Conditions: Emphysema
Keywords: COPD emphysema HRCT losartan
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 220
Healthy volunteers: no

Brief summary:
A randomized, parallel, placebo controlled trial to evaluate the effect of 100mg/day losartan on the progression of emphysema as measured by quantitative HRCT compared to placebo

.

Detailed description:
This is a trial designed to test if a treatment, losartan, may decrease the progression of Chronic Obstructive Pulmonary Disease (COPD). Losartan is an angiotensin receptor blocking agent, commonly used as an antihypertensive agent, which has been shown to alter cardiac remodeling after myocardial infarction and renovascular remodeling in diabetes-mellitus. In this trial participants with mild to severe COPD, with Computed Tomography (CT) evidence of emphysema (5-35% of voxels with \< -950 Hounsfield Units), will be randomly assigned to receive 100mg/day of losartan or placebo for 48 weeks. The primary outcome measure will be the rate of progression of emphysema, quantified as the percent of lung voxels with a density less than -950 HU as measured by High Resolution CT (HRCT, from baseline to 48 weeks.

Arms:
arm 1: At randomization participants will start with a dose of 50mg (one capsule) once a day for 2 weeks. If this dose is well tolerated and systolic BP is \>90 mm Hg and diastolic BP is \> 60 mm Hg, the dose will be increased to 100 mg (2 capsules) once a day for the remaining 46 weeks. arm 2: At randomization participants will start with a dose of one capsule (inactive) once a day for 2 weeks. After two weeks, if systolic BP is \>90 mm Hg and diastolic BP is \> 60 mm Hg, the dose will be increased to 2 capsules once a day for the remaining 46 weeks.

Interventions: intervention 1: Losartan intervention 2: Placebo
Intervention descriptions: intervention 1: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated intervention 2: one capsule per day for two weeks, followed by two capsules per day for 46 weeks

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
Johns Hopkins Clinical Trials Coordinating Center  
Protocol Leadership Group  
Pulmonary Trials Cooperative (PTC) 
Grant number: 1U01HL128951 
 
 
 
Losartan Effects on Emphysema 
Progression (LEEP) 
 
 
 
Protocol 
Version 2.2 
17 May 2018
 
 


LEEP Protocol Version 2.2 
Document history │ ii
 
Document history 
 
 
Version 1, 10 Nov 2015 
Version 1.1, 13 Nov 2015 
Version 1.2, 7 Mar 2016 
Version 1.3, 30 May 2016 
Version 2, 15 Sep 2016 
Version 2.1, 11 Sep 2017 
Version 2.2, 17 May 2018 
 
 
 
 
 
 


LEEP Protocol Version 2.2 
Abstract │ iii
 
Abstract 
 
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United 
States. Despite advances in pharmacotherapy targeting relief of airflow obstruction, no therapy 
except for smoking cessation has been shown to slow disease progression. Evaluation of 
treatments that modify the progression of emphysema have been limited by the requirement for 
large numbers of participants and extended follow-up to establish efficacy by effects on lung 
function or mortality. This trial is testing a treatment that may modify the progression of COPD 
by using losartan, an angiotensin receptor blocker. Preliminary evidence in humans and animals 
suggests that this drug is effective in blocking key pathways thought to be important in the 
genesis of COPD.  
 
Losartan is used as an antihypertensive agent, but is also widely used to alter cardiac 
remodeling after myocardial infarction and renovascular remodeling in diabetes mellitus. 
Losartan inhibits the effect of TGF-beta on the lung, inhibits apoptosis, and has anti-oxidant 
properties; all of these modes of action may be effective in altering the pathogenic mechanisms 
that promote progression of COPD. Currently, losartan is being tested as a disease-modifying 
agent in Marfan's syndrome, a genetic disorder associated with an increased risk of 
emphysema; we postulate that it may also be effective in typical smoking-induced emphysema 
as well. In particular, we want to evaluate whether losartan treatment modifies the structural 
progression of COPD, particularly emphysema, and whether this is reflected in improved clinical 
outcomes.  
 
This is a placebo-controlled, randomized clinical trial with a 48-week follow-up. Two hundred 
and twenty people with COPD and Computed Tomography evidence of emphysema will be 
assigned to losartan 100 mg daily or placebo. The primary outcomes will be an intermediate 
end-point reflecting anatomic lung remodeling, i.e. quantitative measures of emphysema by 
High Resolution Computed Tomography (HRCT). Secondary outcomes that are clinically 
relevant will include measures of lung function, respiratory symptoms and quality of life.  


