Doxycycline for COPD in HIV-Infected Patients
Phase: NA
Conditions: HIV, Chronic Obstructive Pulmonary Disease (COPD), Emphysema
Sponsor: Weill Medical College of Cornell University

Weill Cornell Medicine 
Doxycycline for COPD in HIV-Infected Patients 
              
Clinical Protocol   
 
Amendment 12, v.05.15.18 
 
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CLINICAL STUDY PROTOCOL 
 
 
Doxycycline for COPD in HIV-Infected Patients 
 
IRB Protocol #1208012780 
 
Amendment Version 12: 15 MAY 2018 
 
 
Clinicaltrials.gov ID: NCT01744093 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Weill Cornell Medicine 
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Clinical Protocol   
 
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1. 
TITLE PAGE 
 
Study Title:  
Doxycycline for COPD in HIV-Infected Patients 
 
Investigational Product:  
Doxycycline 
 
Indication Studied:   
Chronic Obstructive Pulmonary Disease in HIV-Infected Patients 
 
Sponsor:  
 
 
National Institutes of Health 
 
Development Phase:  
Pilot Study 
 
Principal Investigator:  
Robert J. Kaner, MD 
 
Compliance Statement: 
The study will be conducted in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki and 
clinical research guidelines established by the Code of Federal 
Regulations (Title 21, CFR Parts 50, 56, and 312) and ICH 
guidelines. Essential study documents are currently archived in 
accordance with applicable regulations.   
 
Amendment Dates: 
Original Submission - Amendment 0, v.08.06.12 
 
Amendment 1, v.07.31.13 
 
Amendment 2, v.07.22.14 
 
Amendment 3, v.10.07.14 
 
Amendment 4, v.11.20.14 
 
Amendment 5, v.01.29.15 
 
Amendment 6, v.06.27.15 
 
Amendment 7, v.09.16.15 
 
Amendment 8, v.12.04.15 
 
Amendment 9, v.01.28.16 
 
Amendment 10, v.05.27.16 
 
Amendment 11, v.05.12.17 
 
Amendment 12, v.05.15.18 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2. TABLE OF CONTENTS AND LIST OF TABLES 
 
1. 
TITLE PAGE 
2. 
TABLE OF CONTENTS 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
4.  
SYNOPSIS 
5. 
INTRODUCTION 
5.1 Background 
5.2  Rationale for study 
6.  
TRIAL OBJECTIVES AND PURPOSE 
7.  
INVESTIGATIONAL PLAN 
7.1 Endpoints 
7.2 Overall study design and plan: Schedule of assessments 
8.  
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1 Sample population 
8.2 Inclusion criteria 
8.3 Exclusion criteria 
8.4 Withdrawal criteria 
9. 
STUDY CONDUCT 
9.1 Study overview 
9.2 Schedule of assessments 
10.  SCREENING/BASELINE ASSESSMENTS 
11. ASSESSMENT OF EFFICACY 
12. ASSESSMENT OF SAFETY 
12.1 Adverse events 
13. 
STUDY ADMINISTRATION 
13.1 Regulatory and ethical considerations 
13.2 Study monitoring 
13.3 Quality assurance 
13.4 Study termination and site closure 
13.5 Records retention 
13.6 Data safety monitoring committee 
13.7 Confidentiality of information 
13.8 Study publication 
 
 
 
 
 
 
 
 

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3. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Placebo 
An inert or innocuous substance used especially in controlled experiments 
testing the efficacy of another substance (as a drug) 
Doxycycline   
Name of the study “drug” in this protocol. Consists of an adenovirus vector 
expressing the human vascular endothelial growth factor gene. 
AE 
Adverse event 
FEV1 
Forced expiratory volume over 1 second 
FVC 
Forced vital capacity 
HRCT 
High-resolution computed tomography 
PFT 
Pulmonary function test 
COPD 
Chronic Obstructive Pulmonary Disease 
HIV 
 
Human immunodeficiency virus 
MMP 
Matrix metalloproteinases 
DLCO 
Carbon monoxide diffusing lung capacity 
CD4 count 
T-cell count 
TLC 
Total lung capacity 
EKG 
Electrocardiogram 
SGRQ 
St. George’s Respiratory Questionanire 
CAT 
COPD assessment test 
Bronchoscopy 
Procedure to examine the airways of the lungs 
BAL 
Bronchoalveolar lavage 
BALF 
Bronchoalveolar lavage fluid 
ELF 
Epithelial lining fluid 
DGM 
Department of Genetic Medicine 
WCMC  
Weill Cornell Medical College 
 
4. SYNOPSIS 
 
Name of Sponsor/Company: National Institutes of Health (NIH) 
 
Name of Investigational Product: Doxycycline 
 
Title of Study: “Doxycycline for COPD in HIV-Infected Patients” 
 
Study Center(s): Weill Cornell Medicine-New York (WCMC-NY)/NewYork-Presbyterian 
Hospital, New York, NY 
 
Principal Investigators:  
Robert J. Kaner, MD 
Weill Cornell Medical College-New York WCMC-NY/New 
York Presbyterian Hospital, New York, NY 
 
Marshall J. Glesby, MD, PhD 
Weill Cornell Medical College-New York WCMC-NY/New 
York Presbyterian Hospital, New York, NY 

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Investigators: Ronald G. Crystal, MD; Thomas Walsh, MD; Sarah O’Beirne, MD, PhD; Odelya 
Pagovich, MD; Grace Mammen, BA, CCRP; Denesy Mancenido, BA, CCRP; Jamico Jacinto, 
BS; Sandra Hyde 
 
Study Period (years):  
Active study: 2 years 
Subject Participation: 24 weeks 
 
Objectives:  
Primary: To determine the safety, tolerability, and biologic effects of twice daily doxycycline 
for 6 months in HIV-infected subjects with COPD and/or emphysema. 
 
Secondary: To characterize changes in FEV1, FVC, FEV1/FVC, DLCO over time; To 
characterizes change in respiratory symptoms over time (using the CAT COPD assessment test); 
To characterize change in BAL absolute cell number (AM, PMN, lymph); To characterize 
change in AM gene expression of MMPs and cytokines; To characterize change in BAL fluid 
MMP enzyme activity and cytokine levels; To characterize change in serum inflammatory 
markers (hsCRP, sIL-6, TNF-alpha, IL-1beta, procalcitonin); To determine doxycycline drug 
concentrations in serum, AM and ELF; To characterize change in quantitative bacterial burden in 
BAL fluid; To characterize frequency of doxycycline-resistant bacteria To describe adherence to 
study therapy by self-report and pill counts; To determine the incidence of non-elective 
hospitalization, classified as respiratory or non-respiratory; To determine the incidence of acute 
exacerbation of COPD (using the GOLD definition of change in symptoms requiring medication 
[we will use systemic steroids and/or antibiotics as the indicators]) To evaluate the role of 
biological mechanisms, such as oxidant stress, apoptosis, VEGF deficiency, etc., in relative gene 
expression of human alveolar macrophages and airway epithelial cells. 
 
Study Design: 
HIV-infected patients are at increased risk of COPD and emphysema may be accelerated in this 
population. While the pathogenesis of COPD in HIV-infected patients is almost certainly 
multifactorial, our preliminary data suggest that upregulation of MMPs may play a role in 
accelerating lung damage. Our overarching hypotheses are: (1) long-term doxycycline therapy 
will be safe and well tolerated; and (2) doxycycline will inhibit the activity of alveolar 
macrophage and epithelial lining fluid MMP. To determine this, we propose to conduct a 
randomized, double-blind, placebo-controlled pilot study of doxycycline 100 mg twice daily (2:1 
doxycycline:placebo randomization) in 30 HIV-infected subjects with COPD and/or emphysema. 
We propose initially to conduct a pilot study as proof of concept of the biological effects of 
doxycycline, and to generate preliminary data that will facilitate the design of a larger Phase II 
clinical trial. For this study, the primary endpoint will be safety/tolerability, and secondary 
endpoints will include change in pulmonary function (FEV1) by spirometry, inhibition of MMP 
activity in a pan-MMP activity assay as well as individual MMPs assessed by gelatinase assays 
and doxycycline levels in serum, epithelial lining fluid and bronchoalveolar lavage cell pellets 
(consisting of alveolar macrophages, lymphocytes and some neutrophils).  
 
Doxycycline (or matching placebo) will be given at a dose of 100 mg po twice daily for six 
months. This is a standard FDA-approved antibacterial dose for which there is abundant safety 

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data. While there are FDA-approved doses of doxycycline that are lower (e.g., 20-40 mg po daily 
for gingivitis or rosacea), we have selected a higher dose in this proof of concept trial in order to 
reduce the likelihood that we falsely conclude that the drug does not have the intended biological 
effects due to inadequate drug levels in the lungs. Pharmacokinetic data from subjects with cystic 
fibrosis support a 200 mg po daily dose of doxycycline to achieve appropriate lung levels.  
 
