Clinical trial NCT02416102
Conditions: COPD Chronic Bronchitis
Sponsor: University of Miami
Start date: 2016-03-31; Completion date: 2017-04-03
Enrollment: 31 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the effect of Losartan on cigarette smoke-induced lung injury in smokers and ex-smokers with and without chronic obstructive pulmonary disease (COPD).

Detailed description:

Arms: arm 1: 10 healthy non-smokers will receive 50 mg of Losartan for 4 consecutive weeks followed by 100 mg of Losartan for 4 consecutive weeks. arm 2: 10 smokers without COPD will receive 50 mg of Losartan for 4 consecutive weeks followed by 100 mg of Losartan for 4 consecutive weeks. arm 3: 10 ex-smokers with COPD will receive 50 mg of Losartan for 4 consecutive weeks followed by 100 mg of Losartan for 4 consecutive weeks.
Interventions: intervention 1: Losartan 50 mg intervention 2: Losartan 100 mg
Intervention descriptions: intervention 1: 50 mg Losartan taken orally once daily for 4 consecutive weeks. intervention 2: 50 mg Losartan taken orally twice daily for 4 consecutive weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 Effect of losartan on Mucociliary dysfunction in patients with Chronic 
Obstructive Pulmonary Disease (COPD) and Chronic Bronchitis 
 
 
PROTOCOL 
VERSION 5.0 
DATE: February 1, 2019 
NCT Number: NCT02416102 
 
 
 
Principal Investigator:  
Rafael Calderon Candelario, MD 
Division of Pulmonary, Allergy, Critical Care, and Sleep 
Medicine 
 
 
 
 
University of Miami School Of Medicine 
1321 NW 14th street suite 606-607 
Miami FL 33136 
Office: 305-243-2568 
 
 
Sponsor:  
 
 
Rafael Calderon Candelario, MD 
Division of Pulmonary, Allergy, Critical Care, and Sleep 
Medicine 
 
 
 
 
University of Miami School Of Medicine 
1321 NW 14th street suite 606-607 
Miami FL 33136 
Office: 305-243-2568 
 
 
 
Funding:  
 
 
Flight Attendant Medical Research Institute  
 
 
 
 
 
 
 
 


Objectives 
On this study we will test the hypothesis that inhibiting TGF-ß signaling with losartan in 
smokers and ex-smokers with chronic obstructive pulmonary disease (COPD) leads to 
increased Cl- conductance through CaCC in vivo by assessing nasal potential difference 
(NPD), a surrogate for potential differences in epithelia of the lower airways and therefore 
an appropriate outcome variable for a proof of concept clinical trial, avoiding the long trial 
durations typical for COPD studies. NPD measurements will be done in the untreated 
cohort and repeated while giving 50 mg and subsequently 100 mg losartan for 4 weeks 
each. The study design will allow intra-individual comparisons of the effects of losartan on 
BK channel function as measured by Cl- conductance through CaCC.  
 
 
Background 
Mucociliary clearance (MCC), a major airway host defense system, is dysfunctional in 
patients with smoking-associated lung diseases such as chronic bronchitis and COPD. 
Mucociliary dysfunction accounts for the clinical hallmarks of these diseases, namely 
chronic productive cough and recurrent respiratory infections. For appropriate MCC, motile 
cilia beat in a highly regulated airway surface liquid (ASL) that optimizes ciliary beat 
frequency (CBF) and efficiency and provides hydration to mucus. Airway epithelia use ion 
transport (absorption of Na+ and secretion of K+ and Cl-) to regulate ASL volume and 
composition to optimize MCC. 
We recently found that ATP-dependent, apical Cl- secretion and ASL fluid regulation 
depend on the activation of apically expressed large conductance, Ca2+ activated and 
voltage-dependent potassium (BK) channels. By secreting K+, apical BK channels provide 
a driving force for apical Cl- secretion via Cl- channels, forming a so-called apical loop 
current. This BK function is critically important since inhibition of BK channels reduces ASL 
volume significantly (in the presence or absence of functional CFTR), thus shifting the focus 
of ASL volume regulation upstream from Cl- channels to BK channels.  
Increased airway TGF-ß1 expression and signaling is common in active cigarette smokers 
and ex-smokers with COPD. Our preliminary data show that TGF-ß1 and cigarette smoke 
exposure decrease BK activity and cause ASL volume depletion. We therefore propose 
that smoke exposure, via TGF-ß1 production, leads to apical BK channel dysfunction to 
cause ASL volume depletion and mucociliary dysfunction in smokers and ex-smokers with 
COPD. BK rescue is associated with increased ASL volume and CBF. Therefore, restoring 
ASL volume requires BK channel rescue or inhibition of TGF-ß signaling. Clinically used 
Angiotensin II Receptor Blockers (ARBs) are known to inhibit TGF-ß signaling and present 
a “low-hanging-fruit” approach (medication already in clinical use) for intervention in 
COPD. In a murine model, losartan has previously been shown to attenuate cigarette 
smoke-induced lung injury and to rescue lung architecture. Our preliminary data suggest 
that losartan partially rescues BK channel function leading to increased ASL volume and 
CBF in airway epithelial cells exposed to smoke. The long-term goal of this study is 
therefore to evaluate the effect of currently available and clinically useful TGF-ß1 signaling 
inhibitors on mucociliary function in individuals with smoke-associated airway diseases, 
such as chronic bronchitis and COPD.  
 
