post allogeneic HCT.  
Response will be defined as (a) Survival to Day 28 of study, plus 
(b) Discontinuation of all supplemental oxygen support for > 72 
consecutive hours by Day 28.  
 
Secondary Objectives: 
To evaluate response to therapy at Day 56. 
To evaluate overall mortality in patients with IPS. 
To evaluate time to discontinuation of supplemental oxygen. 
 
To evaluate pro-inflammatory markers of pulmonary disease, in 
both BAL fluid and plasma, in patients with IPS.   
 
 
Eligibility Criteria: 
Eligible patients are ≥ 18 years of age and must be ≤ 180 days 
status post an allogeneic bone marrow, cord blood, or peripheral 
blood stem cell transplant.  Patients must have evidence of 
idiopathic pneumonia syndrome, based upon the presence of 
bilateral pulmonary infiltrates (on chest radiograph) plus a 
supplemental oxygen requirement.  The patient cannot have 
evidence for sepsis syndrome, or uncontrolled bacterial, invasive 
fungal or viral infections at the time of study registration.  In 
addition, patients receiving mechanical ventilation for > 168 hours 
(7 days) at the time of study registration are ineligible.  


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Registration and Randomization:   
 
Patients will be registered prior to undergoing a broncho-alveolar 
lavage (BAL) procedure.  Initial diagnostic studies are then 
performed on the BAL fluid, and if negative, the patient is eligible 
for study randomization.  Patients whose BAL special stains (gram 
stain and fungal stain) or whose initial BAL fluid cultures are 
abnormal are ineligible for study randomization.   
 
BAL Procedure:  
BAL samples are recommended to be collected from both the right 
and left sided airways and then pooled together.  BAL fluid 
samples shall be sub-divided and distributed for the following 
assays: 
Hematology 
(5 
mL), 
Microbiology 
(5-10 
mL), 
Cytopathology (5 mL) and Cytokine analysis (5 mL) 
 
 
All BAL fluid will be analyzed for the presence of bacterial, viral, 
fungal, PCP, and mycobacterial organisms as outlined in Section 
4.4.2.  BAL fluid will also be analyzed for inflammatory markers 
of disease, including but not limited to IL-1, IL-2, IL-6, TNF, 
sTNFR, TGF-, and for components of the lipopolysaccharide 
(LPS) activation system (LPS, LPB, and CD14).  BAL fluid 
samples for the above biology studies (inflammatory markers) will 
be initially cryopreserved for subsequent analysis.   
 
 
 
See Section 4.4.2 for full discussion of BAL procedure, Section 
2.6.3 for circumstances in which the “on therapy” BAL may be 
waived and Appendix C for sample handling and processing.  
 
Treatment Description: 
Eligible patients will be randomized to receive one of two arms of 
therapy: (A) etanercept plus corticosteroids, or (B) placebo plus 
corticosteroids.  Patients will receive a total of eight doses of study 
drug (etanercept/placebo) over a 4-week period.  The initial dose 
of 
study 
drug 
(etanercept/placebo) 
will 
be 
administered 
intravenously on Day 0, with subsequent doses administered 
subcutaneously (SQ).  Dosing will be administered twice weekly 
over 4 consecutive weeks.  The placebo will be the inert diluent 
used for the etanercept formulation.  
 
Additionally, patients in both arms will receive corticosteroids  
(2 mg/kg/day) Day 0 through Day 7, with subsequent taper as 
clinically indicated.  Chest radiographs shall be obtained weekly 
through Day 28.  Plasma cytokine profiles will be obtained on 
Days 0, 7 and 28.  
 
If, at any point following initiation of study drug therapy, 
previously obtained BAL fluid cultures or other BAL fluid analysis 


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become positive for an infectious pathogen, study drug therapy 
shall be discontinued at that point, and not re-instituted.  The 
patient will discontinue study drug therapy, but will still be 
followed for outcome.  
The primary study endpoint is response at Day 28, with response 
defined as above (see Primary Objectives).  Patients who 
discontinue study drug therapy for any reason will still be followed 
for primary and secondary study endpoints.  
 
Accrual Objective: 
A maximum of 60 patients will be enrolled on study, 30 per arm.   
 
Accrual Period:  
5 years. 
 
Study Duration: 
Patients will be followed for 1 year after randomization. 


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Outline of Treatment Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 
STUDY REGISTRATION  
BRONCHOSCOPY / BAL  
BAL “special stains” abnormal 
BAL “special stains” normal 
STOP: INELIGIBLE FOR THERAPY 
RANDOMIZE (DAY 0) 
Arm A: Etanercept plus corticosteroids 
Arm B:  Placebo plus corticosteroids 
Etanercept/Placebo: Day 0-28 
First dose IV, then subsequent doses SQ 
Total number of doses: 8 
Dosing interval:  Every 3-4 days 
Corticosteroids: Day 0-56 
2 mg/kg/day x 7 days, then taper 
allowed.  IV dosing for first 3 days, 
then IV / PO 
RESPONSE ASSESSMENT: Day 28 and 56 
Key: SQ, subcutaneous, IV, intravenous 


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TABLE OF CONTENTS 
 
 
1. 
BACKGROUND AND RATIONALE ................................................................................... 1-1 
1.1. 
Background ............................................................................................................................ 1-1 
1.2. 
IPS Overview ......................................................................................................................... 1-1 
1.3. 
Incidence of IPS: Investigator’s Experience ......................................................................... 1-1 
1.4. 
Role of Tumor Necrosis Factor Alpha in the Pathogenesis of IPS ....................................... 1-2 
1.5. 
Etanercept (Enbrel, Amgen, Thousand Oaks, CA)............................................................... 1-6 
1.5.1. 
Pharmacokinetics and Pharmacology of Etanercept ............................................................. 1-6 
1.6. 
Clinical Trials and Adverse Events with Etanercept ............................................................ 1-7 
1.7. 
Etanercept/Initial Experience in Allogeneic Hematopoietic Cell Transplantation .............. 1-8 
2. 
STUDY DESIGN.................................................................................................................... 2-1 
2.1. 
Study Overview ...................................................................................................................... 2-1 
2.2. 
Hypothesis and Specific Objectives ....................................................................................... 2-1 
2.2.1. 
Hypotheses ......................................................................................................................... 2-1 
2.2.2. 
Study Objectives ................................................................................................................. 2-1 
2.3. 
Patient Eligibility - Registration ............................................................................................ 2-2 
2.3.1. 
Inclusion Criteria ................................................................................................................ 2-2 
2.3.2. 
Exclusion Criteria ............................................................................................................... 2-3 
2.4. 
Patient Eligibility - Randomization ....................................................................................... 2-3 
2.5. 
Timing of Registration and Randomization .......................................................................... 2-4 
2.6. 
IPS Definition ......................................................................................................................... 2-4 
2.7. 
Study Treatments ................................................................................................................... 2-5 
2.7.1. 
Initiation of Study Therapy (Day 0): Arm A and Arm B ...................................................... 2-5 
2.7.2. 
Corticosteroids (Day 0-28): Arm A and Arm B ................................................................... 2-6 
2.7.3. 
Etanercept/Placebo (Arm A and Arm B) Dosing ................................................................. 2-7 
2.7.4. 
Dosing Schedule Modifications ........................................................................................... 2-8 
2.7.5. 
Other GVHD Therapy ......................................................................................................... 2-8 
2.7.6. 
Other Supportive Care Measures ......................................................................................... 2-8 
2.7.7. 
Additional Therapy after Day 28 ......................................................................................... 2-8 
2.8. 
Study Drug Information: Etanercept (Enbrel) ..................................................................... 2-8 
2.8.1. 
Chemistry ........................................................................................................................... 2-8 
2.8.2. 
Formulation ........................................................................................................................ 2-8 
2.8.3. 
Reconstitution ..................................................................................................................... 2-9 
2.8.4. 
Stability and Storage ........................................................................................................... 2-9 
2.8.5. 
Adverse Events ................................................................................................................... 2-9 
2.8.6. 
Route of Administration .................................................................................................... 2-10 
2.8.6.1. 
Intravenous infusions................................................................................................. 2-10 
2.8.7. 
Supplier ............................................................................................................................ 2-11 
2.8.8. 
Discard Instructions .......................................................................................................... 2-11 
2.8.9. 
Accountability .................................................................................................................. 2-11 
2.9. 
Criteria for Removal from Protocol Therapy ..................................................................... 2-12 
2.9.1. 
Discontinuation Criteria .................................................................................................... 2-12 
2.9.2. 
Additional Discontinuation Criteria ................................................................................... 2-13 


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3. 
STUDY ENDPOINTS AND DEFINITIONS ........................................................................ 3-1 
3.1. 
Primary Endpoint .................................................................................................................. 3-1 
3.2. 
Secondary Endpoints ............................................................................................................. 3-1 
4. 
PATIENT ENROLLMENT AND EVALUATION .............................................................. 4-1 
4.1 
Enrollment Procedures .......................................................................................................... 4-1 
4.1.1. 
Screening and Eligibility Procedures ................................................................................... 4-1 
4.2. 
Study Monitoring ................................................................................................................... 4-1 
4.3. 
Adverse Event Reporting ....................................................................................................... 4-2 
4.4. 
Patient Assessments ............................................................................................................... 4-2 
4.4.1. 
Pre-registration Studies ....................................................................................................... 4-2 
4.4.2. 
Pre-randomization Bronchoscopy: Arm A and Arm B ......................................................... 4-3 
4.4.3. 
Post-randomization Required Observations Arm A and Arm B............................................ 4-3 
5. 
Statistical Considerations ...................................................................................................... 5-5 
5.1. 
Study Design........................................................................................................................... 5-5 
5.1.1. 
Accrual ............................................................................................................................... 5-5 
5.1.2. 
Randomization .................................................................................................................... 5-5 
5.1.3. 
Primary Endpoint ................................................................................................................ 5-5 
5.1.4. 
Primary Hypothesis............................................................................................................. 5-5 
5.2. 
Sample Size and Power Considerations ................................................................................ 5-6 
5.3. 
Interim Analysis and Stopping Guidelines ............................................................................ 5-6 
5.3.1. 
Guidelines for Safety Monitoring ........................................................................................ 5-6 
5.4. 
Demographic and Baseline Characteristics........................................................................... 5-9 
5.5. 
Analysis of Secondary Endpoints ........................................................................................ 5-10 
5.6. 
Safety Analysis ..................................................................................................................... 5-10 
 
 
LIST OF APPENDICIES 
 
APPENDIX A – HUMAN SUBJECTS 
APPENDIX B – CONSENT FORMS 
APPENDIX C – LABORATORY PROCEDURES 
APPENDIX D – REFERENCES 
 


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CHAPTER 1 
 
 
1. 
BACKGROUND AND RATIONALE 
 
1.1. Background 
 
Over the last two decades, allogeneic hematopoietic cell transplantation (HCT) has emerged as 
an important treatment for a number of malignant and non-malignant disorders.  Unfortunately, 
several complications, including graft-versus-host disease (GVHD) and pulmonary dysfunction, 
limit the utility of this aggressive form of therapy.  Infectious and non-infectious lung 
complications occur in 25% to 55% of HCT recipients and account for up to 50% of transplant-
related mortality1,2,3,4,5,6.  In about half of affected patients, no infectious organisms are identified 
in the lungs.  Two major types of non-infectious pulmonary injury are recognized: acute 
idiopathic pneumonia syndrome (IPS) and subacute lung injury (obstructive airway disease or 
bronchiolitis obliterans (BrOb) and restrictive lung disease).  The current study will examine the 
use of etanercept in patients with IPS.   
 
1.2. IPS Overview 
 
IPS refers to diffuse, non-infectious lung injury occurring in the acute setting.  In 1993, a panel 
convened by the National Institutes of Health (NIH) proposed a broad working definition of IPS 
to include widespread alveolar injury in the absence of active lower respiratory tract infection 
following HCT7.  The NIH panel was careful to stress that they considered this definition to be 
that of a clinical syndrome, with variable histopathologic correlates and several potential 
etiologies.  Diagnostic criteria of IPS include signs and symptoms of pneumonia, non-lobar 
radiographic infiltrates, abnormal pulmonary function and the absence of infectious organisms in 
the lower respiratory tract1,7.  A variety of histopathologic findings are associated with IPS; the 
most frequently reported pattern is interstitial pneumonitis, a term historically used 
interchangeably with IPS.  The time of onset for IPS ranges from 14 to 90 days after the infusion 
of donor hematopoietic cells.  Survival after onset is poor; mortality rates of 50% to 70% are 
reported1,3,5,6,7,8.  Although a recent retrospective study showed a lower incidence and earlier 
onset of IPS than previously reported, the typical clinical course (rapid onset of respiratory 
failure leading to death) was similar to historical reports, underscoring the critical nature of this 
transplant related problem6.  Potential etiologies for IPS include direct toxic effects of HCT 
conditioning regimens, occult pulmonary infections, and inflammatory cytokines that have been 
implicated in other forms of pulmonary injury9,10,11,12,13.  Additionally, immunologic factors may 
be important, since IPS is more frequent with allogeneic (vs. autologous or syngeneic) HCT and 
in patients with severe GVHD (vs. mild or absent GVHD)1,3,5,6,8.  In many instances, acute 
GVHD precedes IPS, suggesting a possible causal relationship14,15,16. 
 
1.3. Incidence of IPS: Investigator’s Experience  
 
A retrospective review of 651 allogeneic transplants (304 unrelated donor, 347 related donor) 
performed at the University of Michigan Medical Center from 1996-2002 noted a 9.0% 


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incidence of IPS by Day 100 post-transplant.  IPS was more common in recipients of unrelated 
donor grafts (14.1%) versus recipients of related donor grafts (4.6%).  Donor-recipient HLA 
mismatch was also associated with higher incidences of IPS in both unrelated and related donor 
transplants. 
 
 
Table 1.3  IPS Incidence with Donor Type 
Degree of  
HLA Match 
Incidence of IPS 
Unrelated Donor 
Incidence of IPS 
Related Donor 
6/6 
11.0% 
3.9% 
5/6 
34.0% 
23.0% 
Combined 
14.6% 
4.6% 
 
 
Age, gender, underlying disease and pre-transplant preparative regimen did not predict for IPS in 
this series.  The median time to onset of IPS was 15 days post-transplant (mean 22 days).  Acute 
GVHD was present at diagnosis in 70% of IPS cases.  Affected patients were treated with high 
dose corticosteroids and broad-spectrum antimicrobial therapy.  Survival rates at 28 and 56 days 
post onset of IPS were 33% and 26%, respectively.  Survival was not impacted by donor source 
(unrelated versus related donor) or underlying disease.  The median time to death following the 
onset of IPS was 14 days.   
 
1.4. Role of Tumor Necrosis Factor Alpha in the Pathogenesis of IPS 
 
IPS Pathophysiology: The association between IPS and GVHD suggests a mechanistic 
relationship.  The pathophysiology of GVHD is complex and is now known to involve donor T 
cell responses to host antigens, inflammatory cytokines and endotoxin17,18,19,20,21,22,23.  Endotoxin 
or lipopolysaccharide (LPS) is a component of endogenous bowel flora and is a potent enhancer 
of inflammatory cytokine release.  Translocation of LPS across a gut mucosa damaged early in 
the post-transplant period by the effects of conditioning and GVHD has been demonstrated after 
both experimental and clinical HCT24,25,26,27.  When LPS reaches the systemic circulation, it 
induces the release of inflammatory cytokines from monocytes and macrophages that have been 
“primed” or made more sensitive to LPS via the effects of interferon γ (IFNγ) produced by donor 
lymphocytes.  These cytokines, along with cellular effectors, contribute to GVHD target organ 
damage and dysfunction.  During recent years, several lines of investigation have added to our 
understanding of how inflammatory cytokines contribute to complications of allogeneic 
HCT21,28,29,30.  In particular, tumor necrosis factor  (TNF) is an established effector of both 
clinical29,30,31 and experimental26,27 GVHD.  The clinical importance of TNF was initially 
suggested by studies demonstrating elevated levels of TNF in the serum of patients with acute 
GVHD32,33.  Patients with higher serum TNF levels during the conditioning regimen had a 90% 
incidence of grade II-IV acute GVHD (with mortality > 70% compared to a 20% mortality in 
patients without acute GVHD33.  HCT recipients with a genetic polymorphism associated with 
high TNF production are reported to have enhanced early mortality and an increased incidence 
of severe acute GVHD.  TNF appears critical for the development of early gastrointestinal 


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injury from acute GVHD20,26,27; its role in GVHD mediated damage to other target organs is less 
well defined34.  
 