Eligible subjects will have controlled HIV infection and a diagnosis of mild to moderate COPD 
and/or based on established criteria. Subjects will be randomized by the research pharmacist in a 
2:1 fashion using permuted blocks of size 3 to receive doxycycline or placebo for 6 months and 
will undergo serial measures of lung function by spirometry as well as bronchoscopies at 
baseline and week 12 to collect specimens for translational studies aimed at characterizing the 
biological effects of the intervention. The bronchoscopy will be performed mainly as an 
outpatient procedure. The investigator may stop the procedure at any time if he/she feels that 
sufficient samples have been collected and/or it is not safe to continue the procedure. Subjects 
are expected to have an escort on the day of the bronchoscopy in order to undergo the 
bronchoscopy procedure. If the escort does not arrive or if no responsible adult is available to 
escort the subject home once the bronchoscopy procedure is complete, the subject will undergo 
observation by research staff until deemed stable. Follow-up calls will be performed one day (+/-
3 days) and one week (+/-3 days) post-bronchoscopy. The randomization will be stratified on 
current versus former smoking status.  The study is double-blinded, and only the research 
pharmacist will have knowledge of the treatment assignments, which is needed to dispense the 
study drug. Despite the pilot nature of this study, we have opted to conduct a randomized, 
placebo-controlled trial primarily to ensure that there is a control group to be able to interpret 
changes in biologic and physiologic endpoints that may vary based on the natural variation in the 
course of COPD and/or variability in the assays/assessments. We will randomize 2:1 in favor of 
active study drug to enable us to have a sufficient number of recipients of active drug within the 
constraints of a small study.  
 
Number of subjects (planned): 30 subjects will be enrolled and will be randomized in a 2:1 
fashion. Subjects for this study will be recruited from the referral base of the investigators from 
the population of individuals with COPD and documented HIV as defined by the protocol 
inclusion/exclusion criteria (see below). 
 
Diagnosis and main criteria for inclusion: 
Inclusion Criteria: 
1. Males/Females ages 18-85 years 
2. Documented HIV infection  
3. CD4 cell count greater than 200 cells/mm3  
4. HIV RNA less than 400 copies/ml  
5. Stable antiretroviral therapy for greater than or equal to 12 weeks  
6. Fulfills GOLD definition for COPD (post-bronchodilator FEV1/FVC less than 0.7) and/or 
has radiographic evidence of emphysema  
7. Current or history of smoking with minimum 3 pack-year history  
8. ALT and AST less than 3 x upper limit of normal  
9. For women of childbearing potential: willingness to use 2 forms of birth control 
10. Subjects on therapy for COPD must be on stable therapy for at least 4 weeks 

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Exclusion Criteria: 
1. Pulmonary infection, COPD exacerbation, or acute opportunistic infection within 30 days of 
entry 
2. Conditions associated with increased sedation of bronchoscopy risk, including but not limited 
to Gold class 3 or 4 COPD, requirement for home oxygen, hypercapneic respiratory failure, 
poorly control hypertension  
3. Known allergy/intolerance to doxycycline, atropine, or any local anesthetic  
4. Inability to provide informed consent 
5. Pregnant or lactating women  
6. Men must agree not to attempt to make a woman pregnant of participate in sperm donation 
during the study and for 6 weeks after discontinuing the drug  
7. End stage renal disease  
8. Cirrhosis  
9. INR greater than 1.4  
10. Platelets less than 80,000  
11. Any condition including active drug or alcohol use or dependence that, in the opinion of the 
site investigator, would interfere with adherence to study requirements or increase the risk of 
bronchoscopy 
12. Active or planned participation in any other clinical trial or observational study without prior 
approval from the PI 
 
Endpoints: The primary endpoint will be safety/tolerability, and secondary endpoints will 
include change in pulmonary function (FEV1) by spirometry, inhibition of MMP activity in a 
pan-MMP activity assay as well as individual MMPs assessed by gelatinase assays and 
doxycycline levels in serum, epithelial lining fluid and bronchoalveolar lavage cell pellets 
(consisting of alveolar macrophages, lymphocytes and some neutrophils).  
 
Statistical Considerations: The overall sample size is 30 subjects, all of whom will be recruited 
at WCMC. We anticipate screening 70 subjects to randomize 30. The study investigates the 
safety/ tolerability (grade 2 or higher toxicity) of long-term use of doxycycline. A 20-30% rate of 
grade 2 or higher toxicity is expected. With 20 doxycycline recipients, we will have 
approximately 80% power (one-sided alpha = 0.05) to detect a true proportion of 20% (grade 2 
or higher toxicity) while rejecting the null hypothesis of 45.5% or higher (in other words, ruling 
out the possibility of the event rate being any higher that 45.5%). Below are additional scenarios 
based on a true proportion of 5- 40% (P1), which demonstrate power greater than 80% for n = 20 
doxycycline recipients under these assumptions.  
 
Data will be entered into the REDCap, a PHP-based system developed by Vanderbilt University 
and currently managed and updated through a national consortium that includes the Weill 
Cornell CTSC. In collaboration with the CTSC’s data management group, we will create a 
secure, HIPAA-compliant, web-based study-specific database system with customized full field 
validation capabilities, a full audit trail and user-based privileges. 
 
We will compute summary statistics (e.g. mean, median, SD, interquartile range, minimum and 
maximum) for demographic/clinical variables and the primary outcome data (e.g. spirometry 
endpoints, adverse events, biological endpoints, measurable doxycycline levels in serum and 

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ELF) by study arm. We will compare changes from baseline in continuous variables between the 
two groups by 2-sample t-tests or the non-parametric Wilcoxon’s rank sum test as appropriate. 
We will perform repeated measures ANOVA or Multivariate ANOVA for repeated measures 
data (e.g. spirometry) as deemed appropriate after checking assumptions of sphericity using 
Mauchly’s Test. Given the moderate sample size for this data we will compute confidence 
interval for estimates from RMANOVA or MANOVA to assess their precision. The proportions 
of subjects in each arm experiencing adverse events will be summarized by grade and compared 
by Chi-squared or Fisher's exact tests or generalized Fisher’s test (using Monte Carlo 
approximations) as appropriate. In a pre-specified subgroup analysis, we will explore whether 
the subset of subjects with emphysema by CT respond differently to doxycycline compared to 
those without emphysema. 
 
Our research groups have a strong record of recruiting HIV+ subjects into clinical trials and 
observational studies, and specifically of recruiting HIV+ subjects with emphysema into studies 
requiring bronchoscopies. The HIV clinics at the New York Presbyterian Hospital/Weill Cornell 
Medical Center follow approximately 2,500 active patients (defined as patients with clinic visits 
within the past 6 months. We are presently conducting an observational study to evaluate a 
screening strategy for COPD in our HIV clinics, consisting of a questionnaire and peak flow 
measurement (IRB # 0912010782). Subjects who meet specific criteria, and a random selection 
of controls who do not, will undergo Spirometry (pre- and post-bronchodilator) to assess for 
fixed airway obstruction. We anticipate that this study will lead to the identification of 
approximately 65 subjects with new diagnoses of COPD, in addition to the clinic patients with 
established diagnoses. Furthermore, Dr. Kaner’s research group has independently identified a 
significant number of HIV+ subjects with COPD and a few with emphysema and no airflow 
obstruction who had come to volunteer for a research bronchoscopy study.  
 
5. INTRODUCTION 
 
5.1. 
Background  
In the context of improved survival from HIV infection itself, COPD (chronic obstructive 
pulmonary disease; a form of lung disease that includes emphysema, which makes breathing 
difficult) is emerging as an important cause of morbidity and perhaps ultimately mortality in this 
population. HIV-infected patients are at increased risk of COPD, likely due to multiple factors, 
including an increased presence of smoking, chronic inflammation and progression of 
immunodeficiency, oxidant stress (excessive levels of natural chemicals called oxidants and free 
radicals that can damage tissue), and respiratory infections. While natural history data on COPD 
are limited in the era of potent antiretroviral therapy, earlier data suggest that the course of 
emphysema may be accelerated in this population. Our preliminary data suggest that several 
matrix metalloproteinases (MMPs) derived from alveolar macrophages (a type of immune cell 
found in the lungs) have an increased cellular response in HIV-infected smokers, which could 
contribute to accelerated emphysema.  MMPs are enzymes that break down the structural support 
of tissues, including the airways in the lung. 
 