 
 
 
 
 
 
Study Design 


This is a proof of concept, open label protocol to evaluate the effect of ARB on cigarette 
smoke-induced lung injury in smokers, ex-smokers with and without COPD, giving 50 mg 
and subsequently 100 mg losartan for 4 weeks  
 
Study Population  
  
Group I, COPD:  
 
10 ex-smokers not treated with ARBs with evidence of fixed airflow obstruction by 
pulmonary function testing (PFT), decreased DLco and with the clinical diagnosis of 
chronic bronchitis. 
 
Group II, non-COPD:  
20 active smokers not treated with ARBs without evidence of airflow obstruction by PFT 
and normal DLco but with the clinical diagnosis of chronic bronchitis. 
 
Group III, lung healthy, life-time non-smoker:  
20 never smokers not treated with ARBs without evidence of airflow obstruction by PFT, 
a normal DLco and no evidence of the clinical diagnosis of chronic bronchitis 
 
Groups will be appropriately balanced considering COPD stage, smoking status, lung 
function and age. 
 
Inclusion and Exclusion Criteria 
Inclusion criteria 
 
• 
Age between 35 and 75 years old 
 
• 
ex-smokers (>10 pack-years of cigarette smoking) not treated with ARBs and with 
evidence of fixed airflow obstruction by pulmonary function testing (PFT), decreased DLco 
and with the clinical diagnosis of chronic bronchitis. 
Or 
active smokers (>10 pack-years of cigarette smoking) not treated with ARBs without 
evidence of airflow obstruction by PFT and normal DLco but with the clinical diagnosis of 
chronic bronchitis. 
Or 
never smokers not treated with ARBs without evidence of airflow obstruction by PFT, a 
normal DLco and no evidence of the clinical diagnosis of chronic bronchitis 
 
 
• 
Ability to understand and willingness to sign consent documents 
 
Exclusion criteria:  
 
Current therapy with ACE inhibitor, intolerance to ARB 
 
Women of child bearing potential   
 
Regular use of NSAIDs or potassium supplementation, treatment with 
aliskiren, anticoagulation 
 
COPD exacerbation requiring treatment within 6 weeks 
 
Oral corticosteroid use within 6 weeks  
 
Significant hypoxemia (oxygen saturation <90% on room air), chronic 
respiratory failure by history (pCO2 > 45 mmHg) and forced expiratory volume 
in 1 second (FEV1) below 40%, clinical evidence of cor pulmonale 


 
Untreated arterial hypertension (systolic blood pressure >140 mm Hg, 
diastolic blood pressure > 90 mm Hg) 
 
Blood pressure less than 100 mm Hg systolic or 70 mm Hg diastolic at 
Screening visit and Visit 2. 
 
Cardiac, renal, hepatic (LFTs > 3x normal upper limit), neurological, 
psychiatric, endocrine or neoplastic diseases that are judged to interfere with 
participation in study 
 
History of renal artery stenosis 
 
Concomitant airway disorders other than COPD and chronic bronchitis, such 
as bronchiectasis and asthma (history and reversible airflow obstruction by 
ATS criteria) 
 
History of pulmonary malignancies, and any other malignancies in the last 5 
years  
 
History of thoracic surgery.    
 
Acute pulmonary exacerbation within 6 weeks from the Screening Visit. 
 
Subjects with no airflow obstruction by spirometry but with a decrease in DLco 
< 70% possibly indicating emphysema.  
 
Significant exposure to environmental tobacco smoke or atmospheric or 
occupational pollutants for the non-smokers group. 
 
Urine pregnancy positive test at the Screening Visit.  
 
Treatment arms 
Patients will be given four weeks of 50 mg of losartan daily and consequently an additional 
four weeks of 100 mg of losartan (divided in two doses of 50 mg twice daily). This higher 
losartan dose was used safely in other clinical trials (www.clinicaltrials.gov; search: losartan 
and COPD). At the end of each four-week period, participants will be re-evaluated. We will 
compare treatments using baseline measurements of each individual as his/her own control.  
 
