A Randomized Placebo Controlled Trial of Inhaled Beclomethasone After Community-acquired Respiratory Viral Infection in Lung Transplant Recipients
Phase: PHASE1
Conditions: Lung Transplant Infection
Sponsor: Washington University School of Medicine

Protocol: 
 
A randomized placebo controlled trial of inhaled beclomethasone after community-acquired 
respiratory viral infection in lung transplant recipients 
 
Version: 5 
Date:  5.28.15 
 
1. Abstract 
The randomized placebo controlled trial of inhaled beclomethasone after community-acquired respiratory viral 
(CARV) infection in lung transplant recipients is a single center pilot study evaluating the impact of inhaled 
beclomethasone on the development and progression of chronic lung allograft dysfunction (CLAD) or death after 
CARV infection.  The study will randomize 40 subjects to inhaled beclomethasone or placebo in a 1:1 ratio, and 
follow-up will be complete 12 months after randomization.  The primary objective of the study is to determine if 
inhaled beclomethasone has greater efficacy than placebo for the endpoint of CLAD development or progression 
or death after randomization.  The study will also assess multiple secondary endpoints including the safety and 
tolerability of inhaled beclomethasone in lung transplant recipients, respiratory viral symptom scores, the 
development of donor-specific human leukocyte antigen antibodies and antibodies to lung-specific self-antigens, 
and survival. 
 
2. Background 
Lung transplantation is the ultimate treatment for patients with advanced lung disease.  However, long-term 
outcomes remain disappointing, and the median survival after transplantation is approximately 5.5 years.  While 
infection and graft failure are the leading causes of death in the first year after transplantation, chronic rejection is 
the leading cause of death beyond the first year.  Chronic rejection after lung transplantation is characterized 
histologically as obliterative bronchiolitis, although histologic confirmation is difficult.  Therefore, chronic lung 
allograft syndrome (CLAD) and bronchiolitis obliterans syndrome (BOS), defined and staged based on changes in 
spirometry measurements, are the clinical surrogates of chronic rejection after lung transplantation.  The 
incidence of CLAD approaches 50% at 3 years after transplantation, and there is no effective evidence-based 
treatment.  Unfortunately, this results in a progressive and relentless decline in lung function culminating in graft 
failure and death.  Indeed, the median survival after the diagnosis of CLAD is 3 years, and studies have consistently 
demonstrated a significantly reduced quality of life in patients with CLAD.  Clearly, CLAD is the leading obstacle to 
better outcomes after lung transplantation, and lung allograft recipients urgently need strategies to prevent or 
delay the onset of CLAD.      
The pathophysiology of CLAD has not been elucidated, but clinical risk factors have been identified and these 
provide insights into the underlying immunobiology.  Studies have consistently identified episodes of acute 
rejection, lymphocytic bronchiolitis, primary graft dysfunction, donor-specific HLA antibodies (DSA), 
gastroesophageal reflux disease, and community-acquired respiratory viral (CARV) infections as independent risk 
factors for the development of CLAD.  The exact mechanisms whereby CARV infection increases the risk of CLAD 
are unclear, but this association has been identified in both upper and lower respiratory tract infections.  We have 
proposed that viral infection results in airway epithelial cell injury and the expression of injury-response genes that 
provide signals that initiate immunologic and non-immunologic pathways that result in the airway remodeling 
characteristic of obliterative bronchiolitis.  In addition, CARV infection may increase the expression of HLA 
molecules in the allograft and expose cryptic self-antigens while creating the necessary inflammatory milieu for 
CLAD development and progression. 
Systemic and inhaled corticosteroids are frequently used as anti-inflammatory agents to treat the peribronchiolar 
inflammation seen in viral bronchiolitis.  Beneficial effects from corticosteroids have been reported, but this has 
not been demonstrated in lung transplant recipients.  
 