Based on these observations, we hypothesize that pharmacologic inhibition of MMPs by 
doxycycline will favorably modify the natural history of COPD in HIV-infected patients. To test 

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this hypothesis, we propose conducting a proof of concept pilot study as a prelude to a possible 
phase II randomized, placebo-controlled trial  of doxycycline for COPD in HIV-infected patients 
should the proof of concept be successful. Our research team, led by a pulmonologist/researcher 
with expertise in HIV-associated COPD and an infectious diseases specialist/clinical trials 
expert, is well positioned to propose such a trial to the NIH-funded AIDS Clinical Trials Group 
(ACTG). 
 
5.2. 
Rationale for Study  
Our proposed study of doxycycline in HIV-infected subjects with COPD is highly innovative. 
There are very limited clinical data on the use of doxycycline for COPD in the general 
population, and there are no adequately controlled studies. Our pilot study will not only serve as 
the basis for designing a phase II trial but also will provide a unique opportunity to advance our 
scientific understanding of the biological and physiological effects of MMP inhibition in lung 
tissue. No study, to our knowledge, has evaluated the effects of doxycycline on MMPs and pro-
inflammatory cytokines in the lung in humans. Our approach to use bronchoalveolar lavage to 
quantify the biological effects of doxycycline on MMP and cytokine gene and protein expression 
is novel and will advance knowledge significantly in this field. By correlating these biological 
effects with drug levels in epithelial lining fluid (ELF), alveolar macrophages (AM) and serum 
and changes in pulmonary function, we will be able to characterize the pharmacokinetic and 
pharmacodynamic profile of doxycycline in HIV-infected subjects with COPD.  
 
Controlled HIV infection. We are requiring a CD4 count > 200 cells/mm3 and HIV RNA < 400 
copies/ml to select for a patient population that is at low risk of pulmonary opportunistic 
infections.  
 
This will also minimize any confounding factors related to large scale changes in CD4, 
reconstitution syndrome, etc that might occur in a cohort with higher viral loads who have more 
recently been initiated on antiretroviral therapy. 
 
COPD definition - We will exclude advanced COPD (GOLD III/IV) in this proof of concept 
study in order to minimize risk to subjects from the bronchoscopies. We anticipate including 
more advanced COPD in a Phase II study, which will not necessarily include mandatory 
bronchoscopies. Since HIV+ smokers can have emphysema with a low number of pack-yr we 
will accept anyone with > 3 pack year history. We did not include a 2nd CT in the study design, 
because the time frame is too short to expect to see any favorable radiographic effects on 
preserving lung parenchyma to justify the additional radiation exposure. 
 
5.3 
Preliminary Studies 
MMPs in HIV+ Subjects with Emphysema. Dr. Kaner has recently published on the pattern of 
increased MMP expression in HIV+ individuals with emphysema18 RNA was successfully 
isolated from alveolar macrophages of HIV+ individuals with emphysema (and microarray data 
was deposited in GEO) and gene expression studies were performed and compared with the 
results of gelatinase assays and Western blots. These studies showed increased amounts and 
activation of MMP-2, -7, -9 and -12 in the epithelial lining fluid of HIV+ individuals with 
emphysema.  Using a pan-MMP activity assay, 8/8 HIV+ subjects with emphysema had 
detectable MMP activity in ELF (data not shown). Further studies have addressed the potential 

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upstream cytokine regulation of MMPs by cytokines. Comparing the cytokine protein profile in 
ELF, HIV+ individuals, both smoking and nonsmoking show a broad spectrum expression of 
cytokines, that shares similarities with HIV negative individuals with emphysema, but not with 
HIV-negative nonsmokers and smokers with normal lung function. Interestingly, several of the 
cytokines identified are important in the Th17 pathway. Preliminary data further indicate that IL-
23 (among other cytokines) upregulates human alveolar macrophage MMP-9 production via an 
intermediate step that involves T-lymphocytes (manuscript in preparation). These studies, along 
with the developing literature around the putative role of MMPs in the development of COPD 
and emphysema, provide a biologic rationale for the current proposal to test an MMP inhibitor in 
an effort to slow the progression of COPD and emphysema. 
 
Pulmonary Function in HIV+ Subjects with COPD/Emphysema. In 2011, the Department of 
Genetic Medicine COPD human samples research core headed by Dr. Kaner performed 355 
research bronchoscopies and the group has successfully performed thousands of research 
bronchoscopies over the last 15 years. In addition, the human samples core has independently (of 
Dr. Glesby’s group) screened 262 HIV-infected current or ex-smokers for a COPD study, of 
whom 34 (13.0%) met the PFT criteria for this study (post-bronchodilator FEV1/FVC < 0.7 
and/or DLCO < 80% predicted). 
 
These individuals came for screening to volunteer for a research bronchoscopy. Specifically, 23 
(68%) of 34 had post-bronchodilator FEV1/FVC < 0.7 and 26 (76%) had DLCO < 80%.  
 
6. 
TRIAL OBJECTIVES AND PURPOSE 
 
6.1. 
Primary Objectives 
 To determine the safety and tolerability of twice daily doxycycline for 6 months in HIV-
infected subjects with COPD and/or emphysema. 
 
Secondary Objectives: 
 To characterize changes in FEV1, FVC, FEV1/FVC, DLCO over time 
 To characterizes change in respiratory symptoms over time (using the CAT – COPD 
assessment test) 
 To characterize change in BAL absolute cell number (AM, PMN, lymph) 
 To characterize change in AM gene expression of MMPs and cytokines 
 To characterize change in BAL fluid MMP enzyme activity and cytokine levels 
 To characterize change in serum inflammatory markers (hsCRP, sIL-6, TNF-α, IL-1β, 
procalcitonin) 
 To determine doxycycline drug concentrations in serum, AM and ELF 
 To characterize change in quantitative bacterial burden in BAL fluid 
 To characterize frequency of doxycycline-resistant bacteria 
 To describe adherence to study therapy by self-report and pill counts 
 To determine the incidence of non-elective hospitalization, classified as respiratory or 
non-respiratory 

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 To determine the incidence of acute exacerbation of COPD (using the GOLD definition 
of change in symptoms requiring medication [we will use systemic steroids and/or 
antibiotics as the indicators]) 
 
7. 
INVESTIGATIONAL PLAN 
 
7.1. 
Endpoints 
 
The primary endpoint will be safety/tolerability, and secondary endpoints will include change in 
pulmonary function (FEV1) by spirometry, inhibition of MMP activity in a pan-MMP activity 
assay as well as individual MMPs assessed by gelatinase assays and doxycycline levels in serum, 
epithelial lining fluid and bronchoalveolar lavage cell pellets (consisting of alveolar 
macrophages, lymphocytes and some neutrophils).  
 
7.2. 
Overall Study Design and Plan: Schedule of Assessments 
 
SCREENING 
 Physical examination including vital signs (blood pressure, pulse, and breathing rate) weight 
and height, and amount of oxygen in the blood 
 Lung function tests (lung volumes, spirometry (post-bronchodilator) and diffusing capacity 
of the lung for carbon monoxide [DLCO]) 
 Blood will be drawn from a vein to check blood counts (to look for infection or anemia), HIV 
viral load (amount of virus in the blood), CD4 (T-cell) count, and blood chemistries (blood 
minerals, blood sugar level, kidney and liver function, PT/PTT, complete blood count, 
electrolytes, renal function, CMP, CBC+diff,  c-reactive and carboxy hemoglobin). If 
documentation of an HIV test result is not available, we will do an HIV test at screening. 
 Urine will be collected to measure protein levels, check kidney function, measure poisonous 
alkaloid from tobacco, the break-down product of nicotine from cigarette smoke, PGE 
collection and to evaluate toxicology for drugs 
 For females capable of getting pregnant, urine will be collected to test for pregnancy. If you 
are pregnant, you will not be allowed to participate in this study 
 Electrocardiogram, a non-invasive test that provides a tracing of the heart’s electrical activity 
 
PRE-ENROLLMENT (OPTIONAL)  
 Physical examination including your signs (blood pressure, pulse, and breathing rate) weight 
and height, and amount of oxygen in the blood 
 Blood will be drawn from a vein to check blood counts (to look for infection or anemia), HIV 
viral load (amount of virus in the blood), CD4 (T-cell) count, and blood chemistries (blood 
minerals, blood sugar level, kidney and liver function, PT/PTT, complete blood count, 
electrolytes, renal function, CMP, CBC+diff,  c-reactive and carboxy hemoglobin). If 
documentation of an HIV test result is not available, we will do an HIV test at screening. 
 For females capable of getting pregnant, urine will be collected to test for pregnancy. If you 
are pregnant, you will not be allowed to participate in this study 
 A detailed x-ray of the lungs (High-resolution Computed Tomography, or HRCT) will be 
done if a scan of good quality was not done in the past 6 months 