Study Drug: 
Cozaar, the commercial form of losartan will be obtained from the UMHC Pharmacy and 
given to the subjects by the PI or study coordinators free of charges. FDA has granted IND 
exemption for this study. Study drug will be stored as per package instructions in a locked 
cabined on the research room at UMH 6th floor west room 607. Only the study team has 
access to this room. The storage area at the study center will be monitored by the staff for 
temperature consistency with the acceptable storage conditions.  
The Investigator is responsible for maintaining accurate study drug accountability records 
throughout the study. 
Each dispensing of study drug will be documented in the subject’s study records and in the 
drug accountability log. Subjects will return all unused study drug for drug accountability. 
Study drug will be destroyed at the clinical site as per the Institution regulations. 
 
Study Procedures 
Once informed consent is signed, the subjects will have an initial visit during which they will 
have a physical exam (including vital signs), complete study questionnaires and PFTs. All 
study subjects will undergo the following procedures during a single visit: 
 
History and physical examination will be performed including vital signs and body mass 
index (BMI) will be recorded.  
Laboratory Samples: Urine will be collected for a pregnancy test if applicable and blood 
test for CMP and CRP will be drawn, if results are not available within 6 months of the 
Screening visit. 


Urine cotinine levels will be measured at the time of study visits to assess smoking status 
(active or not). 
Questionnaires: Will collect basic demographic data, history of other medical conditions, 
detailed occupational history (focusing on environmental exposures), prior exposures 
(including biomass, smoke and air pollution), medications, chronic respiratory symptoms and 
exacerbation history. A second part will include standardized questionnaires (Appendix I) for 
subjects on the COPD group. Participants will have an objective assessment of cough and 
sputum production with the Breathlessness, Cough and Sputum Scale (BCSS). For patients 
with COPD we will record dyspnea with the Medical Research Council (MRC) dyspnea scale, 
co-morbidities with the Charlson co-morbidity index   and health-related quality of life with the 
St. George’s Respiratory Questionnaire and the COPD assessment test (CAT) for accurate 
COPD staging  
6-Minute walk test (6MWT) will be done for participants on the COPD group as per 
American Thoracic Society guidelines.(Apendix II) 
Pulmonary function testing will be performed according to American Thoracic Society 
recommendations. Participants will be asked to refrain from using short-acting bronchodilator 
drugs for at least 4 hours before testing and not take any long acting bronchodilator in the 
morning. Spirometry will be repeated 15 min after the administration of 180 µg (two puffs) of 
albuterol from an MDI through a spacer. Lung volumes and DLco will be performed following 
ATS recommendations. Height, weight and oxygen saturation will be measured prior to these 
tests. Since smoking has both biologic and technical effect on DLco  and there is not yet a 
appropriate method of adjusting pulmonary function indices for the effect of smoking, the DLco 
Normal Range (Low 95th percentiles of percent predicted) criteria for this study is ≥70% of 
Crapo predicted values . 
 
BODE score will be calculated from BMI, FEV1, 6-MWT and the MRC dyspnea scale. 
NPD measurement will be performed according to standard procedures. In this aim, we will 
use one side of the nose for the evaluation of the function of CFTR and CaCC by measuring 
the potential differences by initial blocking ENaC with amiloride, then using chloride free 
solution and isoproterenol to evaluate CFTR function, followed by ATP to evaluate CaCC 
function. In the other nostril, the same experiment will be repeated as mentioned above, 
except that after blocking ENaC with amiloride and perfusion with chloride-free solution the 
CFTR will not be stimulated with isoproterenol, but ATP will be used to maximize the CaCC 
signal. We will adjust the way of measuring the NPD for aim 2.2 depending of the results in 
aim 2.1.  
TGF-ß and citokines will be measured using Leukosorb, a noninvasive sampling method 
of the nasal mucosa as previously reported. In addition, we will obtain a small amount of nasal 
epithelial cells to measure TGF-ß by qPCR. 
 
Study Visits:  
V1 (Screening Visit): This will be a single visit for the purpose of determining 
eligibility, obtaining informed consent, and recording the necessary data will include: 
 
Assessment of general health status and physical examination (incl. vital 
signs) 
 
Urine pregnancy test if indicated (female, child bearing age) 
 
Spirometry pre- and post-bronchodilators, DLCO, lung volumes 
 
Pulse oximetry  
 
Review of laboratory values, or if not available: venous blood sampling to 
assess for renal and liver abnormalities (then the measurements will be done 
within a week in an additional visit), CRP 
 
If inclusion criteria fulfilled and no exclusion criteria found: 
• 
Enrollment   


• 
Completion of respiratory questionnaires (COPD only) 
• 
Six minute walk test (COPD only) 
• 
BODE index calculation 
 
 
V2 (week 4): This visit (and the two following ones) will only done for the groups not 
treated with any ARBs. This visit will occur 4 weeks (± 4 days) after V1. 
 