The aim of this single center, randomized, double blind, placebo controlled study is to evaluate the short and long 
term effects of a 6 month course of inhaled beclomethasone on adult lung transplant recipients with CARV 
infection. 
3. Transplant Center Experience  
The study center (Barnes-Jewish Hospital / Washington University) has performed lung transplants (LTx) in over 
1300 recipients since 1988.  This center has long-term experience in evaluating and selecting candidates, 
performing transplantation, and providing high-quality follow-up.  Post-transplant survival outcomes at this center 
are higher than the national average. 
 
4. Study Protocol 
 
4.1. Primary Aim 
To conduct a single center, pilot, randomized placebo controlled trial that compares the efficacy and safety of 
inhaled beclomethasone versus placebo to prevent the development or progression of CLAD, or death after CARV 
infection in lung transplant recipients. 
 
4.2. Hypotheses 
Null Hypothesis 
There is no difference in incidence of new or progressive CLAD, or death between the 
two randomized treatment groups (placebo = inhaled beclomethasone) 
 
Alternative  
There is a statistically significant difference in the incidence of new or progressive CLAD, 
or death between the two randomized treatment groups (placebo ≠ inhaled 
beclomethasone) 
 
4.3. Study Objectives 
Primary Objective  
• 
To determine if inhaled beclomethasone has greater efficacy than placebo in preventing the composite 
endpoint of new or progressive CLAD or death 6 months after CARV infection in adult lung transplant 
recipients. 
Secondary Objectives 
• 
Incidence of new or progressive CLAD at 6 and 12 months  after CARV infection 
• 
Time to development or progression of CLAD 
• 
Safety and tolerability of inhaled beclomethasone 
• 
Respiratory viral symptoms 
• 
Development of donor-specific HLA antibodies (DSA) 
• 
Change in DSA mean fluorescence intensity 
• 
Development of antibodies to lung-specific self-antigens (Collagen V and K-α 1 tubulin) 
• 
Serum cytokine profiles 
• 
Peripheral immune cell phenotypes 
• 
Incidence of other bacterial, viral, or fungal infection at the time of CARV infection 
• 
Incidence of acute rejection and lymphocytic bronchiolitis within 6 months following CARV infection 
• 
Survival at 6 months (+ 10 days) and 12 months (+ 10 days) after CARV infection 
 
4.4. Design 
Single center, double blind, placebo controlled randomized trial 
 
4.5. Setting 
This single center trial will enroll 40 patients from Washington University School of Medicine and Barnes-Jewish 
Hospital academic lung transplant center.  Screening, participant consent, treatment, and data collection will be 
conducted at this transplant center. 
 

4.6. Study Population and Eligibility Criteria 
The study staff will prescreen/screen all lung transplant (LTx) recipients at the institution who develop respiratory 
symptoms suggestive of a CARV infection.  The study will only enroll a patient if he/she can come to the medical 
center to receive study drug.  In general, the study staff will consent patients who have undergone lung 
transplantation, and randomize study participants (consented patients) that develop post-transplantation CARV 
infection.  Table 1 outlines specific study eligibility criteria for enrollment and randomization.  A screening log will 
document limited information regarding patients that undergo screening but not enrollment.  Case report form 
(CRF)/computer data entry system will capture reason(s) for exclusion. 
 
Table 1. Eligibility criteria for enrollment in the study 
Inclusion Criteria: 
• 
Adult  (≥ 18 years old) 
• 
Single, bilateral, or heart-lung transplant recipient 
• 
Confirmed infection with a community-acquired respiratory virus  
o 
Including: adenovirus, coronavirus, influenza A or B, respiratory syncytial virus (RSV), 
parainfluenza virus (PiV), human metapneumovirus (hMPV), and rhinovirus/enterovirus 
• 
At least 6 months post-transplant, with completion of 6 month surveillance bronchoscopy if indicated 
• 
Able and willing to give written informed consent and comply with study procedures (e.g. testing, 
treatment)  
• 
Able to undergo randomization and initiate study drug within 10 days of CARV infection 
Exclusion Criteria: 
• 
BOS Stage 3 [pre-CARV baseline FEV1 < 50% of personal reference] 
o 
Pre-CARV baseline: the average of the 2 most recent FEV1 separated by at least 3 weeks and also 
occurring within the 6 months prior to the CARV infection  
§ 
In the event that only a single FEV1 is available within the previous 6 months, that value 
will function as the pre-CARV baseline 
o 
Personal reference: the average of the 2 highest post-transplant FEV1 at least 3 weeks apart 
• 
Requirement for mechanical ventilation at study entry  
• 
Use of inhaled steroids at the time of CARV infection 
• 
Any condition that in the investigator’s opinion would preclude the patient’s participation in a clinical trial  
• 
Lack of available spirometric data within 6 months preceding CARV infection to establish a baseline FEV1 
and/or FVC  
• 
Pregnancy 
• 
Current participation in another interventional clinical trial  
 