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ENROLLMENT 
 Physical examination including your signs (blood pressure, pulse, and breathing rate) weight 
and height, and amount of oxygen in the blood 
 Lung function tests (lung volumes, spirometry (post bronchodilator)) 
 Assessment of any side effects or symptoms and if there have been any changes in any of the 
medications you may be taking 
 EKG (optional; repeated only if 30 days have passed since last EKG) 
 Blood will be drawn from a vein to check blood counts (to look for infection or anemia), 
blood chemistries (blood minerals, blood sugar level, kidney and liver function), stored 
serum and biomarkers 
 Urine will be collected to evaluate toxicology for drugs 
 Urine will be collected to measure poisonous alkaloid from tobacco and the break-down 
product of nicotine from cigarette smoke  
 For females capable of getting pregnant, urine will be collected to test for pregnancy. If you 
are pregnant, you will not be allowed to participate in this study  
 Study drug dispensing 
 Respiratory symptom and smoking questionnaires 
 Oral rinse to collect samples of the bacterial communities in the oral mouth and upper airway 
and to remove loose debris that may contaminate the airway samples. 
 Bronchoscopy 
 
WEEK 2 
 Physical examination including your signs (blood pressure, pulse, and breathing rate) weight 
and height, and amount of oxygen in the blood 
 Lung function tests (lung volumes, spirometry (post bronchodilator) and diffusing capacity of 
the lung for carbon monoxide [DLCO]) 
 Assessment of any side effects or symptoms and if there have been any changes in any of the 
medications you may be taking 
 Blood will be drawn from a vein to check blood counts (to look for infection or anemia), 
blood chemistries (blood minerals, blood sugar level, kidney and liver function), stored 
serum and biomarkers 
 For females capable of getting pregnant, urine will be collected to test for pregnancy. If you 
are pregnant, you will not be allowed to participate in this study  
 
WEEK 6 
 Physical examination including your signs (blood pressure, pulse, and breathing rate) weight 
and height, and amount of oxygen in the blood 
 Assessment of any side effects or symptoms and if there have been any changes in any of the 
medications you may be taking 
 Blood will be drawn from a vein to check blood counts (to look for infection or anemia), 
blood chemistries (blood minerals, blood sugar level, kidney and liver function), stored 
serum and biomarkers 
 For females capable of getting pregnant, urine will be collected to test for pregnancy. If you 
are pregnant, you will not be allowed to participate in this study  

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 Study drug dispensing 
 
WEEK 11 (OPTIONAL) 
 Physical examination including your signs (blood pressure, pulse, and breathing rate) weight 
and height, and amount of oxygen in the blood 
 Blood collection for safety labs (complete blood count, electrolytes, liver function and renal 
function (CMP, CBC+diff, c-reactive, carboxy hemoglobin, and PT/PTT). 
 
WEEK 12 
 Physical examination including your signs (blood pressure, pulse, and breathing rate) weight 
and height, and amount of oxygen in the blood 
 Lung function tests (lung volumes, spirometry (post bronchodilator)) 
 Assessment of any side effects or symptoms and if there have been any changes in any of the 
medications you may be taking 
 EKG 
 Blood will be drawn from a vein to check blood counts (to look for infection or anemia), 
blood chemistries (blood minerals, blood sugar level, kidney and liver function), stored 
serum and biomarkers 
 Urine will be collected to measure the break-down product of nicotine from cigarette smoke, 
for substances released from cells that are involved in inflammation, PGE collection, and to 
evaluate toxicology for drugs 
 For females capable of getting pregnant, urine will be collected to test for pregnancy. If you 
are pregnant, you will not be allowed to participate in this study  
 Study drug dispensing 
 Oral rinse to collect samples of the bacterial communities in the oral mouth and upper airway 
and to remove loose debris that may contaminate the airway samples. 
 Bronchoscopy 
 
WEEK 18 
 Physical examination including your signs (blood pressure, pulse, and breathing rate) weight 
and height, and amount of oxygen in the blood 
 Assessment of any side effects or symptoms and if there have been any changes in any of the 
medications you may be taking 
 Blood will be drawn from a vein to check blood counts (to look for infection or anemia), 
blood chemistries (blood minerals, blood sugar level, kidney and liver function), stored 
serum and biomarkers  
 Urine will be collected to measure protein levels, check kidney function, measure poisonous 
alkaloid from tobacco and the break-down product of nicotine from cigarette smoke  
 For females capable of getting pregnant, urine will be collected to test for pregnancy. If you 
are pregnant, you will not be allowed to participate in this study  
 Study drug dispensing 
 
WEEK 24 
 Physical examination including your signs (blood pressure, pulse, and breathing rate) weight 
and height, and amount of oxygen in the blood 

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 Lung function tests (lung volumes, spirometry (post bronchodilator) and diffusing capacity of 
the lung for carbon monoxide [DLCO]) 
 Assessment of any side effects or symptoms 
 Blood will be drawn from a vein to check blood counts (to look for infection or anemia), HIV 
viral load (amount of virus in the blood), CD4 (T-cell) count, and blood chemistries (blood 
minerals, blood sugar level, kidney and liver function, CMP, CBC+diff,  c-reactive and 
carboxy hemoglobin), stored serum and biomarkers.  
 For females capable of getting pregnant, urine will be collected to test for pregnancy. If you 
are pregnant, you will not be allowed to participate in this study  

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Table I: Schedule of Evaluations 
 
 
SCREENING 
PRE-ENTRY 
(OPTIONAL) 
ENTRY 
WK 
2 
WK 
6 
WK 11 
(OPTIONAL) 
WK 
12 
WK 18 
WK 24 
PREMATURE 
DISCONTINUATION 
Informed consent, medical 
history 
X 
 
 
 
 
 
 
 
 
 
Clinical Assessments1 
X 
X 
X* 
X 
X 
X 
X* 
X 
X 
X 
Safety labs2 
X  
           X 
 
  
X* 
X 
X 
X 
X* 
X 
X 
X 
Blood test3 
X 
X  
X* 
 
 
X 
X* 
 
 
 
Other labs4 
X 
 
 
 
 
 
 
 
 
 
HIV viral load 
X 
  
  
  
  
 
X 
  
X 
X 
CD4 (T-cell) count 
X 
  
  
  
  
 
X 
  
X 
X 
Research blood (collection 
priority)5 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
Pregnancy test (urine) 
X 
X 
X 
 X  
X 
 
X 
X 
X 
  
Urine toxicology (drug 
panel) 
X 
 
X 
 
 
 
X 
 
 
 
PGE urine collection6 
X** 
 
 
 
 
 
X** 
 
 
 
Urinanalysis7 
X 
 
 
 
 
 
 
 
 
 
Urine Metabolites8 
X 
 
X 
 
 
 
X 
X 
 
 
Spirometry 
X 
  
X 
  
  
 
X 
  
X 
X 
EKG 
X 
 
X 
 
 
 
X 
 
 
 
Bronchoscopy9 
  
  
X 
  
  
 
X 
  
  
  
High resolution chest CT10 
  
X 
X* 
  
  
 
  
  
  
  
Oral rinse11 
 
 
X 
 
 
 
X 
 
 
 
Respiratory (CAT)/smoking 
questionnaires 
  
  
X 
  
X 
 
X 
  
X 
X 
Dispense study drug 
  
  
X 
  
X 
 
X 
X 
  
  
Pill count/adherence 
questionnaire 
  
  
  
X 
X 
 
X 
X 
X 
X 
* Optional procedures if procedures were already conducted during the optional visits. 
 1 Clinical assessments include full physical examination at screening, targeted physical examinations at other visits, ongoing assessments for adverse events and new clinical 
diagnoses and CAT review at each visit. 
2 Safety labs consist of complete metabolic panel, complete blood count, electrolytes, liver function and renal function (CMP, CBC+diff, c-reactive, carboxy hemoglobin). 
3 PT/PTT blood test 
4 Other Labs (Hepatitis panel (A, B and C), alpha-1 anti-trypsin, IgE) 