We will again review laboratory values (CMP, CRP), repeat urine pregnancy 
test if indicated (female, child bearing age). 
 
The following procedures will be executed: 
• 
Completion of respiratory questionnaires (COPD only) 
• 
Six minute walk test (COPD only) 
• 
BODE index calculation 
 
NPD measurement followed by nasal fluid recovered by Leukosorb 
filter paper  and nasal cell collection for TGF-ß 
• 
Subjects will be provided with a 4-week supply of 50 mg losartan for 
daily use (first dose given in clinic; observation with blood pressure 
monitoring for 2 hours).  
 
V3 (week 5 ± 4 days):  
Telephone visit to follow up on symptoms and tolerability of medication. 
 
V4 (week 8 ± 4 days):  
 
The following procedures will be executed: 
• 
Monitor for adverse events. 
• 
Completion of respiratory questionnaires (COPD only) 
• 
Six minute walk test (COPD only) 
• 
Venous blood sampling to assess for renal and liver abnormalities and 
CMP, CRP 
• 
Urine pregnancy test (if applicable) 
• 
BODE index calculation 
 
Nasal fluid recovered by Leukosorb filter paper and nasal cell 
collection for TGF-ß 
• 
Subjects will be provided with a 4-week supply of 50 mg losartan for 
twice daily use (100 mg)  
 
V5 (week 9 ± 4 days):  
Telephone visit to follow up on symptoms and tolerability of medication. 
 
V6 (week 12 ± 4 days) or Early Termination Visit:  
 
We will draw laboratory (CMP, CRP). Repeat pregnancy test if indicated 
(female, child bearing age). 
 
The following procedures will be executed: 
• 
Monitor for adverse events. 
• 
Completion of respiratory questionnaires(COPD only) 
• 
Venous blood sampling to assess for renal and liver abnormalities and 
CMP, CRP 
• 
Urine pregnancy test (if applicable) 
• 
Six minute walk test (COPD only) 


• 
BODE index calculation 
 
NPD measurement followed by nasal fluid recovered by Leukosorb 
filter paper and nasal cell collection for TGF-ß 
 
Unscheduled visit (up to 2 visits) will apply if there is a need to repeat study 
procedures. 
Subjects are allowed to be re-screened one time as per PI discretion.  
 
Specimen Banking 
Not applicable. 
 
 
Data Management 
Data collected will include demographics, clinical symptoms, health-related quality of life, and 
pulmonary function test data. Samples to be collected include NPD measurement followed by 
nasal fluid and cell collection for TGF-ß. We will obtain blood for safety reasons (liver and 
renal function) and for evaluation of an inflammatory marker. No personal identifiers will be 
collected and each patient’s data will be coded. 
 
Safety Reporting 
DSMB: the PI and the co-investigators will continuously monitor the study for side effects. 
If any AE or SAE occur, the physicians will assess the event and report them to the appropriate 
authorities if needed as per Good Clinical Practice. Subjects might be withdrawn from the 
study if they experience intolerance to the study medication and/or the NPD testing. 
Furthermore, a COPD exacerbation will be a reason for subject withdrawal. We expect few 
dropouts for exacerbation given the three-month duration of the study. IND: because this study 
will use a medication released on the market but not for this indication, we will file an IND with 
the FDA for use of losartan in this population. Given our experience with INDs and the long 
experience with use of losartan, we do not believe that this will be a hurdle for the trial.  
 
Assessment of efficacy 
N/A 
  
Statistical analysis  
Differences between groups and doses will be analyzed with regression analysis. Multivariate 
analysis will be done to evaluate differences in the tests results between different groups and 
correlations between different measures will be examined using the Pearson’s correlation 
coefficient. Biostatistics Collaboration and Consulting Core services will be used on a fee for 
service 
 
Risks to Subjects 
Potential Risks: All procedures are performed during this study are routine clinical procedures 
and are associated with minimal risks.  
Pulmonary Function Testing is a routine clinical procedure with few risks. Patients are 
coached to make repeated forceful breathing efforts. The subjects might have chest soreness. 
Unusually, subjects may become lightheaded during these efforts. The risk is minimized by 
having the PFT done in a sitting position.  
NPD measurement: is a non-invasive method with minor risks, which are swallowing and 
aspiration of the solution used for rinsing the nose. Having the patient bending the head 