Although the lung is historically not recognized as a classic target organ of GVHD, the clinical 
association between IPS and GVHD and the demonstration of pathologic lung changes in rodents 
with acute GVHD make this possibility intriguing.  Pertinent to this hypothesis, elevations of 
TNF are reported in the serum of patients who develop IPS32 and in the lungs of animals with 
GVHD35,36,37,38.  Furthermore, evidence for cytokine activation and LPS amplification, 
previously recognized in the broncho-alveolar compartment during adult respiratory distress 
syndrome (ARDS),39 were recently demonstrated in patients with IPS after allogeneic HCT 40,41.  
Clark and colleagues found increased vascular permeability and bronchoalveolar lavage (BAL) 
fluid containing IL-1, IL-12, IL-6 and TNF and components of the LPS amplification system 
(LPB and CD14) in patients with IPS2.  The investigators concluded that pro-inflammatory 
cytokine activation contributed to the pathogenesis of IPS and suggested that patients with this 
complication may be at increased risk for LPS mediated lung injury. 
 
Murine Models of IPS after Allogeneic HCT: During the last several years, the lab of Dr. 
Kenneth Cooke (co-principal investigator for current study) has studied murine models of 
allogeneic HCT to investigate mechanisms of IPS.  The majority of preliminary data has been 
generated using two HCT systems: B10.BR  CBA and C57BL/6  B6D2F1.  The 
B10.BR/CBA donor/recipient combination is matched at the MHC loci but differs at multiple 
minor histocompatibility (H) antigens and therefore most closely models an HCT from a 
matched unrelated, volunteer donor. In the C57BL/6  B6D2F1 strain combination, donor and 
host differ at both major and minor H antigens.  This system provides the unique opportunity to 
use genetically altered mice, bred on the B6 background, as donors in our experiments.  
 
In initial studies, B10.BR donor bone marrow and T cells were transplanted into CBA recipients.  
Mice were killed at various time points after HCT and detailed histopathologic analysis of the 
lungs was performed.  At 6 weeks, lungs of mice receiving syngeneic transplants maintained 
virtually normal histology whereas two major abnormalities were apparent in the allogeneic 
group35.  First, a dense mononuclear cell infiltrate was found around both pulmonary vessels and 
bronchioles.  Second, an acute pneumonitis involving both the interstitium and alveolar spaces 
was observed.  Each of these histopathologic patterns closely resembles microscopic features of 
the nonspecific, diffuse interstitial pneumonias seen in allogeneic HCT recipients7,15,42.  A 
semiquantitative index based on the severity and extent of injury present was used to score lung 
changes35.  Using this system, the values for pneumonitis, periluminal infiltrate, and total index 
were significantly abnormal in allogeneic HCT recipients compared to syngeneic controls35.  
Identical histopathology is also observed using strain combinations across 1) other minor 
antigens, 2) class I or class II antigens only, and 3) major and minor H antigenic 
differences43,44,45.  In each scenario, significant pulmonary pathology is first detected between 
weeks 2 and 4 after HCT and progresses in severity through week 6.  Potential infectious 
etiologies of pulmonary injury were ruled out in these studies by screening sentinel mice from 
each group (minimum n = 5) for a broad panel of pathogenic bacteria, viruses and Pneumocystis 
carinii.  No pathologic organisms were identified in any mice strongly suggesting that the lung 






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Figure 1.4b. Administration of rhTNFR:Fc significantly reduces the development of lung injury 
after HCT. CBA animals received allogeneic HCT and were treated with control Ig (filled 
symbol) or rhTNFR:Fc (shaded symbol) from week 4 to week 6.  Allogeneic animals were 
evaluated at week four and received no treatment (open symbol).  Data are expressed as mean ± 
standard error, n = 8 to 15 per group and represent a combination of 2 similar experiments, #P 
< 0.01, filled symbol vs. open symbol; *P < 0.01, **P < 0.05 shaded symbol vs. filled symbol. 
 
 
In summary, these laboratory data correlate well with clinical reports of an association between 
inflammatory cytokines and IPS (see above) and with our own clinical experience (see below).   
 
1.5. Etanercept (Enbrel, Amgen, Thousand Oaks, CA)  
 
Normally, two distinct cell surface receptors exist for TNF: a 55 kilodalton (kd) (p55) and a 75 
kd (p75) TNF receptor.  Soluble TNF receptors are shed forms of the extracellular portion of the 
TNF receptor, occurring naturally in humans50.  Soluble TNF receptors function by inhibiting 
TNF binding to the target cell surface and therefore are believed to regulate the bioavailability of 
TNF in the body51.  Etanercept is a dimeric protein consisting of two soluble p75 TNF receptors 
fused to the Fc portion of a type I immunoglobulin (IgG1).  The use of an immunoglobulin Fc 
region as a fusion element in the construction of the dimeric receptor imparts a longer half-life to 
the agent and allows alternate day dosing52.  
 
Clinical trials of etanercept have been conducted in healthy volunteers, patients with sepsis 
syndrome, rheumatoid arthritis (RA), psoriasis, HIV infection, and Crohn’s disease.  Injection 
site reactions are the most commonly reported adverse event.  In the sepsis syndrome trial, 
etanercept was associated with increased mortality in patients treated for gram + septicemia.  An 
increased risk of infectious complications or mortality was not noted in other clinical trials.   
 
1.5.1. 
Pharmacokinetics and Pharmacology of Etanercept 
 
The pharmacokinetics of etanercept are reported in multiple studies involving both healthy 
volunteers and patients with RA53.  Pharmacokinetic parameters have been determined following 
intravenous (IV) and subcutaneous (SQ) administration for doses ranging from 0.125mg/m2 to 
60mg/m2 when administered primarily as single doses.  In adults, pharmacokinetic parameters 


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are similar between men and women, and do not vary significantly with age.  In pediatric studies, 
the clearance of etanercept was similar, with a small reduction in clearance in children 4-8 years 
of age (product information, Immunex).   
 
Etanercept is slowly absorbed after SQ injection, and has a relatively slow clearance from the 
body; the elimination half life is 70 hours after a single subcutaneous injection.  When etanercept 
is administered twice weekly, steady state serum concentrations are approximately 2 times that 
of a single dose.  When administered subcutaneously, bioavailability ranges between 25% and 
60%53.  After subcutaneous administration of 10 mg into the abdomen, etanercept reaches peak 
concentrations of 0.43 ± 0.2l mg/mL by 66 ± 22 hours53.  The volume of distribution is 9.6 ± 3.3 
L following IV administration and the mean clearance rates have ranged from 22-73 mL/hr/m2.  
Compared to subcutaneous administration, peak concentrations are achieved earlier following IV 
dosing [mean time to Cmax: 0.8 hours (IV) versus 66 hours (SQ)].  Etanercept is metabolized 
through the reticulo-endothelial system54 and therefore, dose adjustment is not required for 
patients with renal or hepatic impairment.  
 
1.6. Clinical Trials and Adverse Events with Etanercept  
 
Although clinical trials have been conducted in a variety of settings, most of the data come from 
trials in individuals with RA55,56,57,58.  Etanercept was studied extensively in 1039 patients with 
RA (the disease for which etanercept is FDA approved) in 10 individual trials.  In one 
randomized, placebo-controlled, Phase II study of patients with RA, etanercept significantly 
ameliorated the clinical symptoms of active RA and primary efficacy parameters showed a clear 
dose response56.  
 
In healthy volunteers challenged with endotoxin, etanercept significantly decreased release of the 
following inflammatory mediators: bioactive TNFα, IL-6, IL-8, G-CSF, norepinephrine, cortisol, 
plasminogen activator inhibitor, and tissue plasminogen activator59.  However, a subsequent trial 
in patients with sepsis syndrome demonstrated increased mortality with etanercept with a dose-
response relationship between the drug and mortality60.  In this Phase II, randomized, double-
blind, placebo-controlled trial compared single IV doses of etanercept (approximately 6 mg/m2, 
18 mg/m2, or 60 mg/m2) and placebo, which were administered during a period of 30 minutes to 
141 patients with potential sepsis.  Sepsis was based upon having all of the following clinical 
criteria at the time of study entry: temperature > 38.2° C, or < 36.0° C, heart rate > 90/minute, 
respiratory findings (respiratory rate > 20/minute, pCO2 < 32 mmHg, or the need for mechanical 
ventilation), and hypotension (systolic blood pressure < 90 mmHg, a decrease in systolic blood 
pressure > 40 from baseline, or the need for inotropic support above 5mcg/kg/minute of 
dopamine).  The 28-day mortality was 30% in the placebo group and 30%, 48%, and 53% in the 
6 mg/m2, 18 mg/m2, and 60 mg/m2 groups, respectively.  Overall, the relationship of increased 
mortality to increasing etanercept dose level was significant (p=0.016).  Among patients who 
received etanercept, those infected with Gram-negative organisms had no increase in mortality 
rates while those infected with Gram-positive organisms had a statistically significant increase in 
mortality rates.  Only 39% of patients in this study had documented bacteremia at the time of 
study entry.  Patients who were neutropenic, patients receiving > 1.0 mg/kg/day of corticosteroid 


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equivalent, or patients < 18 years in age were also excluded from study60.  No patients received 
SQ etanercept as planned in the current trial. 
 
In placebo-controlled studies for RA with durations of 3 or 6 months, adverse events were 
documented for 349 patients receiving etanercept, compared to 152 patients receiving placebo.  
Most adverse events were mild and the proportion of patients who discontinued treatment due to 
adverse events was the same in both the etanercept and placebo groups (4%).  Other than 
injection site reactions, no other adverse events occurred at increased frequency with etanercept 
alone or when given in combination with methotrexate compared to the control groups.  All 
injection site reactions were described as mild to moderate (erythema and/or itching, pain, or 
swelling), generally occurred in the first month of treatment, and did not necessitate study drug 
discontinuation61.  The mean duration of these local reactions was 3 to 5 days.  No treatment was 
necessary in approximately 90% of cases, and those patients who required treatment received 
topical corticosteroids or oral antihistamines.  Rare occurrences of redness at a previous injection 
site when subsequent injections were given have been reported but have not required treatment61.  
Upper respiratory infections (“colds”) and sinusitis were the most frequently reported infections 
in patients receiving etanercept or placebo.  The frequency of such infections was 0.68 events per 
patient-year in the placebo group and 0.82 events per patient-year in the etanercept group. 
 
1.7. Etanercept/Initial Experience in Allogeneic Hematopoietic Cell Transplantation 
 
Reports on the use of etanercept in HCT are anecdotal to date.  A case report describing the 
successful therapy of an 11 year old with gastro-intestinal GVHD is described.  There were no 
adverse reactions or complications with its use62. The use of etanercept for the treatment of 8 
patients with chronic GVHD was reported in December 2000; 7 of the 8 showed symptomatic 
improvement using the same dosage that will be employed in this current protocol63.  A recent 
study from the University of Michigan reported the use of etanercept in three children with IPS 
in 200064.  In all three patients, a pre-therapy BAL specimen was negative for infectious 
organisms. Each received empiric broad-spectrum antimicrobial therapy and methylprednisolone 
(2 mg/kg/day) prior to and during etanercept therapy.  One patient required bilevel positive 
airway pressure (BiPAP) and two others required mechanical ventilation at the onset of therapy.  
The administration of etanercept was well tolerated and associated with significant 
improvements in pulmonary function within the first week of therapy.  All three patients ceased 
oxygen support during their course of therapy.  Response parameters are noted below (Table 
1.7a, Figures 1.7a and 1.7b). 
 


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Table 1.7a  Ventilatory Parameters and Clinical Response to Etanercept Administration 
Days after Etanercept Therapy 
Patient 1 
Day 0 
Day 1 
Day 3 
Day 7 
Fi02 (%) 
100 
100 
50 
Room air 
 
Patient 2 
Day 0 
Day 1 
Day 3 
Day 7 
Fi02 (%) 
55 
45 
40 
30 
PIP/PEEP 
29/10 
26/8 
22/5 
22/5 
MAP 
14 
14 
8 
7 
 
Patient 3 
Day 0 
Day 1 
Day 3 
Day 7 
Fi02 (%) 
90 
35 
35 
Room air 
PIP/PEEP 
34/9 
29/9 
21/5 
Room air 
MAP 
20 
16 
11 
Room air 
Patient 1 on BiPap, patient 2 and 3 on mechanical ventilation at therapy onset.  Key: FiO2: 
percent inspired oxygen; PIP: peak inspiratory pressure; PEEP: peak end expiratory pressure; 
MAP: mean airway pressure.  
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1.7a 
 
 
 
 
  
Figure 1.7b 
 
Figures 1.7a & 1.7b: Chest Radiographs Obtained on Day 0 (Fig. 1.7a) and  
Day 4 (Fig. 1.7b) of Therapy with Etanercept for Patient #1 
 
 
University of Michigan Trial (UMCC -0078) for the treatment of IPS: 
A pilot study testing the safety and feasibility of using etanercept to treat patients with IPS was 
recently completed at the University of Michigan and the Dana Farber Cancer Institute / Brigham 
and Woman’s Hospital.  Fifteen patients (median 18 yrs, 1 - 60 yrs), each meeting the diagnostic 
criteria for IPS, were enrolled from 05/25/2001 to 02/04/2004.  All patients required 
supplemental oxygen at therapy onset, with seven patients requiring mechanical ventilation.  
Etanercept was administered at 0.4 mg/kg via SQ injection, twice weekly for a maximum of 8 
doses.  Etanercept therapy was initiated a median of 17 days (11-87 days) post-transplant. 
Therapy was well tolerated overall.  All patients underwent BAL prior to initiation of therapy to 
rule out infectious etiologies. From a safety standpoint, all patients who were intubated for the 
BAL procedure were extubated upon completion of the BAL.  There were 17 severe adverse 


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events, including two episodes of bacteremia, and two admissions for acute GVHD within 56 
days of study onset.  One dose-limiting toxicity was noted, a grade 4 dermatologic reaction 
necessitating drug withdrawal.  There were no episodes of septicemia and no pulmonary 
infections.  Nine of 15 patients had a complete response, defined as the ability to completely 
withdraw from supplemental oxygen support within 28 days of initiation of etanercept therapy.  
The median time to response was 7 days (range 3-18 days) and the median time to chest 
radiograph normalization was 6 days (range 2-10 days).  The median survival was extended from 
14 days (historical controls, see above) to 67 days (range 3-822) in treated patients.  Survival at 
Day 28 and Day 56 (from the first etanercept dose) was 73% and 60%, respectively.  The 
duration of mechanical ventilation required prior to study onset impacted survival.  Patients 
requiring < 48 hours of mechanical ventilation prior to study entry had a median survival of 150 
days (range 46-822).  In comparison, patients requiring mechanical ventilation > 48 hours prior 
to study entry had a median survival of only 17 days (range 3–148).     
 
In order to begin to define the biologic parameters associated with the development of IPS, we 
measured inflammatory cytokine levels in BAL fluid samples collected before (and when 
possible) after the administration of etanercept.  Levels from BAL of IPS patients were 
compared to those obtained from untransplanted controls, from HCT recipients with subacute 
lung injury (discussed below), or from HCT recipients whose BAL was positive for infection.  
 
 
 
Figure 1.7c. BAL Fluid Analysis 
 
Figure 1.7c. BAL fluid cytokine levels.  Patients were enrolled on protocols UMCC 0078 (IPS) 
or UMCC 0079 (subacute lung injury) and BAL fluid was collected at the time of study entry and 
at the completion of therapy.  Protein levels for TNF, TNFRI, sCD14 and LPB were measured 
by ELISA.  Untransplanted controls n = 3; HCT recipients with infection n = 8; OLD / RLD n = 
10; IPS n = 7 pre and 4 post therapy. p < 0.05 for IPS compared to OLD/RLD for all cytokines 
shown.