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5 Research blood: Bronchoscopy visits (Week 0/Entry and Week 12), blood samples are collected for: doxycycline blood levels, EMP, DNA, serum (doxycycline assay, 
biomarker assay, DGM biobank), and monocytes. Non-bronchoscopy visits: (Week 2, Week 6, and Week 18 and Week 24) blood samples are collected for: doxycycline 
blood levels and serum for (doxycycline assay, biomarker assay and DGM biobank). Serum for biomarker assay will be frozen at -80°C for future assays (hsCRP, IL-6, TNF-
α, IL-1β, procalcitonin). Should subject pre-maturely discontinue from the study, the subject will be invited to at least provide blood samples for the doxycycline blood assay. 
6 Prostaglandin E urine collection, 9 mL. **All subjects will be assessed for eligibility. PGE will be collected for any subject, who passes the screening as per the PI’s 
recommendation, and has not taken NSAIDS within the past 7 days. Otherwise, subject will not be eligible for the PGE urine collection. 
7 Urine analysis will be collected to measure protein levels and kidney functions 
8 Urine metabolites will be collected to measure poisonous alkaloid from tobacco and the break-down product of nicotine from cigarette smoke 
9 Bronchoalveolar lavage; > 50mL. To minimize any risk of bleeding to a subject after completion of the bronchoscopy procedure, subjects are advised not to take non-
steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and/or ibuprofen, for up to 7 days post-procedure. 
10 CT-scans taken within the last 6 months may be acceptable. Subjects will not be asked to complete more than 2 HRCT scans in one year If subjects complete the maximum 
of two HRCT scans in one year, they will receive no more than 2200mrem of radiation, which is within the guidelines for radiation exposure for human subjects; it is also 
below the maximum permissible dose limits per year for radiation workers according to the Nuclear Radiation Committee (5000mrem/year). 
11 Oral rinse to collect samples of the bacterial communities in the oral mouth and upper airway and to remove loose debris that may contaminate the airway samples. 
Subjects will be asked to cough 5 times and then actively gargle 10 cc of sterile saline for 20 seconds. At the end of the gargle, the subject will be instructed to swish the 
saline in the mouth for 5 seconds. The subject will then spit the oral rinse into the ORAL specimen container, gently spitting into the RNALater. 
12 Refer to Table II for the acceptable “time windows” for the assessment days. 
 
Table II: Assessment Windows 
 
EVALUATION 
SCREENING 
PRE-ENTRY 
(Optional) 
ENTRY 
WK 
2 
WK 
6 
WK 11 
(Optional) 
WK 
12 
WK 
18 
WK 
24 
PREMATURE 
DISCONTINUATION 
All other 
evaluations 
N/A 
N/A  
 N/A 
 ±7 
days 
±7 
days  
N/A  
 N/A  
±7 
days  
±7 
days  
±7 days   
Bronchoscopy 
Visits 
 N/A 
 N/A 
±14 days 
 N/A  
 N/A  
N/A  
±14 
days 
  N/A 
 N/A  
 N/A  
 
Table III: Bodily Fluid Collection 
 
Bodily Fluid 
Amount 
Number of 
Visits 
Total (mL) 
 
(mL per test) 
(To be taken over the course of 24 weeks) 
Blood 
Doxycycline blood levels 
12 
6 
72 
Safety labs 
36 
6 
216 
Blood Test 
3 
2 
6 
Other lab 
21 
1 
21 

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HIV viral load 
7 
3 
21 
CD4 (T-cell) count 
4 
3 
12 
Serum for biomarkers 
18 
4 
72 
Research blood 
76 
2 
152 
Total 
572 
Urine 
 
 
 
Urine Toxicology 
12 
3 
36 
Pregnancy 
7 
8 
56 
PGE Collection  
9 
2 
18 
Urinalysis 
10 
1 
10 
Urine Metabolites 
4 
2 
8 
Total 
128 
BAL fluid Total 
50* 
2 
100 
Oral rinse Total 
10 
2 
20 
*Administer 150mL fluid up to 300 mL max, for a minimum return of 50mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
 
8.1. 
Sample Population 
Recruitment will be from the referral base of the responsible investigator and other physicians in the 
Division of Pulmonary and Critical Care Medicine, the NYPH Center for Special Studies (HIV clinic), and 
from community providers within the NY area.  
 
8.2. 
Subject Inclusion Criteria  
• 
Males/Females ages 18-85 years 
• 
Documented HIV infection  
• 
CD4 cell count greater than 200 cells/mm3  
• 
HIV RNA less than 400 copies/ml  
• 
Stable antiretroviral therapy for greater than or equal to 12 weeks  
• 
Fulfills GOLD definition for COPD (post-bronchodilator FEV1/FVC less than 0.7) and/or has 
radiographic evidence of emphysema  
• 
Current or history of smoking with minimum 3 pack-year history  
• 
ALT and AST less than 3 x upper limit of normal  
• 
For women of childbearing potential: willingness to use 2 forms of birth control 
• 
Subjects on therapy for COPD must be on stable therapy for at least 4 weeks 
 
8.3. 
Subject Exclusion Criteria  
• 
Pulmonary infection, COPD exacerbation, or acute opportunistic infection within 30 days of entry 
• 
Conditions associated with increased sedation of bronchoscopy risk, including but not limited to Gold 
class 3 or 4 COPD, requirement for home oxygen, hypercapneic respiratory failure, poorly control 
hypertension  
• 
Known allergy/intolerance to doxycycline, atropine, or any local anesthetic  
• 
Inability to provide informed consent 
• 
Pregnant or lactating women  
• 
Men must agree not to attempt to make a woman pregnant of participate in sperm donation during the 
study and for 6 weeks after discontinuing the drug  
• 
End stage renal disease  
• 
Cirrhosis  
• 
INR greater than 1.4  
• 
Platelets less than 80,000  
• 
Any condition including active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements or increase the risk of bronchoscopy 
• 
Active or planned participation in any other clinical trial or observational study without prior approval 
from the PI 
 
8.4. 
Withdrawal Criteria 
The investigators, physicians or sponsors may stop the study or remove the subject from the study at any time 
should they judge that it is in the subject’s best interest to do so, if he/she experiences a study-related injury, if 
the subject needs additional or different medication, or if he/she does not comply with the study plan. They 
may remove the subject from the study for various other administrative and medical reasons. They can do 
this without the subject’s consent. 
 
 

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9. 
STUDY CONDUCT 
 
9.1. 
Study Overview 
A subject’s participation in this study is expected to be approximately 24 weeks.  The day the subject begins 
taking the doxycycline will be designated as day 0 and enrollment. The study will include a bronchoscopy 
procedure at the enrollment/entry visit and week 12 visit. 
 
9.2. 
Schedule of Assessments 
The screening period begins at the time of consent/assent of the study subject. Subjects will provide written 
informed consent and/or assent before undergoing the screening procedures at the pre-vector time point. 
Please refer to Table I in Section 7.2. 
 
10. 
SCREENING/BASELINE ASSESSMENTS 
 
Screening is defined as the time of the signing of the informed consent form. Assessments and procedures 
that are to be performed after the informed consent form has been signed. See timeline of proposed clinical 
study for details.  
 
11. 
ASSESSMENT OF EFFICACY 
 
Efficacy will be evaluated through all assessments particularly those of lung function including: (1) primary 
– pulmonary function test; and (2) secondary – respiratory questionnaires.  
 
11.1 Expected Risks 
Risks and adverse effects related to the procedures and the study drug we are studying can be divided into 
the following categories: (1) those associated with taking doxycycline for a prolonged period of time; (2) 
those associated with undergoing evaluation procedures, including risks from undergoing a high resolution 
chest CT scan; and (3) those associated with undergoing a fiberoptic bronchoscopy. 
 
(1) Risks associated with taking doxycycline 
 
Doxycycline has a long track record of safety. The most common adverse events seen with doxycycline use 
are: 
 
Gastrointestinal: anorexia, nausea, vomiting, diarrhea (including Clostridium difficile associated colitis), 
glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital 
region. Esophagitis and esophageal ulcerations (rare). Hepatotoxicity (rare). 
 
Skin: Photosensitivity manifested as an exaggerated sunburn reaction. Toxic epidermal necrolysis, Stevens-
Johnson syndrome, erythema multiforme, maculopapular, erythematous rashes, and exfoliative dermatitis 
 
Renal: Dose-related increases in blood urea nitrogen (BUN). Hypersensitivity reactions: urticaria, 
angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of 
systemic lupus erythematosus. 

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Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia. 
 
Other: Intracranial hypertension in adults. When given over prolonged periods, tetracyclines have been 
reported to produce brown-black microscopic discoloration of the thyroid gland. No abnormalities of thyroid 
function studies are known to occur. 
 
Pregnancy Risk: Doxycycline is a category D drug. There are no adequate and well-controlled studies on the use 
of doxycycline in pregnant women. An expert review of the Teratogen Information System concluded that 
therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk 
 
(2) Risks associated with taking placebo 
 
The risks associated with administering a placebo are that enrolled subjects will not receive active medication and 
possible worsening of COPD in HIV-infected patients.  Enrolled subjects taking placebo will not receive any 
possible benefit associated with doxycycline. 
 