forward will minimize this risk, so that the solution is dripping out of the nose and not in the 
pharynx. The perfusion rate will be set at 5 ml/min, indicating that the nose will be rinsed with 
very low volumes. Even in case of accidental swallowing or aspiration, there are limited risks 
of a severe reaction, even in a respiratory-wise impaired individual. Amiloride is a diuretic and 
can, when given in a higher dose, increase urine production, which is not anticipated here as 
the used dose is low and systemic absorption is not anticipated. Isoproterenol is a beta 
mimetic and can lead to tachycardia, hypertension and migraine. The dose used is low and 
the systemic absorption negligible. Other potential side effects include nosebleed, runny nose 
and coughing. For the study, a subcutaneous insertion of a butterfly needle is required, which 
brings a minimal risk of bruising, bleeding and infection.  
Nasal fluid and cell sampling: this procedure is routine and is sometimes associated with an 
unpleasant feeling due to the fluid, minimal risk of aspiration of part the 5 ml of sterile saline 
solution, and coughing. To prevent this from happening, the head of the patient will be bend 
forward during the collection, so the fluid will be absorbed by Leukosorb and not get into the 
pharynx where it can be swallowed or aspirated. Cell sampling can cause a mild discomfort 
and a mild nosebleed.  
Phlebotomy: The risks from blood draw from a vein are minimal but include discomfort at the 
site of puncture, possible bruising around the puncture site, rarely an infection, and 
uncommonly, fainting from the procedure. Blood draws will be performed with as much care 
as possible to minimize local complications. Subjects will be sitting during the process for their 
comfort and will be asked to not look directly at the site of blood draw.   
Treatment with losartan: Cozaar  is an FDA-approved ARB widely prescribed for treatment 
of hypertension, heart failure, and for renal protection in patients with diabetes. The doses 
proposed in this study are well tolerated by non-hypertensive patients without significant effect 
on blood pressure. The most common side effects are fatigue and dizziness.  Serious adverse 
events that are rare include angioedema, hypotension, renal dysfunction or failure, blood 
dyscrasias, hepatitis, or rhabdomyolysis (clinical assessment of muscle pain). The following 
should lower the risks to the subjects: The first dose of medication will be administered in the 
clinic and the patient observed for two hours with blood pressure monitoring every 30 minutes. 
If systolic blood pressure falls below 100 mmHg, the patient will be discharged from the study 
and dosing not repeated. 
If the patient has symptomatic hypotension, the patient will be put into a supine position until 
recovered. If needed additional interventions will be undertaken (including button limited to 
fluid administration) according to the supervising physician’s instructions. 
Subjects with hyperkalemia, renal dysfunction, or who are taking potassium supplements will 
not be enrolled into the study. Participants will be given at the screening visit written 
descriptions of potential side effects and participants wiil be instructed to contact the study 
doctor if any new symptoms occur. Skin rashes, palpitations or other moderate or severe 
adverse events (interference with usual daily activities) without other clear explanation should 
warrant immediate cessation of treatment and notification of study personnel.  
Six Minute Walk Test: the participant walks for six minutes and the distance traveled is 
measured. As with any exercise test, there is a theoretical risk but in multiple clinical trials 
conducted at our site, we had no adverse events. Risks are minimized by medical supervision 
and trained medical personnel.   
Questionnaires, Health History and Physical Examination No significant physical risks arise 
from these procedures. There is always the risk of psychological distress and breach of 
confidentiality. In order to minimize this risk, electronic medical records are held in HIPAA 
compliant password-protected databases, and written information is stored in locked files or 
file-rooms when not attended by study personnel. Filling out the questionnaires could cause 


psychological distress. Participant will be informed to escape questions if he/she feels 
uncomfortable or upset doing that.  
Adverse Event Monitoring 
Subjects will be carefully monitored for adverse events (AEs) and serious adverse events 
(SAEs). Adverse events will be assessed in terms of their seriousness, severity, and 
relationship to the administration of Losartan 
 
Definitions 
Adverse Event (AE): An AE is any untoward medical occurrence in a clinical study participant 
administered with a pharmaceutical product. The AE does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not considered related to the 
medicinal product.  
Unexpected AE: is any adverse drug event, which is not consistent with the current Losartan 
US Package Insert. 
Serious Adverse Event (SAE): A SAE is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
• requires unanticipated in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability or incapacity 
• results in a congenital anomaly or birth defect 
• any significant medical event as per the investigator’s discretion 
 
Relationship of Adverse Event to Losartan 
The assessment of the relationship of an AE to the administration of study drug is a clinical 
decision based on all available information. An assessment of ‘No’ would include choices of 
“not related” or “unlikely related” in the following cases: 
1. The existence of a clear alternative explanation, or 
2. Non-plausibility (clearly an unrelated circumstance). 
An assessment of ‘Yes’ includes choices of “possibly related or “related” and indicates that 
there is a reasonable suspicion that the AE is associated with the use of the investigational 
drug. 
Factors to be considered in assessing the relationship of the AE to study drug include: 
• The temporal sequence from drug administration: The event should occur after the drug is 
given. The length of time from drug exposure to event should be evaluated in the clinical 
context of the event. We will consider a significant time interval up to  
• Underlying, concomitant, intercurrent diseases: Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other disease 
the subject may have (i.e. a COPD exacerbation) 
• Concomitant medication or treatment: The other drugs the subject is taking or the treatment 
the subject receives should be examined to determine whether any of them might be 
suspected to cause the event in question 