4.7. Sampling Design 
The study staff will assess all LTx recipients with a CARV infection for enrollment. 
 
4.8. Randomization 
Eligible patients who develop a CARV infection after lung transplantation will need to provide written informed 
consent prior to study participation and will undergo randomization using a computer-generated method with a 
1:1 ratio, and stratified by BOS stage (group 1: BOS stages 0 and 0p vs. group 2: BOS stages 1 and 2) to one of the 
treatment assignments: (1) inhaled beclomethasone, or (2) placebo. The site will aim to randomize patients within 
7 days of identification of CARV infection. 
  
 
4.9. Endpoints 
4.9.1. Composite Primary Endpoint 
Freedom from new or progressive CLAD, or death 180 days after CARV infection.  
 
4.9.2. Secondary Endpoints 
Incidence of new and/or progressive CLAD, safety and tolerability of inhaled beclomethasone, respiratory virus 
symptom score, development of DSA, change in DSA mean fluorescence intensity, development of antibodies to 

self-antigens, serum cytokine profiles, peripheral immune cell phenotypes, incidence of other bacterial, viral, or 
fungal pulmonary infections at the time of CARV infection, incidence of acute rejection and lymphocytic 
bronchiolitis within  6 months  (+ 10) days after CARV infection, incidence of new or progressive CLAD within 12 
months (+ 10) after CARV infection, and survival 6 months (+ 10 days) and 12 months(+ 10 days) after CARV 
infection.   
 
4.10. Outcomes Assessment 
The development of CLAD is defined according to the following criteria: 
• 
CLAD:  FEV1 and/or FVC ≤ 80% baseline on 2 measurements obtained 3 weeks apart 
 
Once CLAD has been established, it will be further defined by the following criteria: 
• 
Restrictive CLAD (RAS):  FVC ≤ 80% baseline on 2 measurements obtained 3 weeks apart with an FEV1/FVC 
ratio ≥ 75% 
• 
Obstructive CLAD (BOS): FEV1 ≤ 80% baseline on 2 measurements obtained 3 weeks apart 
 
Progressive CLAD is defined as a ≥ 15% decrement in pre-CARV infection baseline FEV1 or FVC.  The pre-CARV 
infection baseline FEV1 and FVC are defined as the average of the 2 most recent FEV1 or FVC measurements 
separated by at least 3 weeks, and occurring within the 6 months prior to the diagnosis of the CARV infection.  In 
the event that only 1 FEV1 or FVC measurement is available in the previous 6 months, that value with serve as the 
pre-CARV infection baseline FEV1 or FVC.  
 
5. Treatments 
5.1. Randomized Treatment Assignment 
Randomization will occur using an automated online system that will reveal assignment group only after 
investigator/study staff have confirmed eligibility. The system will automatically send the participant study ID 
number and randomized treatment group assignment to the study pharmacist. 
 
5.2. Active or Placebo Study Drug Doses and Schedule 
The study protocol plans for randomized participants to receive 6 months of active drug OR 6 months of placebo. 
 
5.2.1. Active Study Drug 
Inhaled beclomethasone (QVAR®, Teva Pharmaceuticals) 320mcg twice daily for 180 days. The first dose will be 
administered 7 ± 3 days after CARV infection.  
 