(3) Risks associated with the tests and procedures done in this study 
 
Blood Tests. These tests involve drawing blood from a vein in the arm by usual venipuncture. The risks associated 
with the venipuncture procedure will include pain or bruising where the needle is put in the vein, or very rarely, 
damage to the blood vessel. Rarely, people faint after blood drawing. The total amount of blood to be drawn will 
not exceed 150 ml (less than half of a pint), which will be used for general hematologic studies and/or general 
serologic/immunologic studies and/or biochemical analyses and/or HIV-1 serology. The amount of blood is within 
the acceptable limits for human research according to the guidelines for human research according to New York 
Presbyterian Hospital-Weill Cornell Medical College. 
 
Pulmonary Function Tests. These tests involve breathing in and out of a pulmonary function testing 
machine and breath holding as required by the technician performing the tests. They are harmless but may 
occasionally cause slight soreness in the respiratory muscles and chest due to effort. 
 
High Resolution Chest CT Scan. All study individuals will be asked to perform a high resolution CT scan 
of the chest. The amount of radiation a person receives during a CAT scan is between 700-1000 mrem,which 
is a safe level of exposure. In order to avoid the risk of undue radiation to a fetus, women will not be 
included in this study if they are pregnant. There is always a risk of damage to cells or tissue from being 
exposed to any radiation. The HRCT completed as part of this study, might involve unsuspected, incidental 
findings that might or might not be a sign of disease and might or might not lead to further medical work-up. 
This further medical work-up (if it is performed) might have associated risks, potentially cause anxiety, and 
may incur costs to the subject and/or the subject’s insurer. A high resolution chest CT scan involves 
exposure to radiation and that exposure is increased the more often such tests are done.  Radiation exposure 
at certain doses can potentially cause cancer.  Any possible increase in cancer risk associated with 
participation in this study cannot be measured, is uncertain, and assumed to be quite low.  The images from 
the HRCT will be analyzed to quantify emphysema. 
 
Electrocardiogram. There are no risks associated with electrocardiography, per se.  However, some people 
develop allergic reactions (rashes) on their skin to the electrode pads. 
 

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(4) Risks associated with a fiberoptic bronchoscopy 
 
Fiberoptic Bronchoscopy. Dr. Kaner’s group has well established procedures to reduce the risk of 
bronchoscopies. Potential complications from fiberoptic bronchoscopy include: (1) transient fever within 12 
hours of the procedure; (2) bleeding within the nasopharynx due to trauma from passage of the 
bronchoscope; (3) allergic reactions to any of the pre-medications or local anesthesia; (4) cardiac 
arrhythmias due either to vagal stimulation or to toxicity of local anesthesia; (5) aspiration pneumonia (the 
presence of foreign fluid, blood, saliva, or stomach contents in the airways can occur when an individual 
consumes food prior to the bronchoscopy; as a result of vomiting; this risk is prevented by having all 
individuals fast for six hours prior to the procedures); (6) lack of oxygen and the associated shortness of 
breath; and (7) bronchospasm (the narrowing of the windpipes that causes shortness of breath). The most 
common of these problems are transient fever and bleeding and these are usually self-limiting. The 
medications used during the bronchoscopy cause drowsiness and may cause the subject’s mouth and/or nose 
to feel dry. Risks associated with the medications include tachycardia and/or a transient lowering of blood 
pressure, which may be associated with light-headedness, dizziness, nausea, chills, rigors and in rare cases, 
vomiting. The problems affecting individuals with allergies to the medications used in bronchoscopy may be 
minimized by excluding individuals with these allergies from protocol. The difficulties with cardiac 
arrhythmias may be managed and anticipated by continuous cardiac monitoring throughout the procedures. 
In this context, bronchoscopy with bronchoalveolar lavage and/or bronchial brushing as performed in this 
manner is a safe procedure. 
 
Since there has been a report of a death associated with fiberoptic bronchoscopy in a normal individual in 
Rochester, NY (reported in the New York Times, April 3, 1996), it is relevant to discuss the safety issues 
regarding this procedure and how our group insures the safety of study participants. 
 
With regards to using bronchoscopic evaluation to obtain biologic specimens from the lung for research 
purposes, the Principal Investigator and his colleagues over the past 15 yr have performed more than 2,000 
bronchoscopies with bronchoalveolar lavage and over 1000 with brushing, including individuals with lung 
disease, as well as normal volunteers in research studies. To ensure the safety of study participants, all 
procedures are carried out with the subject fully monitored (EKG, pulse oximeter) and with an intravenous 
line in place. A minimum of two physicians, including a fully trained pulmonary/critical care physician 
faculty member, or one physician and one physician assistant participate in each procedure, together with a 
minimum of one nurse. All procedures are carried out with a strict standard operating procedure, including 
guidelines for drug use and post-procedure monitoring. For example, the dose of topical lidocaine is limited 
to 5 mg/kg; (in contrast, in the New York Times reported death following the research bronchoscopy of a 
study individual in Rochester, NY, post-mortem studies revealed toxic levels of lidocaine in the blood. The 
individual had received > 1.5 gm lidocaine; significantly in excess of the amounts used in any bronchoscopic 
procedure). Based on the above approach, we have carried out multiple fiberoptic bronchoscopy procedures 
in many research patients and normal volunteers. 
 
Over 1933 research patients and normal volunteers have had fiberoptic bronchoscopy procedures in our 
clinical protocols at New York Presbyterian Hospital-Weill Cornell Medical Center and The Rockefeller 
University. In our experience dealing with this population, we have encountered such adverse events as sore 
throat, cough, mild chest pain relating to the cough, mild hoarseness for several hours and transient, self-
limiting fever and chills. One volunteer experienced an alteration in taste that lasted for approximately one 
month, which resolved without medical intervention. It is not known whether this event (alteration in taste) 
was related to the bronchoscopy procedure. There have been no other reports of this adverse event by any of 

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the other research participants. Examples of "serious adverse events" associated with this procedure reported 
in the literature are transient cardiac arrhythmia (0.9%), pneumothorax (0.4-4%), pneumonia (0.6%), and 
respiratory failure (0-0.2%). The pneumothorax risk only applies to individuals who are undergoing 
transbronchial biopsies which are NOT being done in this protocol. 
Fiberoptic bronchoscopy performed several times are accepted tests in clinical medicine. Several of our 
previous clinical protocols in which fiberoptic bronchoscopy was performed several times on the same study 
individual found no adverse events or increased risks related to the number of bronchoscopies performed. 
The interval period for the bronchoscopies for those protocols varied from 1 day to several months. We are 
proposing here to do a second bronchoscopy 3 months after the initial one. 
 
12. 
ASSESSMENT OF SAFETY 
 
12.1 Adverse Events  
Adverse events will be graded through use of the Division of AIDS Toxicity Grading Table. Any Grade 4 
and Grade 5 clinical adverse events or laboratory abnormalities that are judged to be possibly, probably, or 
definitely related to blinded study treatment will be promptly (within 72 hours) reported to the IRB and FDA 
as indicated. Full details on recording and reporting adverse events are provided in Section 13.1.2. 
 
12.1a. Definitions 
 
12.1.1a. 
Adverse Events  
An adverse event is any untoward medical occurrence in a clinical study subject. No causal relationship with 
the study drug or with the clinical study itself is implied. An adverse event may be an unfavorable and 
unintended sign, symptom, syndrome, or illness that develops or worsens during the clinical study. Clinically 
relevant abnormal results of diagnostic procedures including abnormal laboratory findings (eg., requiring 
unscheduled diagnostic procedures or treatment measures, or resulting in withdrawal from the study) are 
considered to be adverse events. Surgical procedures are not adverse events, but may constitute therapeutic 
measures for conditions that require surgery. The condition for which the surgery is required is an adverse 
event, if it occurs or is detected during the study period. Planned surgical measures permitted by the clinical 
study protocol and the conditions(s) leading to these measures are not adverse events, if the condition(s) was 
(were) known before the start of study treatment. In the latter case the condition should be reported as 
medical history. Assessment of chronic obstructive pulmonary disease symptoms will be documented and 
analyzed as a measure of efficacy of the study treatment. These symptoms will not be reported as adverse 
events unless the symptom(s) worsen to the extent that the outcome fulfills the definition of a serious adverse 
event (see 13.1.2a for definition), which then must be recorded as such. Adverse events are designated as 
“non-serious” or “serious.” 
 