• Concurrent study procedures: Study procedures should also be considered as possible 
causes of an AE.  
In this study, the investigator will make a separate and independent assessment of every AE’s 
relationship not just to the study drug, but also to concurrent study procedures and to the 
subject’s pre-existing medical condition(s). 
A laboratory test abnormality considered clinically relevant, e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an AE. Each event should be 
described in detail along with start and stop dates, severity, relationship to investigational 
product, action taken and outcome. 
Each AE should be followed up until resolution or stabilization as determined by the 
investigator. 
Severity of the Adverse Event 
The severity of AEs, except for AEs for exacerbations, should be graded as follows: 
• Mild – usually transient in nature and generally not interfering with normal activities 
• Moderate – sufficiently discomforting to interfere with normal activities 
• Severe – prevents normal activities. 
 
 
Potential Benefits to Subjects 
Although there will be no direct benefit for subjects taking part in this study, the researcher 
may learn more about COPD. The study has the potential for an overall benefit in advancing 
knowledge of the disease studied. Because the study drug is well tolerated, the risks to 
subjects are reasonable in relation to the anticipated benefits of knowledge gained. 
 
Vulnerable Populations 
COPD is more common among men than women, although the prevalence is increasing in 
women. COPD is rare among African-Americans. Less information is available about 
Hispanics, which are a heterogeneous group. The planned accrual of minority groups reflects 
the prevalence of COPD in our region in South Florida.  
 
Setting 
The Human Research Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep 
Medicine, is located on the 6th floor of the Doctor’s Office West Building at the University of 
Miami on the Medical School Campus. It has 2,200 square feet of space for evaluation of 
patients for pulmonary research. This space is equipped with spirometers, a nSpire® HDpft 
plethysmograph including DLco measurement, , blood pressure machines, pulseoximeters, 
12-lead ECG machine, ACLS equipment and setup for 6-minute walk tests, including O2 tanks, 
an HP 78352A monitor for heart rate and ECG monitoring (3 lead ECG cables). Other 
equipment includes a DeVilbiss nebulizer, Ultrasonic nebulizer and - 20°C freezer. 
We have the ability to draw blood, prepare specimens for laboratory analysis. Our staff is BLS, 
GCP, OSHA and IATA certified and follows UN 1845 and 3373 regulation for the guidelines 
of shipping biological materials. Physicians are BLS and ACLS certified. We have a fully 
functional nasal potential difference (NPD) measurement unit (use certified by Cystic Fibrosis 
Foundation Therapeutic Development Network: CFF TDN). Dr. Schmid has an office within 
this setting.  
 


Recruitment Methods 
Forty subjects will be enrolled from two outpatient clinics run by members of the Division of 
Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, at the 
University of Miami Miller School of Medicine considering 20% of screening failure to enroll 
30 patients on the treatment phases. Collectively, ~400 patients with COPD are seen at the 
two sites annually. Smokers without COPD and lung-healthy lifetime non-smokers will be 
recruited from the pre-operative clinics at the University of Miami Hospitals and Clinics.  
First, the subjects will be briefed about the study and if interested will be invited to come on a 
separate day with ample time just to discuss the study objectives, procedure risks and benefits 
with the study investigators. The study and informed consent form will be approved by the 
University of Miami’s IRB. Subjects will have sufficient time to meet with the PI or co-
investigators to address all their questions about the research and take the informed consent 
home to discuss with family and possibly PCP.  
Subjects will be paid $100.00 for each completed study visit and $ 25.00 for each of the phone 
calls.  The total amount you could receive for participating in all of the study visits would be 
$450.00. Unscheduled visit if applicable will be paid $50.00 
 
Removal of Subjects from Study 
A subject withdrawal is defined as a discontinuation from the study for any reason. Subjects 
may withdraw or be withdrawn from this study for the following reasons: 
• At their own request or at the request of their authorized representative at any time 
for any reason 
• If, in the investigator's opinion, continuation in the study would be detrimental to the 
subject's well-being 
Also subjects must be withdrawn from the study for the following reasons: 
• Subjects with an occurrence of a concomitant disease, or any medical condition 
which, either because of its severity or duration or necessary change in treatment, 
contravenes the condition of the study or puts the patient at unnecessary risk or harm. 
• Subjects with an occurrence of an AE/SAE which in the opinion of the investigator 
and/or subject requires termination of treatment. For example, skin rashes, 
palpitations or other moderate or severe adverse events (interference with usual daily 
activities) without other clear explanation should warrant immediate cessation of 
treatment and notification of study personnel. 
• Subjects who are noncompliant with the protocol per the investigator’s discretion 
•  Pregnancy. If a patient becomes pregnant during administration of the drug, 
treatment should generally be discontinued.  
• Severe COPD exacerbation during the study. 
Subjects who terminate the clinical study prematurely, either at their own request or on the 
recommendation of the clinical investigator, will be considered early terminations. Subjects 
who withdraw from the study will be replaced. 
Subjects who are discontinued from the study will be requested to return for Early 
Discontinuation and perform procedures as for visit 6  
 