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As shown in Figure 1.7c, BAL levels of TNF, TNFRI, soluble CD14 and LPB levels were 
significantly elevated in patients with IPS as compared to patients with subacute lung injury and 
untransplanted healthy volunteers (p < 0.05).  These findings are consistent with those reported 
by Clark and colleagues in a similar subset of patients.  Of note, total protein levels were also 
elevated in IPS patients consistent with significant endothelial damage and capillary leak that 
accompanies acute lung injury in other clinical and experimental settings.  By contrast, levels of 
IL-1, IFNγ and IL-2 were not consistently elevated in any group (data not shown).  Strikingly, 
BAL fluid protein levels decreased significantly after treatment with etanercept in the 8 patients 
in whom a repeat BAL was performed (p < 0.05 for TNFRI, sCD14 and LPB).  
 
In summary, a pilot study at the University of Michigan employing etanercept plus 
corticosteroids for the treatment of IPS following allogeneic transplantation led to higher than 
expected survival when compared to historical controls.  Survival 28 days and 56 days following 
the onset of etanercept therapy (Group A) or following the use of corticosteroids alone (Group 
B) is summarized below:   
 
Table 1.7b  Day 28 and 56 Survival 
IPS Therapy 
N 
Day 28 
Day 56 
Group A: etanercept plus corticosteroids 
15 
73% 
60% 
(Historical) Group B: corticosteroids 
49 
33% 
26% 
 
The University of Michigan also recently completed a trial of etanercept for the therapy of 
subacute lung injury post allogeneic HCT.  Fifteen patients with either bronchiolitis obliterans or 
restrictive lung injury post-allogeneic transplant were treated over a four-week period.  Similar to 
the IPS trial, therapy was well tolerated, with no injection or local site reactions reported.  One 
patient was documented to have aspergillus fumigatus on a post therapy BAL specimen.  No 
other pathogens or infectious complications were identified.   
 
Over the past year, therapy for five patients with IPS was initiated with IV etanercept instead of 
SQ dosing [Personal communication, G. Yanik].  Therapeutic responses were noted within 24 
hours of administration of the IV dose.  Pharmaco-kinetic data provided by the drug supplier 
(Amgen Inc.) note a marked reduction in the time to Cmax (maximal drug concentration) when 
etanercept has been administered IV, compared to SQ dosing (0.8 versus 66 hours).  Similar drug 
t ½ (half lifes) have been reported comparing IV to SQ dosing (approximately 72 hours).   
 
Overall, over thirty patients have now been treated with etanercept at the University of Michigan 
for either idiopathic pneumonia syndrome or subacute lung injury following allogeneic HCT.  
All patients were treated with 0.4 mg/kg/dose (max 25 mg) over a planned 4-week course of 
therapy, with over 200 doses of administered to this patient group.  Infectious complications 
have been rare, with < 10% of patients treated coming off study therapy due to infectious issues 
that have arisen during therapy.    
 
We now plan to further investigate the role of etanercept in the therapy of IPS post allogeneic 
HCT in a Phase III, double-blind, placebo-controlled multi-center trial. 


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CHAPTER 2 
 
 
2. 
STUDY DESIGN 
 
2.1. Study Overview 
 
This is a Phase III double-blind, randomized, placebo-controlled, multi-center comparison of 
etanercept plus corticosteroids (Arm A) versus placebo plus corticosteroids (Arm B) for the 
treatment of IPS.  All patients will undergo a bronchoscopy at the time of study entry, with the 
exception of those who are less than 30 days post transplant and the patient’s clinical condition is 
such that a bronchoscopy is not possible to be performed.  Study registration will occur prior to 
this bronchoscopy procedure.  Following the bronchoscopy procedure, patients will be 
randomized to Arm A or Arm B of therapy.  Randomization is not allowed until preliminary 
testing on the BAL fluid has been completed (see Section 2.4 for details).  Randomization will be 
performed in a 1:1 ratio using random block sizes for the two arms.  Randomization will be 
stratified by center.  The primary study objective is to compare response rates to therapy between 
the two arms at Day 28 after randomization.  Response is defined as survival plus the ability to 
completely discontinue all supplemental oxygen support for > 72 consecutive hours.  Patients on 
the two study arms will also be followed for Day 28 and Day 56 mortality, time to 
discontinuation of supplemental oxygen, and for BAL fluid and plasma cytokine analysis. 
 
2.2. Hypothesis and Specific Objectives 
 
2.2.1. 
Hypotheses 
 
Primary Hypothesis:  Activation of pro-inflammatory cytokines, including TNF contributes to 
the development of IPS following allogeneic HCT.  The development of IPS is associated with a 
high mortality within 28 days of onset.  Cytokine neutralization with a soluble dimeric TNF 
binding protein (etanercept) will significantly improve both the survival and pulmonary status of 
patients with IPS.  
 
Secondary Hypotheses:  Therapy with a soluble TNF binding protein will be well tolerated, 
with minimal toxicity, in patients with IPS.  
 
Pro-inflammatory cytokine levels are elevated in the BAL fluid of patients with IPS. 
 
2.2.2. 
Study Objectives 
 
This trial is designed to compare the efficacy of etanercept plus corticosteroids versus 
corticosteroids alone in the treatment of patients with IPS following allogeneic HCT.  The 
primary study objective is to determine the Day 28 response rates following therapy in the two 
treatment arms.  Response is defined as above, the ability to survive to Day 28 plus discontinue 
supplemental oxygen support during that time period.  Historical data indicate that IPS develops 
in approximately 10% of allogeneic transplant recipients, with mortality rates as high as 50-75%.  


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Supportive care measures plus corticosteroids are the historical mainstay of therapy.  Recent 
animal model and human data indicate that pro-inflammatory cytokines, including TNF, may 
play a key role in the pathogenesis of this disorder.  The current study will examine the impact of 
a novel TNF inhibitor, etanercept, in the therapy of such patients.  
 
Secondary objectives will examine response to therapy at Day 56, overall mortality post 
randomization, time to discontinuation of supplement oxygen support, and BAL fluid and plasma 
cytokines analysis.  
 
As noted, recent evidence indicates a potential role for pro-inflammatory cytokines, including 
TNF, IL-1, IL-6 and components of the LPS pathway (LPB, CD-14) in the pathogenesis of the 
disorder.  As a secondary objective, the study will examine BAL fluid obtained prior to initiation 
of therapy for the expression of pro-inflammatory cytokines, LPS mediators, and chemokine 
expression.  BAL analyses will be performed in the laboratory of Dr. Kenneth Cooke at the Case 
Western Reserve University Medical Center (see Appendix C).  Plasma will also be obtained 
pre-therapy, Day 7 and Day 28 to examine similar cytokine profiles in the study population.  
Correlations of pre-therapy BAL fluid cytokine profiles and pre- and post-therapy plasma 
cytokine levels with clinical responsiveness to therapy will be examined. 
  
2.3. Patient Eligibility - Registration 
 
Patients must meet specified eligibility criteria to be registered on the study.  Additional criteria 
must also be met to continue to randomization.  All questions regarding eligibility criteria should 
be directed to the Protocol Coordinator at the Data Coordinating Center. 
 
2.3.1. 
Inclusion Criteria  
 
Patients fulfilling the following criteria will be eligible for registration onto this study: 
1. Recipients of an allogeneic bone marrow, cord blood, or peripheral blood stem cell 
transplant.  There are no restrictions based upon underlying disease, donor source, degree 
of HLA match, intensity of the pre-transplant conditioning regimen, or the use of a prior 
donor leukocyte infusion.  
2. Age > 18 years.  
3. Patients with evidence of idiopathic pneumonia syndrome, based upon the presence of 
bilateral pulmonary infiltrates (on chest radiograph) and a supplemental oxygen 
requirement.  
4. Patients < 180 days post-transplant.  
5. Patients who develop IPS within 180 days of a donor leukocyte infusion (DLI) are 
eligible, even if they are > 180 days post-transplant. 
 


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2.3.2. 
Exclusion Criteria 
 
Patients with the following will be ineligible for registration onto this study: 
1. Patients with uncontrolled infections, as determined by progressive radiographic findings 
or a persistence of positive blood, fluid or tissue cultures would be excluded from study 
entry.  Patients who have undergone a BAL within 72 hours of study registration are 
ineligible if the BAL fluid is known to be positive for pathogenic microorganisms.   
2. Patients with evidence of CMV infection or CMV disease, based upon an abnormal PCR 
assay, antigenemia assay, shell vial culture, or tissue biopsy within 7 days of study 
registration. 
3. Patients on mechanical ventilation for > 168 hours (7 days)at study registration.Patients 
with evidence of congestive heart failure by clinical assessment.  
4. Patients on other investigational studies (Phase I, II, or III) for the treatment of acute 
GVHD within 7 days of study registration.  (Note: Patients enrolled on BMT CTN 0302 
are ineligible for study entry.) 
5. Patients who have received etanercept within the prior 14 days. 
6. Patients who are pregnant or breastfeeding. 
7. Patients with known hypersensitivity to etanercept. 
8. Patients with a history of active tuberculosis (TB) infection.  
9. Patients with a history of chronic active hepatitis B or hepatitis C infection.  
10. Patients with a history of a demyelinating disorder or disease.  
11. Patients on > 2 mg/kg/day of methylprednisolone equivalent for > 48 hours, within 7 
days prior to study registration. 
12. Patients who have relapsed or have developed progressive disease post-transplant. 
 
2.4. Patient Eligibility - Randomization 
 
Patients fulfilling the following criteria will be eligible for randomization onto this study: 
1. BAL fluid negative for pathogenic microorganisms as assessed by gram stain and fungal 
stain. 
2. BAL fluid negative for pathogenic microorganisms, or test result pending, as assessed by 
the following tests. 
a. Acid fast bacilli stain (AFB). 
b. Bacterial culture (a quantitative culture ≥ 104 CFU/mL is considered positive). 
c. Viral cultures for respiratory pathogens, including (but not limited to) RSV, 
adenovirus, parainfluenza, influenza A and B, and CMV.  
d. Fungal and mycobacterial cultures. 
e. Pneumocystis carinii pneumonia (PCP) assay, by PCR, direct fluorescent antibody 
(DFA) stain, or cytology (per institutional guidelines).  


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2.5. Timing of Registration and Randomization 
 
Patients should be registered prior to bronchoscopy.  
 
Patients will be randomized following the bronchoscopy procedure, provided that criteria for 
IPS, see Section 2.6, are met at that time.  Patients will be stratified by center.  Patients will be 
assigned to either Arm A (etanercept plus corticosteroids) or Arm B (placebo plus 
corticosteroids) in a 1:1 ratio.  Day 0 is defined as the date of first administration of study drug. 
 
Patients who are registered, but whose BAL is positive for an infectious pathogen prior to 
randomization, will not be randomized or followed for subsequent study endpoints and outcome. 
 
In all cases, both the study team, physicians involved in the care and management of study 
subjects, and the pharmacists/Investigational Drug Pharmacy at the treating center will remain 
blinded to a subject’s study drug therapy.  Only EMMES and Amgen Inc will have access to the 
treatment arm assignments.  Investigational Drug Pharmacies will be provided with study drug 
labels that do not identify which arm of treatment is being administered to a study subject.  A 
code will be available within EMMES and Amgen, if safety concerns arise regarding a particular 
patient or therapy.  
 
2.6. IPS Definition 
 
The term IPS has been developed to describe diffuse lung injury occurring post HCT for which 
an infectious etiology is not identified7.  Patients must meet the following criteria for IPS, which 
includes evidence of both widespread alveolar injury, and the absence of active lower respiratory 
tract infection defined below: 
 
1. Evidence of widespread alveolar injury  
a. Radiographic evidence of bilateral, multi-lobar infiltrates (by chest x-ray or CT scan).  
b. Evidence for abnormal respiratory physiology, based upon a room air oxygen 
saturation (SpO2) < 93%, or the need for supplemental oxygen to maintain an oxygen 
saturation > 93%. 
2. Absence of active lower respiratory tract infection; assessed by broncho-alveolar lavage 
(BAL); BAL fluid negative for pathogenic bacterial and nonbacterial microorganisms.  
Tests to be performed include: 
a. Gram stain, fungal stain, acid fast bacilli stain (AFB). 
b. Bacterial culture (a quantitative culture ≥ 104 CFU/mL is considered positive). 
c. Viral cultures for respiratory pathogens, including (but not limited to) 
RSV,adenovirus, parainfluenza, influenza A and B, and CMV.  
d. Fungal and mycobacterial cultures. 
e. Pneumocystis carinii pneumonia (PCP) assay, by PCR, direct fluorescent antibody 
(DFA) stain, or cytology (per institutional guidelines).  


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3. Other Diagnostic Issues 
a. The presence of mixed oral flora, “rare” Candida species, or Penicillium species on 
BAL fluid analyses (gram stain or cultures) does not exclude a patient from study, as 
such findings may reflect oral pharyngeal contamination. 
b. The terms diffuse alveolar hemorrhage (DAH) or peri-engraftment respiratory 
distress syndrome (PERDS) are included within the definition of IPS.  
c. A radiographic finding of pulmonary edema does not exclude the diagnosis of IPS, 
provided that the treating physician concludes that the pulmonary edema is not 
secondary to cardiac dysfunction or iatrogenic fluid overload. 
d. If viral cultures become positive for other potential viral pathogens not listed above, 
discuss with the study chair (or designee) prior to proceeding further on study. 
e. For patients < 30 days post-transplant: If the patient’s clinical condition is such that a 
BAL is deemed “not possible to be performed” by the treating physician (or 
pulmonologist), then the “on study” BAL may be waived.  In such circumstances, the 
patient may register and be randomized to study therapy without the BAL being 
undertaken. 
For patients not on mechanical ventilation: If a BAL is not done, appropriate virology 
studies on a nasal swab (or nasal washing) are required as a minimum procedure to 
study entry.  
For patients on mechanical ventilation: Microbiologic studies of a deep endotracheal 
aspirate are allowed in lieu of a formal bronchoscopy procedure.  However, no 
protocol-specified biologic studies (see Section 4.4) will be done on these specimens.    
For patients 31-180 days post-transplant: An “on study” bronchoscopy is required in 
all cases.  
 
Patients may be randomized upon completion of the BAL gram stain and fungal stain, while the 
remainder of BAL studies are still pending.  Patients whose BAL special stains (gram stain and 
fungal stain) or those whose initial BAL fluid studies (including cultures) are abnormal by the 
criteria listed above, are ineligible for study randomization. 
 
If a BAL has been obtained within 72 hours of study registration, the procedure need not be 
repeated, provided that no infectious pathogens were identified in that diagnostic specimen.   
 
2.7. Study Treatments 
 
2.7.1. 
Initiation of Study Therapy (Day 0): Arm A and Arm B 
 
Study drug therapy (etanercept/placebo) should begin within 24 hours of randomization.   
 
If, at any point prior to initiation of study drug therapy, cultures, special stains or analysis of 
BAL fluid become positive for any infectious pathogen, therapy shall not be started.   
 
If, at any point following initiation of study drug therapy, cultures, special stains or analysis of 
BAL fluid become positive for any infectious pathogen, study drug therapy shall be discontinued 


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at that point, and not re-instituted.  The patient will discontinue study drug therapy, but will still 
be followed for outcome. 
 
2.7.2. 
Corticosteroids (Day 0-28): Arm A and Arm B 
 
All patients are required to be on methylprednisolone (or corticosteroid equivalent) at  
2 mg/kg/day on Day 0 of study therapy.  Corticosteroids shall be administered in divided doses, 
BID.  While it is preferred that corticosteroids be administered by IV for the first 7 days of study 
enrollment, they may be given orally (PO) if deemed appropriate.  If initially given IV, 
corticosteroids can later be changed to PO dosing when the patient is able to tolerate oral intake.  
Corticosteroid dosing should be based upon actual body weight.  
 
a. Patients not on corticosteroids at the time of study registration may begin corticosteroids 
on Day 0, upon completion of the BAL procedure, and prior to the first dose of study 
drug (etanercept/placebo). 
b. Patients receiving corticosteroids prior to study randomization should remain on 
corticosteroids, with dosing adjusted to 2 mg/kg/day of methylprednisolone equivalent.  
 
c. No corticosteroid taper is allowed during the first 7 days of study therapy  
(Day 0 to Day 6).  Corticosteroid taper is subsequently recommended, beginning Day 7 
of therapy.  Suggested guidelines for the corticosteroid taper schedule are listed below:  
 
 
Table 2.7.2  Corticosteroid Taper Schedule 
Therapy Date 
Methylprednisolone Dose 
Day 0 - 6 
2 mg/kg/day 
Day 7 - 20 
1 mg/kg/day 
Day 21 - 34 
0.5 mg/kg/day 
Day 35 - 48 
0.25 mg/kg/day, 
Day 49 - 55 
0.25 mg/kg Q.O.D. 
Day 56 
Discontinue 
 
 
Patients who require corticosteroids for concomitant therapy of acute or chronic GVHD may 
adjust their taper schedule as clinically indicated, beginning Day 7 of therapy.  Patients whose 
Day 7 oxygen requirement (FiO2) has not declined from baseline (Day 0) may remain on  
2 mg/kg/day of corticosteroid equivalent until response is noted, then taper as clinically 
indicated.  Patients whose oxygen requirement improves by Day 7, but subsequently worsens 
following institution of the corticosteroid taper, are recommended to increase corticosteroid 
dosing to the prior dose level. 
 