Adverse events will be recorded by each site’s study coordinator. Adverse events (AEs) will be entered by 
each site’s coordinator into a cumulative table provided by the sponsor. Additionally, site coordinators will 
fill out a Department of Genetic Medicine case report form for each AE that occurs at their site. The 
cumulative table and associated case report forms will be sent to the sponsor on a regular basis, as agreed 
upon by the site and sponsor (e.g. every 2 months).  
 
12.1.2a. 
Serious Adverse Event  
 
A serious adverse event is an adverse event that results in any of the following outcomes: 

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 Death 
 Is life-threatening (subject is at immediate risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if it were more 
severe) 
 Requires in-subject hospitalization (formal admission to a hospital for medical 
reasons) or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity (ie. there is a substantial 
disruption of a person’s ability to carry out normal life functions) 
 Is a congenital anomaly/birth defect 
 Requires intervention to prevent permanent impairment or damage 
 Other serious (important) medical events that do not fit the other outcomes, but may jeopardize the 
subject and require medical or surgical intervention to prevent one of the other outcomes. 
 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, 
they may jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in subject 
hospitalization, or the development of drug dependency or drug abuse. 
 
12.1b. Method, Frequency, and Time Period for Detecting Adverse Events and Reporting Serious 
Adverse Events  
 
In the event of the occurrence of an adverse event that requires immediate medical intervention, Drs. Kaner 
or Glesby will be notified and will evaluate the subject. If the event is serious, the subject will be referred to 
the hospital’s Emergency Department as appropriate. The data and safety monitoring plan is discussed in 
detail below. The safety data study will be monitored by Drs. Kaner and Glesby. Adverse events will be 
reported to the Weill Cornell IRB in accordance with institutional requirements. 
 
If major adverse events occur and are related to the drug, no additional patients will be treated until the data 
is discussed with the IRB. If the research subject suffers a major bad effect caused by a research study 
related event, he/she will continue in the study as long as it does not interfere with his/her clinical care and 
welfare.  It is also possible that the research subject will not be able to continue with the research study 
because of illness.  All possibilities will be explored to prevent the subject’s removal from the research 
study, as long as his/her welfare is ensured. It will be explained to the research subject that his/her safety and 
welfare comes first. 
 
Serious adverse events (SAEs) will be assessed by the study team and principal investigator at each site. The 
site will inform the sponsor of the SAE within 24 hours, with whatever information is available at that time. 
Further information will be sent as it becomes available. The Department of Genetic Medicine SAE form 
will be completed by the coordinator, and reviewed and signed by the site PI.  
 
 
 
 
 

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12.1c. Definition of Severity 
  
All adverse events will be assessed (graded) for severity and classified using the NIAID Division of AIDS 
Toxicity Grading Table. Any adverse events not covered by the DAIDS’ criteria will be assessed and 
classified into one of four clearly defined categories as follows:  
 
Mild: (Grade 1): Transient or mild symptoms; no limitation in activity; no intervention 
required. The adverse event does not interfere with the participant’s normal functioning level. It may be an 
annoyance. 
 
Moderate: (Grade 2): Symptom results in mild to moderate limitation in activity; no or 
minimal intervention required. The adverse event produces some impairment of functioning, but it is not 
hazardous to health. It is uncomfortable or an embarrassment. 
 
Severe: (Grade 3): Symptom results in significant limitation in activity; medical intervention may be 
required. The adverse event produces significant impairment of functioning or incapacitation. 
 
Potentially Life-threatening: (Grade 4) Symptoms causing inability to perform basic self-care functions 
OR medical or operative intervention indicated to prevent permanent impairment, persistent disability, or 
death. 
 
12.1d. Definition of Relationship to Study Drug  
The blinded Principal Investigator or medically qualified designee must review each AE and make the 
determination of relationship to study drug using the following guidelines: 
 
Not Related: The event can be readily explained by other factors such as the subject’s underlying medical 
condition, concomitant therapy, or accident, and no temporal relationship exists between the study drug and 
the event. 
 
Unlikely: The event does not follow a reasonable temporal sequence from drug administration and is readily 
explained by the subject’s clinical state or by other modes of therapy administered to the subject. 
 
Possibly Related: There is some temporal relationship between the event and the administration of the study 
drug and the event is unlikely to be explained by the subject’s medical condition, other therapies, or accident. 
 
Probably Related: The event follows a reasonable temporal sequence from drug administration and cannot 
be reasonably explained by the known characteristics of the subject’s clinical state. 
 
Definitely Related: The event follows a reasonable temporal sequence from administration of the 
medication, follows a known or suspected response pattern to the medication. 
 
12.1e. Reporting Serious Adverse Events 
 
Any serious adverse event or suspected unexpected serious adverse reaction must be reported to the 
Department of Genetic Medicine within 24 hours of the Investigator’s recognition of the serious adverse 
events / suspected unexpected serious adverse reaction.  
 

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The site is required to fax a completed Serious Adverse Event Report Form (provided as a separate report 
form) within 24 hours. All additional follow-up evaluations of the serious adverse event / suspected 
unexpected serious adverse reaction must be reported and sent by facsimile to the Department of Genetic 
Medicine or its designee as soon as they are available. The Principal Investigator or designee at each site is 
responsible for submitting the IND safety report (initial and follow-up) or other safety information (eg, 
revised Investigator’s Brochure) to the Institutional Review Board/Independent Ethics Committee and for 
retaining a copy in their files. 
 
If the Investigator becomes aware of any serious adverse event or suspected unexpected serious adverse 
reaction occurring within 30 days after a subject has completed or withdrawn from the study, he or she 
should notify the Department of Genetic Medicine. After the 180 day final follow up visit, the Investigator 
should report any unexpected serious adverse events that are discovered during the yearly follow up phone 
calls to DGM.   
 
Any serious adverse event or suspected unexpected serious adverse event considered possibly, probably or 
definitely related to treatment will be reported to the FDA and other Regulatory Competent Authorities as 
applicable via the MedWatch reporting system in accordance with FDA and other applicable regulations.  
 
13. STUDY ADMINISTRATION 
 
13.1 Regulatory and Ethical Considerations 
 
13.1a. Regulatory Authority Approvals  
This study will be conducted in compliance with the protocol; Good Clinical Practices, including 
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals 
for Human Use Guidelines; Food and Drug Administration regulatory requirements and in accordance with 
the ethical principles of the Declaration of Helsinki. In addition, all applicable local laws and regulatory 
requirements relevant to the use of new therapeutic agents in the countries involved will be adhered to. 
 
The Investigator will submit written reports of clinical study status to the Institutional 
Review Board annually or more frequently if requested by the Institutional Review Board. A final study 
notification will also be forwarded to the Institutional Review Board after the study is completed or in the 
event of premature termination of the study in accordance with the applicable regulations. Copies of all 
contact with the Institutional Review Board will be maintained in the study documents file. Copies of clinical 
study status reports (including termination) will be provided to the Department of Genetic Medicine.  
 
13.1b. Ethics Committee Approvals  
Before initiation of the study at each investigational site, the protocol, the informed consent and assent 
forms, the subject information sheet, and any other relevant study documentation will be submitted to the 
appropriate Institutional Review Board. Written approval of the study must be obtained before the 
investigational medicinal product is released to the Investigator and the study site may be opened for 
enrollment. Any necessary extensions or renewals of Institutional Review Board approval must be obtained, 
in particular, for changes to the study such as modification of the protocol, the informed consent and assent 
forms, the written information provided to subjects and/or other procedures. The Investigator will report 
promptly to the Institutional Review Board any new information that may adversely affect the safety of the 

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subjects or the conduct of the study. On completion of the study, the Investigator will provide the 
Institutional Review Board with a report of the outcome of the study. 
 
13.1c. Subject Informed Consent  
Signed informed consent must be obtained from each subject prior to performing any study related 
procedures. The subject will be provided with the consent form prior to arriving at the study site, to allow 
adequate time for review. Each subject should be given both verbal and written information describing the 
nature and duration of the clinical study. The informed consent process should take place under conditions 
where the subject has adequate time to consider the risks and benefits associated with his/her participation in 
the study. Subjects will not be screened or treated until the subject has signed an approved informed consent 
form written in a language in which the subject is fluent. If the subject is not able to provide written informed 
consent, a legally authorized representative may provide written informed consent where applicable local 
directives, guidelines or procedures allow. 
 