Provisions to Protect the Privacy Interests of Subjects 
All patient data will be stored in locked file cabinets or a room that is locked when unattended. 
All electronic data will be secured using password protection. Access to these data will be 
restricted to the research staff only. Because this proposal is a proof-of-principle study, a 
formal data and safety monitoring board will not be created.  
 
Consent Process 


The informed consent document (in English and Spanish) and the protocol will be submitted 
to the University of Miami’s Institutional Review Board for review and approval. Subjects 
interested in volunteering for the study will have a lengthy discussion with the investigators 
about the risks and benefits of their participation. Patients need to agree to practice effective 
pregnancy prevention for the duration of the study. 
 
Direct Access To Source Data/Documents  
Qualified representatives of regulatory agencies, internal auditors or monitors will have the 
right, both during and after this study, to conduct inspections and to audit and review medical 
records and/or study documents (CRFs, source data/documents, etc.) pertinent to the clinical 
study as permitted by the regulations (21 CFR 312.58; 312.68, ICH-GCP E6; 6.10).  
 
Quality Control & Quality Assurance 
 
Monitoring of the study will be provided through the University of Miami’s Office of Clinical 
Research Operations and Regulatory Support (CRORS).  
Medical Monitoring: the PI and the co-investigators will continuously monitor the study for side 
effects. If any AE or SAE occur, the physicians will assess the event and report them to the 
appropriate authorities if needed as per federal regulations, IRB policies and procedures and 
ICH-Good Clinical Practice. Subjects might be withdrawn from the study if they experience 
intolerance to the study medication and/or the NPD testing. Furthermore, a COPD 
exacerbation will be a reason for subject withdrawal. We expect few dropouts for exacerbation 
given the three-month duration of the study.  
 
Ethics 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with the GCP and applicable regulatory 
requirements.  
 
The clinical protocol will be submitted to and approved by the UM IRB and the FDA, and will 
not be initiated until written notification of approval of this study has been received.  
 
IND: because this study will use a medication released on the market but not for this indication, 
we will file an IND with the FDA for use of losartan in this population. Given our experience 
with INDs and the long experience with use of losartan, we do not believe that this will be a 
hurdle for the trial.  
 
 
Record Keeping 
Accurate and complete study records will be maintained and kept at Iron Mountain for a 
minimum of 10 years. 
 
Publication policy 
 
The results of this research will be disseminated to the scientific community. These results 
will include results of primary study outcomes and secondary analyses. Priorities in 
selecting journals and forums for publications submission will be given to peer-reviewed 
journals as well as presentations and publications of abstracts at national and international 
scientific meetings. All individuals who have made substantial intellectual, scientific and 
practical contributions to this research protocol and the manuscript should, where 


possible, be credited as authors; all individuals credited as authors should deserve that 
designation.  
 
 


References  
 
1. Takizawa, H., et al., Increased expression of transforming growth factor-beta1 in 
small airway epithelium from tobacco smokers and patients with chronic obstructive 
pulmonary disease (COPD). Am J Respir Crit Care Med, 2001. 163(6): p. 1476-83. 
2. Konigshoff, M., N. Kneidinger, and O. Eickelberg, TGF-beta signaling in COPD: 
deciphering genetic and cellular susceptibilities for future therapeutic regimen. Swiss 
Med Wkly, 2009. 139(39-40): p. 554-63Celli, B., et al., Symptoms are an important 
outcome in chronic obstructive pulmonary disease clinical trials: results of a 3-month 
comparative study using the Breathlessness, Cough and Sputum Scale (BCSS). 
Respir Med, 2003. 97 Suppl A: p. S35-43. 
3. Knowles, M.R., A.M. Paradiso, and R.C. Boucher, In vivo nasal potential difference: 
techniques and protocols for assessing efficacy of gene transfer in cystic fibrosis. 
Hum Gene Ther, 1995. 6(4): p. 445-55. 
4. Middleton, P.G., et al., Nasal application of the cationic liposome DC-Chol:DOPE 
does not alter ion transport, lung function or bacterial growth. Eur Respir J, 
1994.7(3):p.442-5. 
5. Solomon, G.M., et al., An international randomized multicenter comparison of nasal 
potential difference techniques. Chest, 2010. 138(4): p. 919-28. 
6. Soltani, A., et al., Vessel-associated transforming growth factor-beta1 (TGF-beta1) is 
increased in the bronchial reticular basement membrane in COPD and normal 
smokers. PLoS One, 2012. 7(6): p. e39736. 
7. Mahler, D.A. and C.K. Wells, Evaluation of clinical methods for rating dyspnea. 
Chest, 1988. 93(3): p. 580-6. 
8. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med, 
2002. 166(1): p. 111-7. 
9. Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J 
Respir Crit Care Med, 1995. 152(3): p. 1107-36. 
10. Lung function testing: selection of reference values and interpretative strategies. 
American Thoracic Society. Am Rev Respir Dis, 1991. 144(5): p. 1202-18. 
11. Celli, B.R., et al., The body-mass index, airflow obstruction, dyspnea, and exercise 
capacity index in chronic obstructive pulmonary disease. N Engl J Med, 2004. 
350(10): p. 1005-12. 
12. Ciprandi, G., et al., Cytokines evaluation in nasal lavage of allergic children after 
Bacillus clausii administration: a pilot study. Pediatr Allergy Immunol, 2004. 15(2): p. 
148-51. 
13. Sogut, A., et al., Regulatory-T, T-helper 1, and T-helper 2 cell differentiation in nasal 
mucosa of allergic rhinitis with olive pollen sensitivity. Int Arch Allergy Immunol, 
2012. 157(4): p. 349-53 
  