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2.7.3. 
Etanercept/Placebo (Arm A and Arm B) Dosing 
 
Patients treated on either arm A or arm B will receive a total of eight etanercept/placebo doses 
over a 24-day period.  Etanercept/placebo therapy will be initiated following randomization.  It is 
recommended that etanercept/placebo therapy begins within 24 hours of randomization. 
 
Dose 1 (Intravenous): The first etanercept/placebo dose will be administered by IV infusion at  
0.4 milligrams/kg/dose (maximum dose 25 milligrams).  The etanercept/placebo shall be diluted 
in 100 mL of 0.9 NS and infused over 30 minutes.  Vital signs shall be obtained immediately 
prior to the IV infusion, then q.15 minutes x 2 during the infusion.  The etanercept/placebo may 
be administered via peripheral or central venous catheter.  
 
Doses 2-8 (Subcutaneous):  Subsequent etanercept/placebo doses shall be given subcutaneously 
(SQ) at 0.4 milligrams/kg/dose (maximum dose 25 mg), twice weekly, for a total of 7 SQ 
dosages.  The initial SQ dose shall be given 3 days (approximately 72 hours) after the IV dose.  
All subsequent SQ doses shall be administered 3-4 days following the prior dose (according to 
Table 2.7.3).  All patients should be observed for local reactions at the injection site within 30 
minutes of the dose.  Vital signs shall be obtained immediately prior to, then every 15 minutes x 
2 following the first SQ dose. 
 
 
Table 2.7.3  Etanercept/Placebo (Arm A and Arm B) Dosing 
Dose 
Time 
Dose 
Route 
1 
Day 0, Hour 0 
0.4 mg/kg (max 25 mg) 
IV 
2 
Day 3 
0.4 mg/kg (max 25 mg) 
SQ 
3 
Day 7 
0.4 mg/kg (max 25 mg) 
SQ 
4 
Day 10 
0.4 mg/kg (max 25 mg) 
SQ 
5 
Day 14 
0.4 mg/kg (max 25 mg) 
SQ 
6 
Day 17 
0.4 mg/kg (max 25 mg) 
SQ 
7 
Day 21 
0.4 mg/kg (max 25 mg) 
SQ 
8 
Day 24 
0.4 mg/kg (max 25 mg) 
SQ 
 
 
For both IV and SQ dosing, no pre-medication is required.  In addition, no dosage adjustment is 
required based upon renal or hepatic function, including hemodialysis.  For patients who 
complete therapy as an outpatient, dosing may be adjusted by 24 hours to account for weekend 
scheduling.  The initial IV and SQ dose of etanercept must be administered in an inpatient or 
outpatient medical care facility.  Subsequent SQ doses may be given to the patient as an 
outpatient, once medically stable.  Patients with refractory thrombocytopenia may receive IV 
dosing, in place of SQ dosing, per discretion of the treating physician. 
 


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2.7.4. 
Dosing Schedule Modifications 
 
If for any reason a scheduled dose of study drug is missed or withheld, contact one of the 
Protocol Chairs.  In such a case, study drug dose can be reinstituted or deferred after discussion 
with a Protocol Chair.  In the event a dose is inadvertently missed on a scheduled date, it may be 
administered within a 24-hour period.  Protocol Chairs must also be contacted.  The timing of 
subsequent doses can be resumed. 
 
2.7.5. 
Other GVHD Therapy 
 
The institution of other therapy for the treatment of acute or chronic GVHD is allowed after 
enrollment, with the exception that the patient cannot be concurrently enrolled on the BMT CTN 
#0302. 
 
2.7.6. 
Other Supportive Care Measures 
 
All patients will receive prophylaxis against bacterial, fungal and viral infections during the peri-
transplant period according to the BMT CTN MOP.  CMV: monitoring and preemptive treatment 
strategy will be in accordance with the BMT CTN MOP and local institutional practice.  Anti-
fungal prophylaxis for invasive non-Candidal organisms should be considered while on study 
therapy. 
 
2.7.7. 
Additional Therapy after Day 28 
 
Patients who survive to Day 28 but remain on supplemental oxygen may be considered for 
additional therapy, including etanercept, at the discretion of the treating physician.  Such patients 
will be deemed non-responders regardless of subsequent clinical course. 
 
2.8. Study Drug Information: Etanercept (Enbrel) 
 
2.8.1. 
Chemistry 
 
Recombinant human etanercept is a dimer of two molecules of the extracellular portion of the 
p75 TNF receptor (TNFR) each consisting of 235 amino acids.  The two receptors are fused to 
the Fc portion of human IgG1 consisting of 232 amino acids.  The gene fragments encoding the 
truncated TNFR and the Fc portion of human IgG1 are expressed in a Chinese hamster ovary 
(CHO) expression vector. 
 
2.8.2. 
Formulation 
 
Etanercept is supplied as a sterile lyophilized powder containing 25 mg etanercept; 40 mg 
mannitol, USP; 10 mg sucrose, NF; and 1.2 mg tromethamine (TRIS), USP per vial.  For 
parenteral administration, etanercept is reconstituted with 1 mL of sterile bacteriostatic water for 
injection, USP, containing 0.9% benzoyl alcohol.  Investigational product, not commercially 
available product, will be used for this trial. 


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2.8.3. 
Reconstitution 
 
To reconstitute, remove the plastic vial cap and swab the stopper with antiseptic.  Using a 
syringe with a 25 gauge needle, aseptically inject 1.0 mL bacteriostatic water for injection, USP, 
(containing 0.9% benzyl alcohol) for a final concentration of 25 mg/mL.  The water should be 
directed against the side of the vial and the contents gently swirled to avoid foaming during 
reconstitution.  To avoid excessive foaming, do not shake or vigorously agitate the vial.  
Foaming will interfere with the ability to draw up an accurate dose.  Do not filter reconstituted 
solution during preparation or administration.  After reconstitution, draw up the prescribed dose 
using a 25 gauge needle.  
 
2.8.4. 
Stability and Storage 
 
Lyophilized product (25 mg etanercept):  Vials of study drug should be stored refrigerated at  
2-8oC (36-46oF).  Do not freeze.  Lyophilized 25 mg vials of etanercept are stable for at least 12 
months at 2oC to 8oC.   
 
Reconstituted etanercept:  After reconstitution with bacteriostatic water for injection, the solution 
should be stored at 2oC to 8oC.  Reconstituted etanercept in the original vial or a plastic syringe 
is stable for 28 days at 2oC to 8oC.  Do not freeze.  In the absence of compatibility and stability 
data, no other medications should be added to infusion solutions containing etanercept/placebo.  
The medication should not be prepared or administered using filtration.  Etanercept shows 
stability when reconstituted and diluted in 100 mL saline and stored for 24 hours at 4oC.  
 
2.8.5. 
Adverse Events 
 
Etanercept should not be administered to patients with known hypersensitivity to this drug or any 
of its components.  Etanercept should not be administered to patients with sepsis syndrome as 
defined as a patient requiring dopamine > 5 mcg/kg/min or use of > one vasopressor, e.g. 
norepinephrine or epinephrine, or steroid prescribed with septic shock as an indication.  
Administration of etanercept should be discontinued immediately if a patient develops an active 
systemic or pulmonary infection or evidence of impending sepsis syndrome. 
 
Parental administration of any biologic product should be attended by appropriate precautions in 
case an allergic or untoward reaction occurs.  Allergic reactions associated with administration of 
etanercept during clinical trials have been rarely reported.  If any serious allergic or anaphylactic 
reaction occurs, administration of etanercept should be discontinued immediately and 
appropriate therapy initiated. 
 
The inhibition of TNF hypothetically may be associated with malignancy, autoimmunity, or 
infection.  Although malignancies have been reported in clinical trials, epidemiologic analyses 
do not support a causal relationship with etanercept.  Furthermore, no patient has developed 
other autoimmune systemic or rheumatic diseases while on etanercept nor has there been a 
reported increase in frequency or severity of infections in placebo-controlled trials. 


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Further information related to potential adverse events, precautions, and product warnings may 
be found at www.enbrel.com, listed under “Important Product Information.”   
 
2.8.6. 
Route of Administration 
 
Both IV and SQ route of administration have been used, with SQ administration the current 
approved route of administration.  For subcutaneous administration, the etanercept product label 
suggests rotating sites of SQ injections between the thigh, abdomen, and upper arm.  Use a 27-
gauge needle for administration.  New injections should be given at least one inch from an old 
site and never into areas where the skin is tender, bruised, red or hard.  
 
2.8.6.1. 
Intravenous infusions 
 
For intravenous infusion, dilute in 100 mL of 0.9 NS and administer as a 30 minute IV infusion.  
 
Etanercept has been administered in healthy volunteers and patients with a variety of conditions 
(e. g., rheumatoid arthritis, sepsis, human immunodeficiency virus, and heart failure) as a single 
IV infusion in doses ranging from 1 to 60 mg/m2.  In these studies, etanercept was further diluted 
in 100 mL of normal saline and was administered as a 30-minute infusion.  Data on chronic or 
multiple doses given by IV infusion are not available. 
 
The pharmacokinetic profile of etanercept was determined in a crossover study comparing two 
10 mg etanercept doses administered SQ or IV (over 30 minutes) to healthy volunteers.  Serum 
samples were collected for 21 days following SQ administration and for 14 days following IV 
administration.  These samples were analyzed using an enzyme-linked immunosorbent assay 
(ELISA).  The results are presented in the Table 2.8a below.    
 
 
Table 2.8a.  Summary of Pharmacokinetic Parameters of SQ and IV Etanercept 
Parameter 
SQ* 
IV* 
Absolute bioavailability (%) 
58  (23%) 
1  (-) 
Maximum concentration 
(mcg/mL) 
0.43  (48%) 
2.32  (29%) 
Time to maximum concentration  (h) 
66  (34%) 
0.8  (31%) 
Area under the curve (mcgh/mL) 
79  (31%) 
132  (15%) 
Volume of distribution (L) 
17  (34%) 
9.6  (35%) 
Clearance (L/h) 
0.137  (32%) 
0.077  (17%) 
Half-life (h) 
92  (9%) 
72  (25%) 
Ka (h-1) 
0.08  (50%) 
- 
* Value in parenthesis represents the coefficient of variation 
   Abbreviations:  Ka = absorption rate constant, h = hours 
 
 


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In this trial, the pharmacokinetic parameters observed are consistent with those observed in 
rheumatoid arthritis patients.  In addition, etanercept was determined to be generally well 
tolerated.  Side effects following IV administration were not specifically described. 
 
An earlier safety trial of etanercept also evaluated the pharmacokinetic parameters in 14 healthy 
volunteers over a wide range of doses.  Patients were given a single IV dose of etanercept over 
30 minutes.  The results are presented in Table 2.8b. 
 
 
Table 2.8b.  Summary of Pharmacokinetic Parameters of IV Etanercept 
Parameters 
Dose of Etanercept (mg/m2) 
1 
5 
10 
15 
30 
60 
No. of patients 
2 
2 
2 
2 
2 
3 
Max conc. (mcg/mL) 
0.4 
2.1 
3.8 
8.8 
14.3 
30.6 
AUC (mcgh/mL) 
44.97 
158.52 
305.39 
585.75 
1005.93 
2028.30 
Clearance (mL/min/m2) 
0.39 
0.53 
0.55 
0.43 
0.50 
0.50 
Half-life (h) 
84.6 
70.5 
63.3 
57.9 
77.4 
79.9 
 
 
The authors reported that the infusion was not associated with any clinical or laboratory 
abnormalities.  They concluded that etanercept had no acute toxic effects following IV 
administration to healthy volunteers and that the achievable serum levels had potent TNF 
inhibitory activity in vitro.  No anti-etanercept antibodies were detected at 14 or 28 days. 
 
2.8.7. 
Supplier 
 
Etanercept will be supplied by Amgen Inc, and distributed through an independent contractor.  
Questions regarding study drug orders and study drug distribution should be directed to the trial 
protocol coordinator at EMMES, 301-251-1161.   
 
2.8.8. 
Discard Instructions 
 
Discard each vial, with its remaining contents, after each dose is given.  At the completion of the 
study, unused vials should be discarded, not returned.  
 
2.8.9. 
Accountability 
 
The investigator (and/or hospital pharmacist) will ensure that all study drug is stored in a secured 
area under recommended storage conditions and is dispensed by qualified staff members.  All 
study drug will be accounted for on medication inventory sheets. 
 
The BMT CTN clinical monitor will be allowed at intervals, and upon request during the study, 
to check unused supplies.  Accounting for the use of supplies will be by reference to each 
center's record of supplies received, the dispensing records for the total number of patients 
enrolled at each center and the unused and returned supplies. 


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The investigator is responsible for maintaining drug accountability records.  Drug accountability 
records will be reviewed during monitoring visits.  Each institution may use their own drug 
accountability log.  Study drug must be administered only to patients enrolled in this study as per 
the protocol. 
 
2.9. Criteria for Removal from Protocol Therapy 
 
2.9.1. 
Discontinuation Criteria 
 
Study drug therapy (etanercept/placebo) shall be discontinued and not re-instituted if any one of 
the following criteria are met.  The patient will be taken off study drug therapy at that point, but 
still followed for primary and secondary study endpoints.  A response assessment will be made at 
the time of therapy discontinuation and at subsequent defined study endpoints.  The patient will 
not be replaced on study.  In cases where a potential pathogen is identified by BAL fluid PCR 
analysis ONLY, the treating investigator should discuss the case with the Study Chair prior to 
study therapy discontinuation.  Note: though the study drug will be immediately discontinued in 
the following circumstances, corticosteroid dosing will be tapered as clinically indicated by the 
treating physician.  Follow-up data will be required unless consent for data collection is withdrawn.   
 
1. If pre-therapy BAL fluid cultures, special stains or PCR analysis, become positive for any 
potentially infectious pathogen, study therapy will be discontinued and not re-instituted.  
(Exception: The presence of mixed oral flora, “rare” Candida species, or a Penicillium 
species on BAL fluid analysis does not warrant discontinuation of study therapy, as such 
findings may reflect oral pharyngeal contamination.)  
 
2. If pre-therapy blood cultures become positive for an infectious pathogen following 
initiation of study therapy, study therapy will be discontinued and not reinstituted.  
 
3. If the patient develops signs and symptoms consistent with sepsis syndrome, defined as 
fever 
plus 
hypotension 
requiring 
inotropic 
support 
(excluding 
dopamine  
< 5mcg/kg/minute), study therapy will be discontinued and not re-instituted.   
 
4. If the patient develops an invasive fungal infection, study therapy will be discontinued 
and not re-instituted.  Patients with asymptomatic viruria may continue on therapy.  
 
5. Regarding CMV, adenovirus and other viral infections:  If during the course of study 
therapy, the patient develops a viral infection that in the opinion of the treating physician 
is not responding to conventional treatment, study drug will be held.  If > 2 doses of 
study drug are missed, study drug therapy will be discontinued at that time and not re-
instituted.  The patient will still be followed for outcome.  
 
6. If the patient develops bacteremia for > 72 hours despite antibiotic therapy for that 
organism, the study drug (etanercept/placebo) shall be held until the patient is no longer 
bacteremic.  If > 2 doses of study drug are missed, study drug therapy will be 


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discontinued at that time and not be re-instituted.  The patient will still be followed for 
outcome.   
 