The informed consent form that is used must be approved both by the Department of Genetic Medicine and 
by the reviewing Institutional Review Board. The informed consent should be in accordance with the current 
revision of the Declaration of Helsinki, current International Council on Harmonisation and Good Clinical 
Practice guidelines, and the Department of Genetic Medicine policy. The Investigator must explain to 
potential subjects or their legal representatives the aims, methods, reasonably anticipated benefits, and 
potential hazards of the trial and any discomfort it may entail. Subjects will be informed that they are free not 
to participate in the trial and that they may withdraw consent to participate at any time. They will be told that 
refusal to participate in the study will not prejudice future treatment. They will also be told that their records 
may be examined by competent authorities and authorized persons but that personal information will be 
treated as strictly confidential and will not be publicly available. Subjects must be given the opportunity to 
ask questions. After this explanation and before entry into the trial, consent should be appropriately recorded 
by means of the subject’s dated signature. The subject should receive a signed and dated copy of the 
informed consent form, and, if applicable, the assent. The original signed informed consent should be 
retained in the study files. The Investigator shall maintain a log of all subjects (or their representatives), who 
sign the informed consent form and indicate if the subject was enrolled into the study or reason for non-
enrollment. 
 
13.1d. Payment to Subjects  
 
Subjects will be reimbursed $50 for completion of the screening visit, $200 for a completed bronchoscopy 
and $50 for any additional non-bronchoscopy study visit.  
 
13.2 Study Monitoring 
 
Weill Cornell Medical College-New York (WCMC-NY) 
The Clinical Operations and Regulatory Affairs (CORA) Core of the Department of Genetic Medicine will 
oversee and carry out the relevant monitoring and reporting of conduct of this trial. CORA Core provides the 
Weill Cornell clinical projects the infrastructure and expertise to conduct clinical gene therapy projects that 
follow the regulations and guidelines of the Food and Drug Administration (FDA) and Institutional Review 
Board (IRB). Included in the CORA Core are four components: Clinical Operations; Regulatory Affairs; 
Monitoring; and Data Management and Analysis. In addition, the CORA Core has the responsibility of 
reporting to the Weill Cornell Gene Therapy Data Safety Monitoring Board. The CORA Core also 

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participates in the Education Program at Weill Cornell, providing training in Clinical Operations/Regulatory 
Affairs relating to pulmonary diseases. 
 
The Monitoring component is the verification arm of the CORA Core. It provides services that ensure that all 
aspects of the clinical projects maintain the quality critical for insuring compliance with the institutional 
oversight committees, federal regulations and GCPs. The responsibilities of the Monitoring component are 
divided into three categories: those pertaining to management of the Clinical Operations component (at Weill 
Cornell and at all other sites); those pertaining to the Regulatory Affairs component; and those pertaining to 
the Data Management and Analysis component. Monitoring will oversee the general activities of CORA, 
identify the responsibilities of CORA personnel involved in the clinical trial, and verify that all CORA staff 
is performing their specified study functions.  
 
The function of the monitor involves several aspects: (1) perform the initiation visit - this visit takes place 
just before the study starts and the objective is to make sure the site is equipped to initiate the study and 
understand all the research procedures; (2) perform the routine monitoring visit - routine visits are all those 
made as needed to check site compliance with the protocol and regulatory requirements; and (3) perform the 
closeout visit - this is the final visit when the study has been completed or terminated. During this visit final 
arrangements are made for correcting and retrieving study records, writing final reports, and retrieving or 
otherwise disposing of surplus drug and clinical supplies. The monitor ensures the following relating to study 
drug: accountability of the study drug; acceptable storage area; sufficient supplies throughout the study; the 
drug is only administered only to subjects who are eligible to receive it; the protocol specified dose(s) is 
appropriately given; the receipt, use, and return of the drug are controlled and documented adequately; and 
the disposition of unused drug at the study site complies with applicable regulatory requirement(s). 
 
13.3. Quality Assurance  
 
The trial site may be subject to review by the Institutional Review Board and/or to quality assurance audits 
performed by Independent Contractors and/or to inspection by appropriate regulatory authorities. It is 
important that the investigator(s) and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process. 
 
13.4. Study Termination and Site Closure  
 
The Department of Genetic Medicine reserves the right to discontinue the trial prior to inclusion of the 
intended number of subjects but intends only to exercise this right for valid scientific or administrative 
reasons. After such a decision, the Investigator must contact all participating subjects immediately after 
notification. As directed by the Department of Genetic Medicine, all study materials must be collected and 
all case report forms completed to the greatest extent possible. 
 
13.5. Records Retention 
 
To enable evaluations and/or audits from regulatory authorities or the Department of Genetic Medicine, the 
Investigator agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, case report forms and hospital records), all original signed informed consent, copies of all 
case report forms and detailed records of treatment disposition. The records should be retained by the 
Investigator according to the U.S. FDA’s 21 Code of Federal Regulations. If the Investigator relocates, 

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retires, or for any reason withdraws from the study, the study records may be transferred to an acceptable 
designee, such as another investigator, another institution, or to the Department of Genetic Medicine. The 
Investigator must obtain Department of Genetic Medicine’s written permission before disposing of any 
records. 
 
13.6. Data Safety Monitoring Committee 
 
Weill Cornell Medical College has a Data Safety Monitoring Board, but its policy is to monitor phase I and 
II trials only if the risk to subjects is “unusually high” or if there is potential for a conflict of interest for the 
investigators to monitor safety. Given that the proposed intervention for the pilot study is likely to be very 
safe, the study will be monitored by the PIs (Drs. Glesby and Kaner). They will review adverse events in 
aggregate in a blinded fashion on a monthly basis. Adverse events will be reported to the Weill Cornell IRB 
as per their guidelines. 
 
13.6.1 Adverse Event and Serious Adverse Event Submission Guidelines  
 
Expected and/or Unrelated Adverse Events. All adverse events that are considered expected and/or 
unrelated to the study drug will be recorded in a cumulative table by the site coordinator. In addition, a 
DGM-AE case report form must be completed by the site coordinator, signed by the site PI, and sent to the 
sponsor on a regular basis, to be agreed upon (e.g. every 2 months). The study site will submit their local 
cumulative adverse event tables to their local oversight agencies, as required by local reporting guidelines. 
The sponsor is responsible to submitting the cumulative tables to the central FDA and central WCMC IRB 
with the annual reports.  
 
Serious Adverse Events. All events that are considered serious, per the FDA’s definition of serious adverse 
events, will be reported to the sponsor within 24 hours of occurrence. Additional information will be sent to 
the sponsor as it becomes available. Each site will be responsible for completing a DGM-SAE form, 
including assessing intensity, and submitting it to the sponsor, with the signature of the site PI. The Principal 
Investigator must then review and sign the SAE form. The site is responsible for submitting any SAEs which 
are reportable to their local regulatory agencies per the guidelines outlined by the agency. The sponsor is 
responsible for submitting the reportable SAEs to the FDA and central WCMC IRB, within the timeframe 
outlined by each agency.   
 
13.7. Confidentiality of Information  
 
The Department of Genetic Medicine affirms the subject’s right to protection against invasion of privacy. 
Only a subject identification number, initials and/or date of birth will identify subject data retrieved by The 
Department of Genetic Medicine. However, in compliance with federal regulations, the Department of 
Genetic Medicine requires the investigator to permit the Department of Genetic Medicine’s representatives 
and, when necessary, representatives of the FDA or other regulatory authorities to review and/or copy any 
medical records relevant to the study. DGM will ensure that the use and disclosure of protected health 
information obtained during a research study complies with the HIPAA Privacy Rule, where this rule is 
applicable. The Rule provides federal protection for the privacy of protected health information by 
implementing standards to protect and guard against the misuse of individually identifiable health 
information of subjects participating in DGM-sponsored Clinical Trials. "Authorization" is required from 
each research subject, ie, specified permission granted by an individual to a covered entity for the use or 
disclosure of an individual's protected health information. A valid authorization must meet the 

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implementation specifications under the HIPAA Privacy Rule. Authorization may be combined in the 
Informed Consent document (approved by the Institutional Review Board/Independent Ethics Committee) or 
it may be a separate document, (approved by the Institutional Review Board/Independent Ethics Committee) 
or provided by the Investigator or Sponsor (without Institutional Review Board/Independent Ethics 
Committee approval). It is the responsibility of the investigator and institution to obtain such 
waiver/authorization in writing from the appropriate individual. HIPAA authorizations are required for U.S. 
sites only. 
 
13.8. Study Publication  
 
All data generated from this study are the property of DGM and shall be held in strict confidence along with 
all information furnished by DGM. Independent analysis, presentation, and/or publication of these data by 
any Investigator or any member of his/her staff are not permitted without prior written consent of the 
Department of Genetic Medicine. Written permission to the Investigator will be contingent on the review by 
DGM of the statistical analysis and manuscript and will provide for nondisclosure of DGM confidential or 
proprietary information. In all cases, the parties agree to submit all manuscripts or abstracts to all other 
parties 30 days prior to submission. This will enable all parties to protect proprietary information and to 
provide comments based on information that may not yet be available to other parties. 
 
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