5.2.2. Placebo Study Drug 
The first dose of placebo for inhaled beclomethasone (provided by Teva Pharmaceuticals) will be administered 7 ± 
3 days after CARV infection.  
 
5.2.3. Packaging and Labeling of Study Drug 
All packaging and labeling will be completed by the investigational drugs pharmacy. The pharmacist(s) will prepare 
the study drug (active therapy or placebo) for administration to randomized participants based on treatment 
assignment. The study pharmacist(s) will label each drug kit with the participant’s study identifier information, 
study information, appropriate drug/placebo information, and administration instructions.  
 
5.2.4. Handling and Dispensing 
Handling and dispensing of drug will occur by the study pharmacist(s) in the investigational drugs pharmacy. The 
study pharmacist(s) will store the study drugs in a secure area, and they will follow local and FDA regulations. The 
study pharmacist(s) will ensure that the study drugs are stored in the appropriate environmental conditions.  Only 
authorized personnel will dispense study drug, and they will follow local and FDA regulations.   
 
5.2.5. Blinding 

The study pharmacist(s) practicing in the Investigation Drugs Service will remain aware of treatment 
allocation/assignment.  Lung transplant clinical pharmacists, non-pharmacist study staff, the participants, and 
those involved in clinical care or study testing will remain blinded to treatment assignment (double-dummy 
design).  
 
5.3. Immunosuppression 
Patients’ induction and maintenance immunosuppression will be prescribed and managed according to our 
transplant program’s standard clinical practice.  Likewise, we will treat and manage acute rejection, lymphocytic 
bronchiolitis, and BOS according to our standard clinical practice. 
 
5.4. Treatment of CARV Infection 
The decision to institute antiviral therapy specific for CARV infection and the choice of agent will be based on our 
program’s standard clinical practice.  Influenza is generally treated with oseltamivir.  Respiratory syncytial virus 
(RSV) and parainfluenza virus (PIV) are generally treated with aerosolized ribavirin according to our standard 
clinical practice.  Human metapneumovirus (hMPV) is sometimes treated with aerosolized ribavirin and 
intravenous immunoglobulin depending on the severity of the associated illness.  The study will not influence the 
decision to treat with specific antiviral therapy nor the choice of agents. 
 
In addition, all patients with a decline in pre-CARV baseline FEV1 of ≥ 10% will receive oral prednisone (1 mg/kg) 
orally daily (maximum of 60mg), initiated per standard protocol at the time of CARV infection. This dose will be 
rapidly tapered over two weeks back to the patient’s pre-CARV maintenance prednisone dose.  
 
At study entry, for the purposes of baseline CARV infection characterization, patients will receive a diagnosis of 
either upper or lower respiratory tract infection. Lower respiratory tract infection will be defined according to the 
ISHLT criteria as follows: 
• 
≥ 2 clinical symptoms (fever > 38 ° C, rhinorrhea, nasal congestion, sore throat, sneezing, chills/rigors, 
myalgia, headache) PLUS one or more of the following symptoms of lower respiratory tract involvement: 
o 
Cough 
o 
Dyspnea 
o 
Physical findings (one or more of the following): 
§ 
Hypoxia (new onset or increasing) 
§ 
New or increased O2 requirement 
§ 
New crackles, rales, wheezing 
o 
Acute respiratory distress syndrome 
o 
Decline in pre-CARV baseline FEV1 by ≥ 10% 
o 
Viral pathogen detected from bronchoalveolar lavage specimen 
 
6. Testing 
 
6.1. Patient Symptom Score Card 
Subjects will be asked to complete symptom score cards (Appendix 1) daily for 7 days following enrollment.  
 