Persistent fever, without the presence of at least one criteria listed in 3-6 above, will not warrant 
discontinuation of study therapy. In addition, empiric changes in antimicrobial therapy, without 
change in clinical status or documented evidence of infection will not warrant discontinuation of 
study drug therapy. 
 
2.9.2. 
Additional Discontinuation Criteria 
 
In addition, study drug therapy shall be discontinued and not re-instituted if:  
1. A patient develops hypersensitivity to the study drug injections or if any serious allergic 
or anaphylactic reaction occurs.  
2. Refusal of further protocol therapy by patient (or legal guardian). 
3. Per investigator discretion.  In this circumstance, a patient will be deemed a non-
responder at the time of study drug therapy discontinuation, provided the patient is within 
the first 28 days of study therapy.  Patients who discontinue study after Day 28 will 
undergo the Day 28 response evaluation as described in Chapter 3.   
 
In the event that an investigator elects to “temporarily hold” study drug therapy to 
evaluate a potential toxicity issue, the patient may remain on study drug until greater than 
two consecutive doses of study drug are withheld.  If less than or equal to two 
consecutive doses of study drug are withheld, the investigator may elect to continue study 
drug therapy.  The missed doses of study drug will not be given.  If three consecutive 
study drug doses are withheld, the patient can no longer receive study drug therapy. 
 


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CHAPTER 3 
 
 
3. 
STUDY ENDPOINTS AND DEFINITIONS 
 
3.1. Primary Endpoint 
 
The primary study endpoint is the number of patients with IPS who respond to etanercept plus 
corticosteroids (versus placebo plus corticosteroids) at Day 28 following randomization. 
 
Response to therapy will be defined as: 
a. Survival to Day 28 of study, PLUS 
b. Discontinuation of all supplemental oxygen support for > 72 consecutive hours by Day 
28. 
 
The “time to response” will be defined as the first of 3 consecutive days in which all 
supplemental oxygen has been discontinued, provided that the patient survives until Day 28 of 
study.  Patients who require re-institution of supplemental oxygen to achieve a SpO2 > 93% 
during this 72 hour time period will be deemed non-responders.  Patients who require re-
institution of supplemental oxygen support beyond the 72 hour time period will still be deemed 
as responders provided they meet the response criteria listed in “a” and “b” above.    
 
Patients who are unable to completely withdraw from supplemental oxygen support or those who 
die from IPS or non-IPS related causes by Day 28 of therapy are defined as non-responders.   
 
Patients who discontinue supplemental oxygen within the last 72 hours of the observation period 
(Days 25-28) will be classified as responders provided they survive to Day 28 and remain off 
supplemental oxygen for > 72 consecutive hours.   
 
Survival duration will be the interval from the first dose of etanercept (or placebo) to the date of 
death or last follow-up.  Patients who are treated with open-label study drug or other new therapy 
for lung complications before Day 28 are considered a failure for the primary endpoint. 
 
3.2. Secondary Endpoints  
a. Response to therapy at Day 56 
Response to therapy at Day 56 will be defined as the ability to survive to Day 56 of 
study, plus the ability to completely discontinue all supplemental oxygen support for > 72 
consecutive hours during this time period. 
b. Overall mortality 
c. Time to discontinuation of supplemental oxygen 
The “time required to discontinue supplemental oxygen” will be measured in the number 
of days from study entry.   


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d. BAL fluid and plasma cytokine analysis 
BAL fluid and plasma will be collected for cytokine analysis using standard ELISA 
assays.  This analysis will include but be not limited to TNF, sTNFRI, sTNFRII, LBP, 
IL-1, IL-6, MCP-1 and sCD14.  BAL fluid will be collected at study entry only.  Plasma 
will be collected at study entry, Day 7 and Day 28.  


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CHAPTER 4 
 
 
4. 
PATIENT ENROLLMENT AND EVALUATION 
 
4.1 
Enrollment Procedures 
 
4.1.1. 
Screening and Eligibility Procedures 
 
Patients will be registered using the BMT CTN Advantage Electronic Data Capture (EDC)SM 
system.  The following procedures should be followed: 
1. Once a patient is identified with respiratory distress requiring oxygen support, an 
authorized user at the clinical center completes a screening form with demographic 
information and Segment A of the Eligibility Form (primary eligibility screening 
questions and date informed consent was signed).   
2. If the patient is eligible, a study number is generated.  A BAL must be obtained prior to 
initiation of study therapy. 
3. An authorized user at the clinical center completes the enrollment process by entering 
Segment B of the Eligibility Form (eligibility for randomization) when the results of the 
BAL are available. 
4. If the patient is eligible for randomization, a random treatment assignment is generated. 
 
If a connection is interrupted during a randomization session, the process is completely cancelled 
and logged.  A backup manual registration and randomization system will also be available to 
provide for short-term system failure or unavailability. 
 
4.2. Study Monitoring  
 
Criteria for Forms Submission: Criteria for timeliness of submission for all study forms are 
detailed in the Data Management Handbook.  Forms that are not entered into the web-based data 
entry system within the specified time will be considered delinquent.  A missing form will 
continue to be requested either until the form is entered into the web based data entry system and 
integrated into the DCC's master database, or until an exception is granted and entered into the 
Missing Form Exception File, as detailed in the Data Management Handbook. 
 
Reporting Patient Deaths: Death information must be entered into the web-based data entry 
system within 24 hours of knowledge of the patient’s death.  If the cause of death is unknown at 
that time, it need not be recorded at that time.  However, once the cause of death is determined, 
the form must be updated in the web-based data entry system. 
 
Center for International Blood and Marrow Transplant Research (CIBMTR) Data 
Reporting:  Centers participating in BMT CTN trials must register pre and post-transplant 
outcomes on all consecutive hematopoietic stem cell transplants done at their institution during 


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their time of participation to the Center for International Blood and Marrow Transplant Research 
(CIBMTR).  Registration is done using procedures and forms of the Stem Cell Transplant 
Outcomes Database (SCTOD).  (Note: Federal legislation requires submission of these forms for 
all US allotransplant recipients.)  Additionally, CIBMTR pre- and post- transplant Report Forms 
must also be submitted for all patients enrolled on this trial according to the randomization 
assigned to the patient at the time of initial registration with the CIBMTR.  CIBMTR forms will 
be submitted directly to the CIBMTR at the times specified on the Form Submission Schedule.  
 
4.3. Adverse Event Reporting 
 
Unexpected, grade 3-5 adverse events (AE) will be reported through an expedited AE reporting 
system via AdvantageEDC.  Unexpected, grade 4-5 AEs must be reported within 24 hours of 
knowledge of the event.  Unexpected, grade 3 AEs must be reported within three business days 
of knowledge of the event.  Expected AEs will be reported using NCI’s Common Terminology 
Criteria for Adverse Events (CTCAE) Version 3.0 at regular intervals as defined on the Form 
Submission Schedule. 
 
The Data and Safety Monitoring Board will receive summary reports of all grade 3-5, 
unexpected adverse experiences on an annual basis. 
 
4.4. Patient Assessments 
 
4.4.1. 
Pre-registration Studies 
 
The following observations are to be obtained within 48 hours prior to study registration, unless 
otherwise noted.  
1.  History and physical exam including weight 
2.  Blood and serologic tests 
a. CBC with differential and platelets 
b. Serum electrolytes, BUN/creatinine, AST, ALT, total bilirubin 
c. Plasma cytokine analysis (1 -2 green top tubes) (see Appendix C).  To be obtained 
within 24 hours of registration 
d. CMV assay, by PCR, antigenemia testing or shell vial culture (if not obtained within 
the prior 7 days) 
3. Pregnancy test (if applicable).  May be waived if testing done prior to admission 
4. Karnofsky performance score 
5. Radiographic studies: CXR (PA/lateral or portable AP) 
6. Supplemental oxygen required to support a SpO2 > 93% 
7. Chest CT may be informative and is suggested 
8. Buccal swab for recipient DNA for cytokine polymorphism analysis (see Appendix C). 
 


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4.4.2. 
Pre-randomization Bronchoscopy: Arm A and Arm B 
 
All patients will undergo a bronchoscopy with broncho-alveolar lavage (BAL) at baseline, prior 
to randomization, unless criteria for Section 2.6.3.e are met.   
 
The BAL procedure shall be performed, with the following guidelines:  It is recommended that  
< 2 mL/kg of sterile normal saline (max volume 150 cc) be instilled into the patient’s lungs.  If 
possible, BAL samples should be collected from both the right and left sided airways and then 
pooled together.  BAL fluid samples shall then be sub-divided and distributed for the following 
assays: 
1. Hematology:  Recommended 5 mL (minimum 2 mL) 
a. Cell count and cytospin 
2. Microbiology: Recommended 5 -10 mL (minimum 5 mL) 
a. Stains for bacteria, fungi, AFB  
b. Culture for bacteria (quantitative culture if available) 
c. Fungal, mycobacterial and viral cultures (as defined in Section 2.5) 
d. PCP testing by PCR, direct fluorescent antibody stain, or cytology (per local 
institution) 
3. Cytopathology: Recommended 5 mL (minimum 2 mL) 
4. BAL fluid cytokine studies: 5-10 mL in sterile container.  Samples for BAL cytokine 
studies should be placed in a sterile container and kept on ice (or refrigerated at 4° C) 
until processing at the local institution.  Ideally, the BAL fluid specimen should be 
processed (for cryopreservation) within 30 minutes of collection (see Appendix C). 
 
If BAL fluid samples are being obtained on a weekend or holiday, and the lab is unable to 
process BAL fluid for required cytokine studies, please notify Study Chair (Gregory Yanik, MD 
at gyanik@umich.edu or Kenneth Cooke, MD at Kenneth.Cooke@uhhospitals.org ). 
 
4.4.3. 
Post-randomization Required Observations Arm A and Arm B 
 
Required assessments are also shown in Table 4.4.  The target day range = ± 1 day up to Day 28, 
and ± 7 days after Day 28, unless otherwise noted. 
1. Blood and serologic tests 
a. CBC with differential and platelet count (Days 7, 14, 21, and 28, ± 2 days) 
b. Serum electrolytes, BUN/creatinine, AST, ALT, total bilirubin (Days 7, 14, 21, and 
28, ± 2 days) 
c. Plasma cytokine analysis (1-2 green top tubes) Days 7 and 28 
2. Radiographic tests: Chest X ray (Days 7, 14, 21, and 28) 
3. Pulmonary function analysis: Record current level of supplemental oxygen support, and 
the duration of time (in days) that supplemental oxygen and mechanical ventilation were 
required (Days 7, 14, 21, 28, and 56) 
4. GVHD assessment (Days 7, 14, 21, 28, and 56) 


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5. Toxicity assessment (Days 7, 14, 21, 28, and 56) 
6. Infectious disease surveillance will be performed according to institutional guidelines 
 
 
Table 4.4:  REQUIRED ASSESSMENTS 
 
 
Pre-
Registration 
Pre-
Randomization 
Days  
Post-Randomization 
7 
14 
21 
28 
56 
History and physical exam 
X 
 
 
 
 
 
 
CBC with differential and platelets1 
X 
 
X 
X 
X 
X 
 
Pregnancy test (if applicable)2 
X 
 
 
 
 
 
 
Karnofsky performance status 
X 
 
 
 
 
 
 
Serum electrolytes, BUN/creatinine, AST, 
ALT, bilirubin1 
X 
 
X 
X 
X 
X 
 
Plasma cytokine analysis3 
X 
 
X 
 
 
X 
 
CMV assay4 
X 
 
 
 
 
 
 
Chest X-Ray (PA/lateral or portable AP)  
X 
 
X 
X 
X 
X 
 
Pulmonary analysis5 
X 
 
X 
X 
X 
X 
X 
Chest CT (optional) 
X 
 
 
 
 
 
 
Buccal swab 
X 
 
 
 
 
 
 
BAL  
 
X 
 
 
 
 
 
GVHD assessment 
 
 
X 
X 
X 
X 
X 
Toxicity assessment5,6 
 
 
X 
X 
X 
X 
X 
 
Notes: 
1 Serologic tests (including CBC, electrolytes, liver panel) should be performed within 48 hours of the indicated day.  
2 Pregnancy test may be waived if testing had been done pre-admission or at the time of admission. 
3 Plasma cytokine analysis must be performed within 24 hours of registration, Day 7, and Day 28. 
4 CMV assays are only required if the patient or donor were CMV positive pre-transplant, and if no CMV assay has been 
performed within 7 days prior to study registration.  Study therapy may be subsequently initiated while the CMV assay results 
are pending.  CMV assays may be performed by PCR, antigenemia, or shell vial culture. 
5 Record current level of oxygen support and the duration of time (in days) that mechanical ventilation and supplemental oxygen 
have been required.  Record oxygen saturation (SpO2) by pulse oximetry. 
6 Includes overall survival / mortality by Day 28, Day 56 and 1 year from study onset.  
 
 
  .


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CHAPTER 5 
 
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. Study Design 
 
The study is designed as a Phase III, double-blind, randomized, placebo-controlled, multi-center 
comparison of etanercept plus corticosteroids versus placebo plus corticosteroids for the 
treatment of IPS.  The target enrollment is 60 patients. 
 
5.1.1. Accrual 
 
It is estimated that five years of accrual will be necessary to enroll the targeted sample size.  
Over 25 centers, both Core and Affiliate Centers, will enroll patients on this study.  Accrual will 
be reported by race, ethnicity, gender, age and donor type. 
 
5.1.2. Randomization 
 
All patients will be randomized following the BAL provided that the required special stains (on 
BAL fluid) are negative (see Section 2.6.1).  Randomization will be performed in a 1:1 ratio 
using random block sizes for the two arms.  Randomization will be stratified by center.  
  
5.1.3. Primary Endpoint 
 
The primary endpoint is the response rate to therapy at Day 28 after randomization defined in 
Section 3.0 as:   
a) The ability to survive to Day 28 of study, PLUS   
b) The ability to completely discontinue all supplemental oxygen support for > 72 
consecutive hours by Day 28 (see Section 3.0 for details). 
 
The primary analysis will be performed using the intent-to-treat principle, beginning at the time 
of study randomization, so that all randomized patients will be included in the analysis.   
 
5.1.4. Primary Hypothesis 
 
The primary null hypothesis of the study is that there is no difference between the response rates 
to etanercept plus corticosteroids compared to placebo plus corticosteroids. 
 
Ho: 
pEt = pPl 
Ha: 
pEt  pPl 
 


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5.2. Sample Size and Power Considerations 
 
Response rates at Day 28 will be compared between the standard and experimental therapy arms 
using the binomial comparison of proportions.  The primary analysis will be performed after all 
patients are followed for a minimum of 28 days post-randomization.  At this time point, all 
individuals will be completely observed for the primary outcome.  The sample size of 30 patients 
per group is sufficient to provide 80% statistical power for a two-sided test to detect an increase 
in the response rate from 0.3 in the placebo arm to 0.69 in the etanercept arm.  While this effect 
size is large, it is similar to what was observed in pilot data at the University of Michigan as 
described in Section 1.7. 
 
5.3. Interim Analysis and Stopping Guidelines 
 
There will be no planned interim analyses for efficacy or futility, due to the small sample sizes 
planned.  Monitoring of key safety endpoints will be conducted monthly, and if rates 
significantly exceed pre-set thresholds, the NHLBI will be notified in order that the DSMB can 
be advised and if an ad-hoc meeting will be convened.  Policies and composition of the DSMB 
are described in the BMT CTN Administrative Manual of Procedures.   
 
5.3.1. 
Guidelines for Safety Monitoring 
 
Historical data at the University of Michigan Medical Center indicate that 76% of patients with 
IPS die within 56 days of the onset of IPS.  These data also indicated that 50% of patients with 
IPS required mechanical ventilation, 70% exhibited grade II-IV acute GVHD, 42% had 
concurrent hepatic veno-occlusive disease, and 36% were on hemodialysis at the time of their 
IPS diagnosis.  Given the high acuity of this patient group, many patients will enter this study 
with both grade III-IV non-pulmonary toxicity and grade IV pulmonary toxicity already present 
(Common Terminology Criteria for Adverse Events, CTCAE version 3.0).   
 