 
 


 
 
Appendix I 
 
For all 
subjects 
For subjects who are not on ARBs treatment 
 
Visit 1 
Screening 
Visit 2g 
4 weeks (± 
4 days) 
after V1 
Visit 3 
Phone 
Call  
1 weeks (± 
4 days) 
after V2 
Visit 4 
8 weeks (± 
4 days) 
after V2 
Visit 5-
Phone 
Call 
 9 weeks 
(± 4 days) 
after V2 
Visit 6 
12 weeks 
(± 4 days) 
after V2 
Informed Consent 
 
X 
 
 
 
 
 
Assessment of health status 
X 
X 
 
X 
 
X 
Medical History  
X 
 
 
 
 
 
Occupational history 
X 
 
 
 
 
 
Smoking History 
X 
 
 
 
 
 
Concomitant medication 
X 
 
X 
 
X 
 
Urine cotinine test 
X 
X 
 
X 
 
X 
AE and SAE 
 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
 
X 
 
X 
Vital signs 
X 
X 
 
X 
 
X 
Urine pregnancy testa 
X 
X 
 
X 
 
X 
β−HGCb 
X 
X 
 
X 
 
X 
Complete Pulmonary function 
test pre and post 
X 
 
 
 
 
 
Renal and liver blood testc 
X 
X 
 
X 
 
X 
CRPd 
X 
X 
 
X 
 
X 
Respiratory Questionnairese 
X 
X 
 
X 
 
X 
6 Minute Walk Testf 
X 
X 
 
X 
 
X 
NPD measurement 
 
X 
 
X 
 
X 
Nasal fluid for TGF -β  
measurement 
X 
X 
 
X 
 
X 
Drug Dispensation 
(losartan 50 mg or 100 mg ) 
 
X 
 
X 
 
 
Drug Compliance 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
a- Only for female   
b- If urine pregnancy test is positive 
c- Only if results are not available on the last 6 month 
d- Only if results are not available on the last 6 month 
e- Respiratory Questionnaire (BCSS, MRC, Charlson co-morbidity index, SGRQ, CAT) will be 
performed at each visit before any study procedure (COPD group only) 
f- 
6MWT will be performed for participants on the COPD group only 
g- Visit 1 and 2 could be combined if the subject is not on ARBs treatment and has renal and 
liver blood test results available on the last 6 month. 
 
 


 
 
 
Appendix II 
Questionnaires used on this protocol could be found at the following links: 
  
St George’s RespiratoryQuestionnaire: 
http://www.thoracic.org/assemblies/srn/questionaires/sgrq.php 
 
COPD assessment test (CAT) 
http://www.thoracic.org/assemblies/srn/questionaires/copd.php 
 
Medical Research Council (MRC) dyspnea scale 
http://www.thoracic.org/statements/resources/archive/rrdquacer.pdf 
 
Breathlessness, Cough and Sputum Scale (BCSS). 
http://journal.publications.chestnet.org/data/Journals/CHEST/22001/2182.pdf 
 
 
 


 
Appendix III 
Changes from version 1.2 of the protocol 
 
 
1.Version and date to the protocol were updated 
2.The address for the PI and the study site were updated. 
3. The address for Drug storage was updated to at UMH 6th floor west room 607. 
4. to clarify footnote “a” on the Appendix I : “child bearing age” was deleted from the footnote 
of Urine pregnancy test. Woman in child bearing age were excluded from the study