6.2. Spirometry 
Subjects will have spirometry testing at the time of CARV infection and on months 1, 3, 6 and 12 (all +/- 10 days) 
following CARV infection.  In addition, spirometry will be performed every 1-2 months (+/- 10 days) until month 12.  
Participants will also undergo spirometry testing when clinically indicated (new respiratory symptoms, pulmonary 
infiltrates, etc).  Certified and trained technicians will conduct spirometry measurements according to American 
Thoracic Society (ATS) guidelines. 
 
6.3. Bronchoscopy 
Bronchoscopy will only be performed if clinically indicated.  Surveillance bronchoscopy to evaluate for occult acute 
rejection is performed at 1, 2, 3, 6, and 12 months after transplantation based on our clinical practice.  In addition, 
bronchoscopy is performed to evaluate respiratory symptoms or clinical signs of allograft dysfunction (e.g., 

hypoxemia, pulmonary infiltrates, clinically significant decrements in spirometry).  Bronchoscopy will not be 
performed for study reasons only.   
 
6.4. HLA Antibody Testing 
Participants will be tested for the development of donor-specific HLA antibodies (DSA) at enrollment, and at 
months 1, 3 and 6 (± 10 days for each time point) after CARV infection using the clinical assay in our center’s 
histocompatibility laboratory.  This will require a blood draw at those time points. 
 
6.5. Testing for Antibodies to Self-antigens and Inflammatory Cytokines 
At the same time points that testing is conducted for DSA (enrollment and months 1, 3 and 6[+/- 10 days for each 
time point]), participants will be tested for the development of antibodies to collagen V and K-α 1 tubulin.  In 
addition, participants’ serum will be tested for a battery of pro-inflammatory and anti-inflammatory cytokines.  
This will be conducted in Dr. Mohanakumar’s research laboratory.  
 
7. Statistical Considerations 
We estimate an incidence of new or progressive CLAD of 50% at 6 months after CARV infection in the placebo 
group and an absolute risk reduction of 25% in the inhaled beclomethasone group.  Therefore, a sample size of 40 
subjects would provide 80% power.  The primary endpoint of the development or progression of CLAD or death at 
6 months will be evaluated as a binary endpoint and will be analyzed using the chi-squared method.  In addition, 
the primary endpoint will be evaluated as a time to event analysis using the Kaplan-Meier method and the two 
groups will be compared using the log rank test.  Secondary endpoints consisting of continuous data will be 
analyzed using either the Student’s t- test or Mann-Whitney U Test and those consisting of categorical data will be 
analyzed using the chi-squared method. 
 
8. Ethical Considerations and Safety 
8.1. Good Clinical Practice 
Study personnel will have the appropriate qualifications related to education, training, and experience to perform 
study-related tasks. The study personnel will conduct the study in accordance with Good Clinical Practice (GCP), 
institutional review board (IRB), local and institutional guidelines.  
 
8.2. Institutional Review Board 
Prior to study initiation, the study investigator(s) will have written approval from the IRB for the protocol, consent 
form, and standardized written information that the study staff will provide to patients.  
 
8.3. Informed Consent 
Patients will be informed about the study and its purpose when a diagnostic nasopharyngeal swab for CARV is 
obtained.  Eligible patients who have a positive swab result or a positive bronchoscopy specimen PCR for CARV will 
be approached by the study investigators. The consent process will involve a dialogue between the potential 
participant and the study staff.  Study participation will require written informed consent from the patient.  The 
study staff will not conduct study procedures prior to obtaining informed consent.  Patients eligible for 
randomization will be informed that they may withdraw their consent and drop out of the study at any time point.   
 
 

8.4. Adverse Events 
 
8.4.1. Serious Adverse Event Definition 
The protocol defines a serious adverse event (SAE) as any untoward medical occurrence that  
• 
Results in death 
• 
Threatens life (defined as an event in which the subject was at risk of death at the time of the event) 
• 
Requires inpatient hospitalization or causes prolongation of an existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Results in the development of drug dependency or drug abuse 
• 
Is a serious adverse event drug experience 
 
All SAEs will be reviewed by the investigator to determine relationship to the study drug (definitely, likely or 
possibly related to the study product).  
 