We will monitor three different toxicities separately in each treatment arm: (1) the cumulative 
incidence of new serious or life-threatening infections developing after Day 1 but by 28 days 
post-randomization; (2) the cumulative incidence of grade 4 dermatologic toxicity (CTCAE 
version 3.0) by Day 28 post-randomization; and, (3) the incidence of mortality by Day 28.  The 
rationale for examining dermatologic toxicity is based upon data from the Dana Farber Cancer 
Institute and the University of Michigan Medical Center.  Grade 4 dermatologic toxicity (rash 
with desquamation) was noted in 4 of 12 patients treated with etanercept at the Dana-Farber 
Cancer Institute, and in 0 of 40 patients treated with etanercept (for IPS or acute GVHD) at the 
University of Michigan Medical Center [personal communication, G. Yanik MD, V. Ho MD]. 
Dermatologic toxicity will now be examined in this multi-center trial, in a larger cohort of 
patients.  
 
In the first two endpoints (serious infections and dermatologic toxicity), death prior to the 
toxicity occurring will be considered as a competing risk.  Monitoring will be performed 
monthly until enrollment to that treatment arm is closed.  Each month, the null hypothesis that 
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against the alternative that it is greater than 15%.  Similarly, the incidence of grade 4 
dermatologic reactions and mortality will be compared to a threshold of 5% and 65%, 
respectively. 
 
A truncated Sequential Probability Ratio Test (SPRT) for a binomial outcome will be used for 
each endpoint, as described in greater detail below.  Note that in the absence of censoring, the 
binomial proportion of patients experiencing the toxicity prior to death is equal to the cumulative 
incidence.  This sequential testing procedure conserves type I error across all of the monthly 
examinations for a single toxicity endpoint, but not across two treatment arms or across the three 
endpoints.  Thus for a single endpoint and study arm, the type I error is < 5%, and across both 
treatment arms and all three endpoints, the study-wide type I error is < 30%. 
 
The rationale for not conserving type I error across multiple treatments and outcomes is twofold.  
First, adjusting the size of the test for multiple comparisons would reduce statistical power to 
detect adverse outcomes, which seems imprudent.  Secondly, the procedure is a guideline for 
requiring additional review by the Data and Safety Monitoring Board, and is not a formal 
“stopping rule” that would mandate automatic closure of study enrollment.   
 
The SPRT can be represented graphically.  At each monthly interim analysis, the total number of 
patients enrolled is plotted against the total number of endpoints observed in those patients, (e.g., 
patients with new serious infection).  The continuation region of the SPRT is defined by two 
parallel lines.  Only the upper boundary will be used for monitoring each treatment arm to 
protect against high incidences of new infection.  If the graph falls above the upper boundary, the 
SPRT rejects the null hypothesis, and concludes that there are more new serious infections than 
predicted by the observed number of patients enrolled on study.  Otherwise, the SPRT continues 
until enrollment to the treatment arm reaches the target goal.   
 
The usual measures of performance of an SPRT are the error probabilities  and  of rejecting 
H0 when  = 0 and of accepting H1 when  = 1, respectively, and the expected sample size 
E(N|I).  The tests to be used in this protocol were developed from the following SPRTs:   
 
 A SPRT contrasting 15% versus 30% Day 28 incidence of new serious infection, with 
nominal type I and II errors of 5.6% and 20%, respectively.  The common slope of the 
parallel lines is 0.219 and the intercept for the upper boundary is 2.997. 
 A SPRT contrasting 5% versus 15% Day 28 incidence of subcutaneous reaction, with 
nominal type I and II errors of 6.5% and 20%, respectively.  The common slope of the 
parallel lines is 0.092 and the intercept for the upper boundary is 2.075. 
 A SPRT contrasting 65% versus 80% Day 28 mortality, with nominal type I and II errors 
of 5.6% and 20%, respectively.  The common slope of the parallel lines is 0.729 and the 
intercept for the upper boundary is 3.466. 
 
Note that since the test uses only the upper boundary, and is truncated by a finite sample size, the 
size of the test will be lower than the nominal level given %.  
 


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Table 5.3c demonstrates the stopping points for various numbers of enrolled patients for 
illustration. 
 
 
Table 5.3c – Sample Stopping Boundaries for SPRT 
 
Number of 
Patients Enrolled, 
n 
Stop if Number of Events in First n Patients is ≥ x 
Infection 
Dermatologic 
Mortality 
5 
5 
3 
 
10 
6 
3 
 
15 
7 
4 
15 
20 
8 
4 
19 
25 
9 
5 
22 
30 
10 
5 
26 
 
 
Note that because there is a lag from randomization to complete follow up (28 days), the 
stopping rule may be triggered before complete follow up is available.  For example, there may 
be 6 infection events in the first 10 patients even though the first 10 patients do not all have 28 
days of follow-up.  This implies that the plot of the number of patients transplanted against 
events observed in those patients may change for earlier accrual points as follow-up is 
completed, and will therefore be updated each month.   
 
The actual operating characteristics of the truncated test, shown in Table 5.3d, were determined 
in a simulation study that assumed uniform accrual of 30 individuals over a five-year time 
period.  No assumptions are made about the time to event distribution for either the toxicity 
event of interest or the competing event of death prior to observing that toxicity.  The monitoring 
rule is based only on the binomial outcome of whether a patient experienced the toxicity by 28 
days and prior to death.  Because the simulations only use a binomial outcome, the mean month 
stopped is calculated based on the accrual time of the patient triggering the stopping rule + 28 
days for complete follow-up.  In practice, because of the potential for the stopping rule to be 
triggered prior to complete follow up of a particular patient, the actual mean month stopped may 
be earlier than shown in the simulation results.  However, this is difficult to estimate because it is 
dependent on assumptions about the time to event distribution for both the toxicity event and the 
competing risk, as well as the dependence between them.   
 
 


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Table 5.3d – Operating Characteristics of Sequential Testing Procedure 
 from a Simulation Study with 10,000 Replications 
 
Serious Infection 
True 28-Day Rate 
15% 
25% 
30% 
35% 
Probability Reject Null 
0.028 
0.287 
0.500 
0.722 
Mean Month Stopped 
60.3 
53.9 
48.0 
40.6 
Mean # Endpoints in 28 Days 
4.4 
6.7 
7.1 
7.1 
Mean # Patients Enrolled 
29.7 
26.6 
23.7 
20.1 
 
Dermatologic Reaction 
True 28-Day Rate 
5% 
15% 
20% 
Probability Reject Null 
0.029 
0.538 
0.775 
Mean Month Stopped 
60.1 
46.0 
37.2 
Mean # Endpoints in 28 Days 
1.5 
3.5 
3.7 
Mean # Patients Enrolled 
29.6 
22.7 
18.5 
 
Mortality 
True 28-Day Rate 
65% 
75% 
80% 
85% 
Probability Reject Null 
0.025 
0.173 
0.362 
0.634 
Mean Month Stopped 
60.5 
58.0 
54.3 
48.4 
Mean # Endpoints in 28 Days 
19.4 
21.4 
21.4 
20.3 
Mean # Patients Enrolled 
29.8 
28.5 
26.7 
23.9 
 
 
For example, the testing procedure for serious new infections rejects the null hypothesis in favor 
of the alternative 3% of the time when the true 28-day incidence is 15%, and 72% of the time 
when the rate is 35%.  When the true 28-day infection incidence is 35%, on average, the Data 
and Safety Monitoring Board will be consulted 40.6 months after opening, when 7.1 events have 
been observed in 20.1 patients.   
 
5.4. Demographic and Baseline Characteristics 
 
Demographics and baseline characteristics will be summarized for all patients.  Characteristics to 
be examined are: age, gender, race/ethnicity, performance status, primary disease, risk status, 
donor type, donor age, donor gender, donor ethnicity, donor-recipient CMV status.  Between 
group comparisons will be performed for continuous variables via a t-test and for categorical 
variables, via the chi-square test. 
 


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5.5. Analysis of Secondary Endpoints 
 
1. Response to therapy at Day 56: A binomial test of proportions will be computed after 
all patients are followed for 56 days post randomization to compare the standard and 
experimental treatment arms. 
2. Overall mortality: Kaplan-Meier curves will be computed by treatment, and the groups 
will be compared using the log-rank test.  Estimates and 95% confidence intervals will be 
tabulated also specifically for Day 28 and Day 56 mortality.  The groups will be 
compared using a test based on the difference in the Kaplan-Meier estimates at a fixed 
point in time (Day 28 and Day 56).   
3. Time to discontinuation of supplemental oxygen support: cumulative incidence 
curves will be computed by treatment, with death prior to discontinuation as the 
competing risk.  A log-rank test will be used to compare the two arms.     
4. BAL Fluid and Plasma Cytokine Analysis: BAL fluid and plasma will be collected for 
cytokine analysis using standard ELISA assays.  This analysis will include but be not 
limited to TNF, sTNFRI, sTNFRII, LBP, IL-1, IL-6, MCP-1 and sCD14.  
Measurements will be summarized with means and standard deviations for patients in 
each arm at each timepoint.  Baseline or 7 day measurements, and the change between 
them, will be correlated with Day 28 response by using two-sample t-tests or 
nonparametric tests to compare responders vs. nonresponders.  In addition, cytokine 
measurements over time will be correlated with time until death using Cox regression 
models with time-dependent covariates for the cytokine levels.   
 
Two-sided tests will be used throughout.  A p-value of 0.05 or less will be considered 
statistically significant.     
 
5.6. 
Safety Analysis 
 
All entered patients will be included in the safety analysis.  All reported serious adverse events 
potentially associated with study drug will be carefully examined with respect to the severity and 
relationship to study drug.  Adverse events will be graded according to the NCI Common 
Terminology Criteria for Adverse Events Version 3.0.  The incidence for each reported study 
drug associated adverse event will be presented for each group.   
 


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APPENDIX A 
 
HUMAN SUBJECTS 
 
 
1. Subject Consent 
 
A conference will be held with the patient, donor and family to discuss this study and alternative 
treatments available for the treatment of the underlying disease.  The conference will be 
conducted by the principle investigator or other designated physician.   
 
 
2. Confidentiality 
 
Confidentiality will be maintained by individual names being masked and assigned a patient 
identifier code.  The code relaying the patient’s identity with the ID code will be kept separately 
at the center.  The ID code will be transmitted to the network. 
 
 
3. Participation of Women and Minorities and Other Populations 
 
Women and ethnic minorities and other populations will be included in this study.  Accrual of 
women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities 
expected from data reported to the CIBMTR and from published data on incidence of IPS in 
these groups.  Centers will be notified if their rates differ significantly from those expected and 
asked to develop appropriate recruitment strategies. 


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APPENDIX B 
 
CONSENT FORMS 
 
 
 
PATIENT INFORMED CONSENT 
 
 


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Informed Consent to Participate in Research 
 
A Randomized Double-Blind, Placebo-Controlled 
Trial of Soluble Tumor Necrosis Factor Receptor: 
Enbrel (Etanercept) for the Treatment of Acute 
Non-Infectious Pulmonary Dysfunction 
(Idiopathic Pneumonia Syndrome) Following 
Allogeneic Cell Transplantation 
 
Your name:_________________________________________________   
 
Introduction 
You are being invited to participate in a clinical trial.  A clinical trial is a research study to 
answer specific medical questions.  The information from this study may help future patients.  
This form tells you about the study.  In addition, the study doctor (the person in charge of the 
research) will explain the study to you.   
 
Please read this information and ask your study doctor about anything you do not understand.  
Please take your time to decide if you want to join this study.  Some people find it helpful to 
have a family member or friend with them while learning about the study.  You are being asked 
to join this study because you have a serious complication of transplantation affecting the lungs 
called Idiopathic Pneumonia Syndrome (IPS).   
 
Before you decide whether or not to join the study, please read the information below. Feel free 
to ask questions.  You do not have to participate in this research study - it is your choice. You 
and the medical staff at your transplant center will discuss other options before you make your 
decision. 
 
It is important that you know: 
 You will not be paid to be in this study. 
 You or your insurance company will pay the bills for your medical treatment except that,  
 You will not be charged for research tests or study medications. 
 
Principal Investigator Contact Information at your Institution  
Name/Title/Phone number/ 
 
Contact information for emergencies after hours or on weekends or holidays: 
Name/Phone number/ 
 


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Study Sponsor 
The research in this study is paid for by the National Institutes of Health (NIH), which supports the 
Blood and Marrow Transplant Clinical Trials Network (BMT CTN).  The BMT CTN will direct the 
research study.  Some support will also be given by the Amgen Corporation, which makes the drug 
being tested in this study.  All decisions about how the study is done are made independently by the 
BMT CTN and NIH.   
 
Why is this study being done?   
Pneumonia is a term that refers to the presence of fluid, congestion, or irritation or swelling in 
the lungs.  Patients with pneumonia often have a cough and/or chest pain.  They can be short of 
breath.  Oxygen may be needed to help them breathe.  In many cases, pneumonia is caused by 
germs such as viruses.  However, sometimes patients develop symptoms of pneumonia but no 
germs are present.  This is called Idiopathic Pneumonia Syndrome (IPS).  IPS usually occurs 
within the first 180 days after transplant.   
 
No one knows what causes IPS.  No one knows why some patients get it and others do not.  
Recent studies have found that the lung fluid of patients with IPS contains certain chemicals that 
may directly damage the lung.  One of these chemicals is called Tumor Necrosis Factor (TNF).  
Some recent tests suggest that TNF may be involved in causing lung damage.  
 
Currently, there is no proven treatment for IPS.  Patients may receive oxygen to help with 
breathing.  They may receive medications (called diuretics) to remove fluid from their lungs.  
Patients often receive steroids to decrease some of the irritation and swelling in the lungs.  
Despite these treatments, many patients with IPS do not get better.   
 
Etanercept is a drug approved by the Food and Drug Administration (FDA) for the treatment of 
rheumatoid arthritis (joint disease) and psoriasis (skin disease).  We know that TNF is 
responsible for the damage caused to the joints or skin in patients with these diseases.  
Etanercept blocks the effects of TNF.  Since we think that TNF may cause some of the lung 
damage in patients with IPS, it is possible that etanercept will help this disease too.  In a previous 
small study of etanercept in patients with IPS, no serious side effects were seen.  Some of the 
patients got better.    
 
The purpose of this study is to find out whether adding etanercept to a commonly-used treatment 
for IPS (steroids) is more effective in treating IPS than steroids alone.  Patients will receive 
either “etanercept and steroids” (Group A) or “placebo and steroids” (Group B).  The placebo 
has no good or bad effect on IPS.  Thus patients in Group B are actually receiving only steroids 
to treat IPS. 
 
Steroids are the most common treatment for IPS. 
 
Doctors want to know if giving etanercept plus steroids is better, the same or worse than giving 
steroids alone.  The study will also see whether side effects result from adding etanercept to the 
commonly-used steroids.  The study may help doctors make better treatment choices for future 
patients with IPS.   


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How many people will take part in the study? 
A total of 60 patients will participate in this study.  Thirty patients will be assigned to each 
group.  This study will be done at more than 25 different medical centers in the United States, 
including [Center Name/Location]. 
 
What will happen if I take part in this research study?   
The diagram below outlines the research study (the details follow the diagram).  Start reading at the 
top and read down the list following the lines.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
         Screening studies:  
Blood tests and chest X ray 
Bronchoscopy procedure 
If an infection is noted:  
You are not eligible for 
treatment on this study 
If no infection is noted:  
You may be eligible to be on this study 
       Randomize:  
Treatment on Group A or Group B 
Group A:  
Etanercept twice per week x 4 weeks. 
Steroids: daily for 8 weeks (Day 0-56)  
Group B:  
Placebo twice per week x 4 weeks. 
Steroids: daily for 8 weeks (Day 0-56) 
On-study tests: blood tests and chest X rays 
weekly through week 4 (Day 28) 


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Screening studies: 
You will need to have the following tests or procedures to find out if you are eligible for this 
study.  We refer to these as “screening studies.”  These screening studies are often part of regular 
care, and may be done even if you do not join the study.   
 Chest X ray 
 Blood tests  
 Bronchoscopy  
 
Bronchoscopy: A bronchoscopy is a procedure performed by lung specialists.  A small flexible 
tube is inserted into your nose (or mouth), and passed into your lungs.  The tube has a light on 
one end that allows doctors to see into your lungs.  The doctors will take out a sample of fluid 
from your lungs.  This lung fluid will be tested for the presence of germs.  If any germs are 
found, you can not be on this study but will receive treatment for the specific germs found.  A 
portion of the fluid will also be tested for research purposes.  The research will look for the 
presence of chemicals such as TNF.   
 
During the bronchoscopy, you may or may not be put to sleep.  In some cases, your doctor may 
place you on a breathing machine (called a mechanical ventilator).  This will make sure you get 
enough oxygen during the procedure.  At the end of the procedure, the breathing tube is usually 
removed.  In some cases, however, the breathing machine may need to remain in place longer.  
 
If you have had a bronchoscopy in the past 3 days, this procedure will not need to be repeated as 
long as no germs were found. 
 
In some cases, your physician may choose not to do the bronchoscopy procedure.  If your 
medical condition is such that a BAL is deemed “not possible to be performed” by your treating 
physician, then the “on study” BAL may be waived (not done).  In this circumstance, you may 
enroll and still be randomized to study therapy without the BAL being undertaken. 
 
Randomization: 
If the results of tests and procedures show that you can be in the study, you will be “randomized” 
into one of the study groups described below.  Randomization is done by a computer.  
Randomization puts you into a group by chance, much like flipping a coin.  You will have an 
equal chance of being placed into either group.  You will not be able to choose which group you 
are assigned.  Neither you nor your doctors will know your group.   
 If you are in Group A, you will receive treatment with etanercept plus steroids.   
 If you are in Group B, you will receive treatment with steroids plus a placebo.  The 
placebo will be a salt solution without medication.   
 
You will not be able to tell the etanercept from the placebo, as both will look the same.  Once 
you start treatment, you may not change to therapy in the other group while on this study.  
 
Study Treatment: 
The etanercept (or placebo) may begin within 24 hours after the bronchoscopy procedure.  You 
will receive either etanercept or the placebo two times per week, for 4 weeks (see Table below).  


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There will be a total of 8 doses given.  You will receive the first dose of etanercept (or placebo) 
as a 30-minute intravenous (IV) infusion.  You will receive the second dose of etanercept (or 
placebo) as an injection under the skin (SQ) 3 days after the first dose.  You will receive the 
remaining etanercept (or placebo) doses as injections under the skin approximately 3-4 days after 
the previous dose. The dosing plan is provided below. 
 
GROUP A 
 
GROUP B 
Etanercept 
Dose 
Time 
How 
Administered 
 
Placebo 
Dose 
Time 
How 
Administered 
1 
Day 0 
IV 
 
1 
Day 0 
IV 
2 
Day 3 
SQ 
 
2 
Day 3 
SQ 
3 
Day 7 
SQ 
 
3 
Day 7 
SQ 
4 
Day 10 
SQ 
 
4 
Day 10 
SQ 
5 
Day 14 
SQ 
 
5 
Day 14 
SQ 
6 
Day 17 
SQ 
 
6 
Day 17 
SQ 
7 
Day 21 
SQ 
 
7 
Day 21 
SQ 
8 
Day 24 
SQ 
 
8 
Day 24 
SQ 
 
Key: IV, intravenous; SQ, injection under the skin 
 
 
In addition to the etanercept (or placebo), you will also be given steroids (such as prednisone, 
Medrol, or Solumedrol).  The steroids may be given to you by IV or by mouth.  The dose of 
steroids you receive varies according to your weight.  If you are getting better (requiring less 
oxygen to breathe) by Day 7 of treatment, the dose of steroids may be decreased.   
 
If you continue to get better (requiring less oxygen to breathe), the steroid dosage will be 
decreased further over a 2-month period.  In some cases, the steroids will be continued for a 
longer period of time (after 2 months).  
 


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Required tests while you are on the study: 
 
Day: 
Process: 
Tests within 24 hours  
of study registration 
Blood tests 
Chest X ray 
Day 0 
Bronchoscopy 
Week 1 
Blood tests 
Chest X ray 
Week 2 
Blood tests 
Chest X ray 
Week 3 
Blood tests 
Chest X ray 
Week 4 
Blood tests 
Chest X ray 
 
 
Weekly blood tests will be obtained through week 4 (Day 28).  Tests will include routine 
measurements of blood counts and electrolytes.  Research tests will measure levels of certain 
chemicals called cytokines (including TNF) in the blood. 
 
How long will I be in this study? 
You will be treated on this study for 8 weeks.  You will be given etanercept (Group A) or 
placebo (Group B) over 4 weeks, and steroids over about 8 weeks.  Your participation on this 
study will last for one year as we follow how you are doing through regular visits with your 
transplant doctor.  Follow-up for your transplant will last as long as you require care.  However, 
we would like to keep track of your medical condition for the rest of your life.  We will do this 
by contacting you and the doctor providing your regular medical care by phone or mail once a 
year.  Keeping in touch with you and checking on your condition every year helps us know 
whether there are any unexpected long-term side effects of treatment.  Many transplant centers 
include this type of long-term follow-up as part of their regular care.    
 
Can I stop being in this study?  
Yes.  You can decide to stop at any time.  Tell your doctor if you are thinking about stopping or 
decide to stop.  He or she will tell you how to stop safely. 
 
It is important to tell the study doctor if you are thinking about stopping so any risks can be 
evaluated by your doctor.  Another reason to tell your doctor that you are thinking about 
stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
If you have any questions about your rights as a study subject, you may contact the Institutional 
Review Board (IRB) office at /number/. 
 
Can the Principal Investigator withdraw me from this research study? 
The study doctor may stop you from taking part in this study at any time if he/she:  
 Believes it is in your best interest;  


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 If you do not follow the study rules; or,  
 If the study is stopped. 
 
You can be taken off the study (with or without your consent) for any of these reasons: 
 If, after undergoing the bronchoscopy procedure, lab testing indicates that germs were 
present in your lungs.  Your study treatment will be stopped.  No further study treatment 
will be given.   
 If you develop a severe side effect from the study treatment. 
 You need treatment not allowed in this study. 
 You do not follow directions that are important to being in the study. 
 The study is cancelled. 
 Other study-specific reasons, for example, if study doctors determine the study should be 
closed early because of side effects found in other patients. 
 If your physician feels it is in your best interest to stop. 
 
What side effect or risks can I expect from being in the study? 
There are risks involved in this study.  There may be side effects from the drugs or study 
procedures.  The side effects we know about now are described below.  Side effects can range 
from mild to severe.  Some side effects may last only a short time (hours – days).  Others may 
last longer.   
 
Please talk with your doctor about possible side effects.  If you want to read more about the 
drugs used in this study, please ask your doctor.  We have grouped side effects according to how 
likely they are to happen: 
 
 
Likely Side Effects 
What it means: This type of side effect is expected to occur in more 
than 20% of patients.  This means that 21 or more patients out of 100 
might get this side effect. 
Less Likely Side Effects 
What it means: This type of side effect is expected to occur in 20% of 
patients or fewer.  This means that 20 patients or fewer out of 100 
might get this side effect. 
Rare Side Effects 
What it means: This type of side effect does not occur very often – in 
fewer than 2% of patients – but is serious when it occurs.  This means 
that 1 or 2 patients (or fewer) out of 100 might get this side effect. 
 
 
I. 
Risks related to the bronchoscopy procedure: 
Bronchoscopy is a standard procedure for evaluating patients with pneumonia.  You will be 
given a separate consent form to sign that explains the risks and discomforts. 
 


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II. 
Risk of steroids:  
All patients on this trial will receive steroids.  This is the most commonly used treatment for IPS.  
The following table shows expected side effects of steroids.   
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in more 
than 20% of patients) 
 Difficulty sleeping 
 Increased susceptibility to infections 
 Weight gain, especially around the face/cheeks, shoulders, 
belly or legs 
 Muscle weakness 
 Pimples/acne 
 Increase in appetite 
 Increase in blood pressure 
 Increased levels of glucose (sugar) in the blood 
 Mood swings 
 Upset stomach (heartburn or gastritis) 
Less Likely 
 
(“Less likely” refers to a side 
effect that is expected to occur in 
20% or fewer patients) 
 
 Red face 
 Slow healing of cuts or other wounds 
 Slowed growth 
 Stretch marks and easy bruising of the skin 
 Abnormal electrolyte (salt) levels in the blood 
 Increased pressure in the eyes 
 Weakened bones (due to lower calcium levels in the bones) 
 Cataracts (thickening of the lens of the eye)  
 Headache 
 Dizziness 
 Infections 
Rare, but Serious 
 
(These possible risks have been 
reported in rare occurrences, 
typically < 2% of patients.  They 
may be serious if they occur) 
 
 Joint damage, which can cause pain and loss of motion in that 
joint 
 Irritation of the pancreas (pancreatitis) 
 Irregular heart beat 
 Stomach and intestinal bleeding ulcers 
 Increased pressure in the brain, which can lead to difficulty 
seeing and headache 
 Bone fractures 
 Serious changes in mood, personality and/or severe depression 
 


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III. 
Risks related to etanercept: (this applies if you are assigned to Group A therapy) 
 
Etanercept has been studied in both children and adults with a number of other conditions.  
These conditions include rheumatoid arthritis (a joint disease), psoriasis (a skin disorder), 
Crohn’s disease, AIDS, heart failure, or serious infections.  Infections, some serious, have been 
reported in these studies.  Many infections occurred in patients who already had diseases that 
tended to weaken their body’s ability to fight infection.  In all cases, the occurrences of these 
side effects were rare.  Also it is unclear whether or not etanercept was the cause.  In patients 
with rheumatoid arthritis or psoriasis, the number of infections in patients treated with etanercept 
did not differ from the number in patients treated with a placebo.  This included serious 
infections. 
 
We cannot determine how etanercept may affect your risk of getting cancer.  To date, the 
incidence of cancer in patients receiving etanercept has been similar to the risk in untreated 
people. 
 
A small number of people receiving etanercept have formed antibodies (proteins that attack 
foreign matter) against etanercept.  Although these antibodies do not appear to decrease the 
effect of the drug, it is a possibility that it may in some patients.  The effects of a person 
developing antibodies to etanercept are not known.  Your chances of developing antibodies are 
believed to be very low, < 5%. 
 
Etanercept given by injection under the skin may cause local pain, bleeding, bruising, and rarely, 
an infection at the site of injection.  A summary of the possible risks of etanercept is shown 
below:  
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in more 
than 20% of patients) 
 Pain at the site of the injection 
Less Likely 
 
(“Less likely” refers to a side 
effect that is expected to occur in 
20% or fewer patients) 
 
 Increased risk of infections.  Some of these infections 
may be serious or even life threatening 
 Irritation, itching, bruising, swelling or redness at the site 
of the etanercept injection 
 Hyper or hypothyroidism, where the thyroid gland 
produces too little or too much thyroid hormone 
 Belly pain, nausea and/or vomiting 
 High blood sugar levels 
 Blurred vision 
 Headache, or dizziness 
 Runny nose, sore throat 


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Rare, but Serious 
 
(These possible risks have been 
reported in rare occurrences, 
typically < 2% of patients, but 
may be serious if it occurs.  In 
most cases it is unclear whether 
or not etanercept was the cause.) 
 
 Severe allergic reactions during the infusion or injection 
 Severe rashes which can affect the skin and mouth, 
leading to pain, peeling of the skin and increased risk of 
infections 
 Headaches, seizures, strokes 
 Onset of multiple sclerosis or muscle weakness  
 Decreased blood counts, such as  
­ A low number of white blood cells, which can make it 
easier to get infections 
­ A low number of red blood cells, which can make you 
feel tired and weak 
­ A low number of platelets, which causes you to bruise 
and bleed more easily 
 A relapse of one’s cancer, or the development of a new 
cancer such as leukemia or lymphoma.  Patients with 
Wegener’s granulomatosis, a known immune system 
disorder, have had an increased risk of developing 
lymphoma. 
 Weakened heart muscle which may make you feel tired, 
weak, or short of breath 
 Recurrence of certain viral infections, such as the 
hepatitis B virus, which can lead to severe liver damage 
or liver failure 
 Recurrence of tuberculosis, if you have been previously 
infected with tuberculosis 
 Development of proteins (called antibodies) that react 
against your own body tissue.  Collectively, these are 
called auto-immune reactions.  They are often associated 
with rashes and fever.  
 Blood clots, or bleeding problems 
 
 
There may be other, as yet unknown, side effects of etanercept. 
 
 
IV. 
Reproductive risks:  The effects of etanercept on your ability to get pregnant is not 
known.  Its risks to an unconceived, unborn or newborn child are also unknown.  Because the 
drugs in this study may affect an unborn baby, you should not become pregnant or father a baby 
while on this study.  You should not nurse a baby while on this study.  Women or men of child-
bearing potential are not allowed to be in the study unless they use birth control (which may 
include abstinence).   
 
 


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V. 
Risks related to the placebo: (this applies if you are assigned to Group B therapy)  
The treatment with placebo is anticipated to have few side effects.  Pain at the site of the 
injections of the placebo may be noted in > 20% of patients receiving the placebo injections.  
 
Are there benefits to taking part in the study?  
Being in this study may or may not lead to any direct benefit for you.  We also hope that 
information gathered in this study will help future patients with IPS.   
 
What other choices do I have if I do not take part in this study? 
If you do not take part in this study, you will be followed and treated according to the usual practice 
at your transplant center.  This may include, for example:  
 
 Bronchoscopy.   
 Supportive care such as oxygen, or medications to remove fluid from your lungs. 
 Steroid medications to treat IPS. 
 Etanercept to treat IPS (this etanercept is the same as the study drug, but it would be given to 
you not as part of this study). 
 
You should know about your treatment choices before you decide if you will take part in this 
study.   
 
What are the costs of taking part in this study? 
You or your insurance company will pay for all standard care relating to your transplant and IPS.  
This includes (but not limited to) routine blood tests, chest X-rays, and bronchoscopy 
procedures. 
 
You will not be billed for tests that are only done for research purposes.  These include the cost 
of the etanercept or placebo, and the cost of laboratory studies to measure chemicals called 
cytokines, such as TNF.   
 
You will not be paid to be in this study. 
 
Amgen, the company that makes etanercept, is providing funds for some of the costs of this 
study.  However, Amgen did not plan or design this clinical trial.  Amgen will also not have a 
part in analyzing the results of this study. 
 
Some health plans will not pay these costs for people taking part in studies.  Check with your 
health plan or insurance company to find out if they will pay.   
 
For questions about your costs, financial responsibilities, and/or medical insurance coverage for 
your transplant and this study, please contact /Center/ Financial Counselor at /Number/. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 


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Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
What if I am injured as a result of being in this study? 
In the event that this research activity results in an injury, treatment will be available.  This 
treatment includes first aid, emergency treatment and follow-up care as needed.  Care for such 
injuries will be billed to your insurance company.  If you think you have suffered a research 
related injury, let the study doctors know right away.  Unexpected side effects or accidents might 
result in your getting sicker than anticipated.  All available medical care will be provided to you, 
but you and your insurance company are responsible for the costs of all such care. 
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.  No 
matter what decision you make, there will be no penalty to you.  You will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.  
 
We will tell you about new information that may effect your health or your willingness to stay in 
the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.  
 
Will my medical information be kept private? 
Your participation in this research study will be kept private and confidential.  All your medical 
and demographic (such as race and ethnicity, gender and household income) information will be 
kept private and confidential.  (Name of Transplant Center) and the organizations listed below 
will not disclose your participation by any means of communication to any person or 
organization, except by your written request, or permission, or unless required by federal, state or 
local laws, or regulatory agencies.  
 
Individuals authorized by the organizations below will have access to your research and medical 
information.  They may use this information for inspections or audits to study the outcomes of 
your treatment.  In agreeing to participate, you consent to such inspections and to the copying of 
parts of your records, if required by these organizations. 
 