8.4.2. Site Adverse Event Collection 
The study investigator and staff will monitor and evaluate for study participant SAEs. They will collect and record 
SAE information on the CRFs. 
 
8.4.3. Adverse Event Monitoring and Reporting 
Investigators and study staff will follow Federal and local regulations regarding SAE reporting.  After 
randomization, the study staff at each site must report SAEs considered definitely, likely or possibly related to the 
study medication (as assessed by the study investigator).  A study team member will complete an SAE report for all 
SAE events. 
 
8.4.4. Treatment of Adverse Events 
The study staff will handle any AE(s) according to clinical practice.  The study personnel will implement treatment 
procedures and therapy in the best interest of the patient. 
 
8.4.5. Discontinuation of Participants from Treatment 
Study participants MUST discontinue study drug for any of the following reasons: 
• 
Withdrawal of informed consent 
• 
Any condition in which, in the opinion of the investigator, indicates that continued study drug treatment 
is not in the best interest of the patient. 
• 
Termination of the study. 
• 
Ineligibility for continued study drug treatment (Table 1) 
 
Participants who discontinue study drug treatment should still comply with the protocol and undergo the study 
follow-up procedures, except for those who withdraw informed consent or become unable to freely participate in 
the ongoing informed consent process.  CRF/computer data entry system will capture reason(s) for discontinuation 
and withdrawal. 
 
9. Study Organization and Administration 
9.1. Compliance 

Study investigators should conduct the study as described in the protocol.  Investigators should not implement 
deviations or change the protocol except when deemed necessary to eliminate an immediate hazard to a study 
participant.  The investigator must document any significant deviation in the CRF and report the deviation to the 
IRB. 
 
9.2. Record Keeping and Retention 
The investigators must retain copies CRF and source documents for the period required by applicable regulations 
and guidelines, and institution procedures, whichever is longer. 
 
9.3. Case Report Forms 
Investigators and study staff should maintain adequate and accurate records. They should demonstrate 
consistency of data derived from source documents and CRF data, and they should explain inconsistencies.  
 
9.4. Study Drug Records 
The primary investigator at each site has the responsibility to ensure that study personnel (e.g., investigational 
pharmacist) maintain records of study drug disposition.  Records or logs must comply with the applicable 
regulations and guidelines, and should include: 
• 
Amount received 
• 
Amount stored 
• 
Label identification number or batch number 
• 
Expiration date 
• 
Dates and initials of person responsible for each investigational product inventory entry/movement 
• 
Amount dispensed to and returned by each subject 
• 
Non-study disposition (e.g., lost, wasted, broken) 
• 
Amount returned to manufacturer 
• 
Amount destroyed at study site 
 
9.5. Return and Destruction of Study Drug 
Upon completion or termination of the study, all unused and/or partially used study drug must be returned to the 
manufacturer or, if authorized, destroy it at the site.  Returned study drug must have appropriate documentation 
regarding the study protocol identifier(s) and the study site. 
 
 
 
 
 
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• 
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• 
Billings JL, Hertz MI, Savik K, et al. Respiratory Viruses and Chronic Rejection in Lung Transplant 
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Gottlieb J, Schulz TF, Welte T, et al. Community-Acquired Respiratory Viral Infections in Lung Transplant 
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Khalifah AP, Hachem RR, Chakinala MM, et al. Respiratory Viral Infections Are a Distinct Risk for 
Bronchiolitis Obliterans Syndrome and Death. Am J Respir Crit Care Med 2004;170:181-187. 
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Kumar D, Erdman D, Keshavjee S, et al. Clinical Impact of Community-Acquired Respiratory Viruses on 
Bronchiolitis Obliterans After Lung Transplant. Am J Transplant 2005;5:2031-2036. 
• 
Magnusson J, Westin J, Andersson L, et al. The Impact of Viral Respiratory Tract Infections on Long-Term 
Morbidity and Mortality Following Lung Transplantation: A Retrospective Cohort Study Using a Multiplex 
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