Organizations with access to your research and medical records: 
 /Institution/ 
 The National Institutes of Health (NIH) 
 The National Heart, Lung, and Blood Institute (NHLBI)  
 The National Cancer Institute (NCI) 


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 Office of Human Research Protection (OHRP) 
 The Food and Drug Administration (FDA)  
 Institutional Review Boards (IRBs) responsible for this study 
 Data and Safety Monitoring Board (DSMB), not part of /Institution/ 
 Blood and Marrow Transplant Clinical Trials Network (BMT CTN), including the Center 
for International Blood and Marrow Transplant Research (CIBMTR), the National 
Marrow Donor Program (NMDP) and the EMMES Corporation who are coordinating the 
studies of the BMT CTN 
 Representatives of Amgen, Inc. (drug supplier for the etanercept used in this study) 
 Study investigators 
 
Scientific and medical findings resulting from a study may be presented at meetings.  They may 
be published so that the information can be useful to others.  You will not be identified in these 
presentations and publications. 
 
Information related to or resulting from your transplant will be reported to the CIBMTR.  The 
CIBMTR is a voluntary organization of basic and clinical scientists working together to gather 
results of stem cell and marrow transplants.  This information is used to guide clinical decisions 
and identify ways to improve transplant outcomes.  Scientific data or medical information (not 
identifiable with you) that could be useful to others may be presented at meetings and/or 
published in medical journals. 
 
For questions about access to your medical records, please contact /name/ at /number/. 
 
HIPAA1 authorization to use and disclose individual health information for research 
purposes 
 
a. Purpose:  As a research participant, I authorize the Principal Investigator and the researcher’s 
staff to use and disclose my individual health information for the purpose of conducting the 
research study entitled A Randomized Double-Blind, Placebo-Controlled Trial of Soluble 
Tumor Necrosis Factor Receptor: Enbrel (Etanercept) for the Treatment of Acute Non-
Infectious Pulmonary Dysfunction (Idiopathic Pneumonia Syndrome) Following Allogeneic 
Cell Transplantation. 
 
b. Individual Health Information to be Used or Disclosed: My individual health information that 
may be used or disclosed to conduct this research includes: demographic information (e.g., 
age, date of birth, sex, weight), medical history (e.g., diagnosis, complications with prior 
                                         
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health 
information 


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treatment), physical examination findings, and laboratory test results obtained at the time of 
work up and after transplantation (e.g., blood tests, biopsy results).  
 
c. Parties Who May Disclose My Individual Health Information: The researcher and the 
researcher’s staff may obtain my individual health information from: 
(list hospitals, clinics or providers from which health care information can be requested) 
 
 
 
 
d. Parties Who May Receive or Use My Individual Health Information: The individual health 
information disclosed by parties listed in item c and information disclosed by me during the 
course of the research may be received and used by the following parties: 
 Principal Investigator and the researcher’s staff at the University of Michigan 
 Staff/laboratories identified in the protocol for the evaluation of other laboratory samples 
 National Heart, Lung and Blood Institute (NHLBI) and the National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH), study sponsors  
 Blood and Marrow Transplant Clinical Trials Network (BMT CTN), including the Center 
for International Blood and Marrow Transplant Research (CIBMTR), the National 
Marrow Donor Program (NMDP) and the EMMES Corporation who are coordinating the 
studies of the BMT CTN 
 U.S. government agencies that are responsible for overseeing research such as the Food 
and Drug Administration (FDA) and the Office of Human Research Protections (OHRP) 
 U.S. government agencies that are responsible for overseeing public health concerns such 
as the Centers for Disease Control (CDC) and federal, state and local health departments. 
 Others: 
 
 
 
 
e. Right to Refuse to Sign this Authorization: I do not have to sign this Authorization.  If I 
decide not to sign the Authorization, I will not be allowed to participate in this study or 
receive any research-related treatment that is provided through the study.  However, my 
decision not to sign this authorization will not affect any other treatment, payment, or 
enrollment in health plans or eligibility for benefits.   
f. Right to Revoke:  I can change my mind and withdraw this authorization at any time by 
sending a written notice to the Principal Investigator to inform the researcher of my decision.  
If I withdraw this authorization, the researcher may only use and disclose the protected health 


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information already collected for this research study.  No further health information about me 
will be collected by or disclosed to the researcher for this study. 
g. Potential for Re-disclosure: My individual health information disclosed under this 
authorization may be subject to re-disclosure outside the research study and no longer 
protected.  Examples include potential disclosures for law enforcement purposes, mandated 
reporting or abuse or neglect, judicial proceedings, health oversight activities and public 
health measures. 
h. This authorization does not have an expiration date. 
 
******************************************** 
 
Is there an expiration date for keeping my records? 
Study records will be kept indefinitely by the transplant center for re-analysis and follow-up.  If 
you have questions about the keeping of your research records or access to your files, please call 
/name/ at /number/. 
 
Will researchers benefit from me being in this research study? 
Your doctors have no money invested and will not get any financial gain from this study.  
Presenting research results may help the career of a doctor.  Therefore, the doctors running this 
research study may benefit when the results are presented at scientific meetings or in the scientific 
press.  
 
************************************************* 
 
BLOOD AND LUNG FLUID FOR FUTURE RESEARCH: 
Please note: This section is about future research studies.  These studies will be done using 
blood and lung fluid samples.  You may give samples for these future research studies if you 
want to.  You can still be a part of the main study even if you say 'no' to allowing these 
samples to be used for future research studies.  Please mark your choice at the end of this 
section. 
 
The study investigators ask your permission to store and use any remaining blood or lung fluid  
for future research.  If your blood/lung fluid has already been collected, any remaining 
blood/lung fluid will be used for research, if you agree.  These future studies may help 
researchers learn more about IPS and your response to treatment.  Researchers may also perform 
genetic studies to determine whether there are correlations among your genetic make-up, the risk 
of developing IPS, and your response to treatment.  This new research will be unlinked to your 
private personal information or other medical history.  The doctors involved in running this study 
will not give other researchers your name, address, phone number, or any other information that 
will let the researchers identify you.  Data generated from your blood/lung fluid will be entirely 
investigational.  Reports about research done with your blood/lung fluid will not be given to you 
or your doctor.  These reports will not be put in your health record. 
 


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Your blood/lung fluid may be distributed to the researchers in the BMT CTN and other qualified 
researchers interested in IPS or other transplant-related complications.  As noted above, the 
researchers will be given these samples without any potentially identifying information.  
Information gained from research on your blood/lung fluid may be used for the development of 
diagnostic procedures or new treatments for lung complications after transplant.  Your 
blood/lung fluid will not be sold to any person, institution, or company for financial gain or 
profit.  Moreover, neither you nor your heirs will gain financially from discoveries made using 
the information and/or specimens that you provide. 
 
In some cases, you may have already given consent to your treating institution or the National 
Marrow Donor Program (if you were the recipient of stem cells from an unrelated donor) for the 
collection of blood samples prior to your bone marrow transplant.  If this has occurred, your 
treating institution (or the NMDP) will also be requested to, when possible, supply a portion of 
these samples for research purposes.  In addition, you will be asked to provide a tissue sample 
that could be collected by rubbing a cotton swab on the inside part of your cheek. 
 
Things to Think About: The choice to let us use these samples for future research is up to you.  
No matter what you decide to do, it will not affect your care.  
 
If you decide now that your blood/lung fluid can be kept for research, you can change your mind 
at any time.  If you change your mind, we ask that you tell [the study Principal Investigator] in 
writing; his/her mailing address is on the first page of this form.  Tell your doctor that you do not 
want us to use your blood or lung fluid.  Then any blood/lung fluid that remains will no longer be 
used for research.  
 
Benefits: You may not get any direct benefit for providing blood/lung fluids for this study, but 
the research performed with these samples may help us learn more about what causes IPS and 
other complications after transplantation, and how to prevent and/or treat them. 
 
Risks: The greatest risk to you is the release of information from your health records.  We will 
do our best to make sure that your personal information will be kept private and secure.  The 
chance that this information will be given to someone else is very small.  
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the 
National Institutes of Health.  With this Certificate, the researchers cannot be forced to disclose 
information that may identify you, even by a court subpoena, in any federal, state, or local civil, 
criminal, administrative, legislative, or other proceedings.  The researchers will use the 
Certificate to resist any demands for information that would identify you, except as explained 
below. 
 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects or for 
information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA). 
 


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You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research.  If an insurer, employer, or other person obtains your written consent to receive 
research information, then the researchers may not use the Certificate to withhold that 
information. 
 
Making Your Choice: Please read each sentence below and think about your choice.  After 
reading each sentence, please indicate your choice below.  If you have any questions, please talk 
to your doctor or nurse, or call our research review board at ___________________.  
 
No matter what you decide to do, it will not affect your care. 
 
 
I agree to allow my blood, lung fluid and cheek swab used to be used for future research. 
 
 
I do not agree to allow my blood, lung fluid and cheek swab to be used for future 
research. 
 
 ____________________________________   _____________________________  
Signature 
Date 
 
Who can I contact if I have questions or problems? 
If you think you have suffered an injury as a result of this study, or have any other problems, you 
may contact (INSERT CONTACT INFORMATION).  If it is after normal business hours or a 
weekend, you may contact (INSERT CONTACT INFORMATION). 
 
If you have any questions about this study, you may contact the study Principal Investigator 
listed on the first page of this form. 
 
If you have questions about your rights as a research participant, you may contact (INSERT 
CONTACT INFORMATION). 
 


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Consent for Treatment:  
 
I have been informed about this study’s purpose, procedures, possible benefits and risks.  I have 
been given a chance to ask questions and have had them answered to my satisfaction.  I 
understand that I can ask more questions at any time. 
I voluntarily agree to participate in this study. 
By signing this consent form, I have not given up any of the legal rights which I otherwise would 
have as a subject in a research study. 
 
 
_________________________________________________ _______________________  
Signature of Subject 
Date 
 
 
 ___________________________________ 
Print Name of Subject 
 
 
________________________________________________________________________ 
Signature of Legally Authorized Representative 
Date 
 
 
Certification of Counseling Healthcare Professional 
 
 
I certify that the nature and purpose, the potential benefits, and possible risks associated with 
participation in this study have been explained to the above individual and that any questions 
about this information have been answered. 
 
 
 _______________________________________   _____________________________  
 
Counseling Healthcare Professional 
Date 
 
Use of an Interpreter: Complete if the subject is not fluent in English and an interpreter was 
used to obtain consent: 
 
Print name of interpreter:  _____________________  Date:  ___________________  
 
Signature of interpreter:  ______________________   
 
An oral translation of this document was administered to the donor in ________________ (state 
language) by an individual proficient in English and __________________ (state language).  See 
the attached short form addendum for documentation. 
 


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APPENDIX C 
 
LABORATORY PROCEDURES 
 
 
C-1 
CYTOKINE AND INFLAMMATORY MARKERS 
 
BAL fluid and plasma specimen will be analyzed for a panel of cytokine and inflammatory 
markers (listed below) in the laboratory of Dr. Kenneth Cooke, Case Western Reserve University 
Medical School.  BAL fluid samples will be obtained at study entry and plasma will be collected 
at study entry, Day 7 and Day 28 of study, as outlined below:  
 
 
Table C.1  Sample Collection Summary: 
 
Study Date 
Sample 
Sample Volume 
Pre-randomization 
BAL 
5-10 mL in sterile container 
Day 0 
Plasma 
5-10 mL in green top tubes 
Day 7 
Plasma 
5-10 mL in green top tubes 
Day 28 
Plasma 
5-10 mL in green top tubes 
 
 
I. Processing of BAL fluid sample (at Local Institution): 
A minimum of 5 mL (range 5-10 mL) of BAL fluid is required for the cytokine studies.  Upon 
completion of the bronchoscopy procedure, the BAL fluid should be placed in a sterile container 
and kept on ice (or refrigerated at 4o C) until processing.  Ideally, the BAL fluid specimen should 
be processed within 30 minutes of collection.  Specimen should be spun at 400x g for 5 minutes 
in order to separate supernatant from the cell pellet.  Supernatant will be extracted and divided 
into 1-2 mL aliquots in five sterile cryovials and frozen at –80oC.  The samples will remain 
cryopreserved until later shipment to the laboratory of Dr. Kenneth Cooke (see below).   
 
 
II. Processing of serum samples (at Local Institutions):  
Five to ten mL of peripheral blood should be obtained in green top tubes on Day 0, 7, and 28 of 
study.  The initial plasma sample should be obtained prior to the first dose of study drug on Day 
0 of study.  Samples should be separated within 30 minutes of sample acquisition.  Samples 
should be centrifuged a 400x g for 10 minutes, the supernatant separated from the cell pellet, 
aliquoted into two sterile cryovials, and frozen at –80oC.  The samples will remain cryopreserved 
until later shipment to the laboratory of Dr. Kenneth Cooke. 
 
 


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III. Sample shipping:  
The BAL and plasma samples should be kept frozen until Day 28, then batched and collectively 
shipped with all samples for a patient overnight on dry ice. 
 
 
IV Cytokine analysis:  
BAL fluid and plasma will be analyzed in the laboratory of Dr. Kenneth Cooke for the following 
cytokines using commercially available ELISA kits that have no cross-reactivity with other 
related cytokines/chemokines.  
 
Pro-inflammatory proteins to be analyzed: 
TNF, TNFR I and II, LPS, LBP and CD14, and IFNγ.  
 
Pro-fibrotic panel of proteins to be analyzed: 
IL-1ra, TGFβ, IL-6, IL-8, and MCP-1. 
 
Additionally, plasma samples will be analyzed by mass spectroscopy for proteomics analysis. 
 
 
C-2 
CYTOKINE GENE POLYMORPHISM 
 
To assess recipient cytokine genes, if available, pre-transplant recipient blood collected in an 
ACD-A anticoagulant-containing tube or an EDTA tube for DNA will be used.  In addition, a 
buccal swab will be collected for recipient DNA. 
 
The buccal swab should be allowed to dry at room temperature.  Remove the tip of the swab and 
store in a 1.8 mL cryovial. Freeze cryovial at -80° C.  
 
The pre-transplant blood and buccal swab samples should be kept frozen until Day 28, then 
batched and collectively shipped with all samples for a patient overnight on dry ice. 
 
 


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TABLE C.2  LABORATORY SCHEDULE 
 
TEST 
TYPE OF 
SAMPLE 
(Collection Container) 
TYPE OF STORAGE 
DATES SAMPLES 
OBTAINED 
SHIPPING 
SPECIFICATIONS 
LOCATION OF 
TEST PERFORMED 
Cytokine and 
Inflammatory 
Markers – BAL 
5-10 mL BAL fluid (sterile 
container). 
Keep on ice (or refrigerate at 4 o 
C) until processing.  Centrifuge at 
400 x g for 5 minutes.  Aliquot 
supernatant into 1-2 mL aliquots 
into five sterile cryovials and 
freeze at -80o C. 
Prior to randomization. 
Batch ship on dry ice with all 
samples for one patient. 
Dr. Kenneth Cooke’s 
Laboratory. 
Cytokine and 
Inflammatory 
Markers – Plasma 
5-10 mL peripheral blood 
(green top tube). 
Centrifuge at 400 x g for 10 
minutes.  Aliquot the plasma into 
five sterile cryovials and freeze at 
-80o C. 
Day 0 (prior to first dose of study 
drug), Day 7, Day 28. 
Batch ship on dry ice with all 
samples for one patient. 
Dr. Kenneth Cooke’s 
Laboratory. 
Cytokine Gene 
Polymorphism – 
Buccal Swab 
Buccal Swab allowed to dry 
at room temperature and 
transferred into a 1.8 mL 
cryovial. 
Frozen at -80C 
Day 0. 
Batch ship on dry ice with all 
samples for one patient. 
Dr. Kenneth Cooke’s 
Laboratory. 
Cytokine Gene 
Polymorphism – Pre 
Transplant Blood 
Sample (If Available) 
3 mL pre-transplant 
peripheral blood (preferable 
collected in ACD-A or 
anticoagulant yellow top 
tube or EDTA purple top 
tube) aliquoted into two 1.8 
mL cryovials. 
Frozen at -80C 
Pre-transplant (if available). 
Batch ship on dry ice with all 
samples for one patient. 
Dr. Kenneth Cooke’s 
Laboratory. 
 
Attn: David Zhou 
Case Western Reserve University School of Medicine 
Wolstein Research Building 
6th Floor, Room 6524 
2103 Cornell Road 
Cleveland, OH 44106-7288 
Phone: 216-368-4644 
Email: Lxz37@cwru.edu 


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APPENDIX D 
 
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