LEEP Protocol Version 2.2  
Contents │ iv
 
Contents 
 
Document history .................................................................................................................... ii 
Abstract .................................................................................................................................. iii 
1.  Introduction ....................................................................................................................... 6 
1.1.  Title… ....................................................................................................................... 6 
1.2.  Sponsor and support ................................................................................................ 6 
1.3.  Investigators and study centers ............................................................................... 6 
1.4.  Background and significance ................................................................................... 6 
2.  Study design ..................................................................................................................... 8 
2.1.  Hypotheses .............................................................................................................. 8 
2.2.  Study aims ............................................................................................................... 8 
2.3.  Trial design /Schema ............................................................................................... 8 
3.  Eligibility criteria .............................................................................................................. 10 
3.1.  Inclusion criteria: .................................................................................................... 10 
3.2.  Exclusion criteria: ................................................................................................... 10 
4.  Summary of study visits .................................................................................................. 12 
4.1.  Study data collection schedule .............................................................................. 15 
5.  Outcomes ........................................................................................................................ 16 
5.1.  Primary outcome measures ................................................................................... 16 
5.2.  Secondary outcome measures .............................................................................. 16 
5.3.  Other data .............................................................................................................. 16 
6.  Study treatments ............................................................................................................. 18 
6.1.  Description of study treatments ............................................................................. 18 
6.2.  Side effects of drug ................................................................................................ 18 
6.3.  Handling of drug ..................................................................................................... 21 
6.4.  COPD treatment .................................................................................................... 21 
7.  Specific procedures ........................................................................................................ 22 
7.1.  HRCT scans ........................................................................................................... 22 
7.2.  Pulmonary Function Testing .................................................................................. 22 
7.3.  Randomization ....................................................................................................... 23 
7.4.  Phlebotomy and biospecimens .............................................................................. 23 
7.5.  Unmasking ............................................................................................................. 23 
7.6.  Treatment termination ............................................................................................ 24 


LEEP Protocol Version 2.2  
Contents │ v
 
8.  Analysis plan ................................................................................................................... 25 
8.1.  Primary analysis ..................................................................................................... 25 
8.2.  Secondary analyses ............................................................................................... 26 
8.3.  Exploratory analyses .............................................................................................. 26 
8.4.  Subgroups of interest ............................................................................................. 26 
8.5.  Sample size ........................................................................................................... 27 
9.  Protection of human subjects .......................................................................................... 29 
9.1.  Recruitment and consent procedures .................................................................... 29 
9.2.  Potential risks and procedures to minimize risk to the participants ........................ 29 
9.3.  Data and safety monitoring plan ............................................................................ 31 
9.4.  Data confidentiality ................................................................................................. 32 
10. Acronyms ........................................................................................................................ 34 
11. Literature cited ................................................................................................................ 35 
  
 


LEEP Protocol Version 2.2 
Introduction │ 6
 
 
Confidential, not for attribution or citation. 
 
1. Introduction 
1.1. Title 
Losartan Effects on Emphysema Progression (LEEP) 
 
1.2. Sponsor and support 
Funded and sponsored by the National Heart, Lung, and Blood Institute (NHLBI) under the 
Pulmonary Trials Cooperative (PTC).  
 
Organization of the Pulmonary Trials Cooperative (PTC). 
The organizational structure of the PTC is outlined in the RFA-HL-15-015 and RFA-HL-15-016 
which outlines the responsibilities of each of the components. In brief, an Operations Committee 
(OC) oversees the organization of the cooperative which consists of a Network Management 
Organization (NEMO) and multiple Protocol Leadership Groups (PLG). The PLGs (one of which 
is the LEEP trial) will provide clinical and data coordination for each of the trials while the NEMO 
is charged with organization, communications, monitoring, quality control, and distribution of 
capitation payments and study drug. 
 
1.3. Investigators and study centers 
Network Chair 
David Center  
 
 
Boston University 
  
PLG – Principal Investigators 
Robert Wise  
 
 
Johns Hopkins University 
Janet Holbrook 
 
 
Johns Hopkins University 
 
Computed Tomography Analysis Core 
Robert Brown  
 
 
Johns Hopkins University 
 
 
 
Participating Centers 
To be determined by the NEMO of the PTC 
 
1.4. Background and significance 
COPD is a heterogeneous disease that is associated with increasing morbidity and mortality in 
the United States1. Current treatments for COPD consist mainly of bronchodilators and anti-
inflammatory agents, which are used for treatment of symptoms and prevention of 
exacerbations. Although smoking cessation slows the progression of the disease2 3, there are no 
pharmacologic agents that clearly modify disease progression. Angiotensin receptor blockers 
(ARBs) are potential agents to modify the progression of COPD. In a retrospective database 
study, Mancini found that ARB-treated COPD patients had reduced mortality and COPD 


LEEP Protocol Version 2.2 
Introduction │ 7
 
 
Confidential, not for attribution or citation. 
 
hospitalization regardless of cardiovascular risk factors4 5. Andreas and colleagues tested 
whether 4 months of irbesartan treatment would increase skeletal muscle strength in 30 patients 
with COPD. Although there was no effect on peripheral or respiratory muscle strength, the 
FEV1/FVC ratio increased (p = 0.07), and the TLC (p < 0.001) and RV (p<0.08) decreased in the 
irbesartan group compared to placebo6. There is evidence that these observations reflect direct 
biological effects of ARBs on the lung beyond the anti-hypertensive effect for which they are 
clinically indicated. Angiotensin 1 (AT1) receptors are expressed in lung tissue and are involved 
in apoptosis of alveolar epithelial cells7 8 which is theorized to be an essential component of 
emphysema progression9. There is evidence that the lung remodeling effects of AT1 receptor 
activation is mediated by Transforming Growth Factor Beta (TGFb) signaling. Fibrillin-deficient 
mice exhibit emphysema which is caused by excessive signaling by TGFb, and can be 
prevented or reversed by the ARB losartan10 11. Podowski and Neptune also found that 
cigarette-smoke exposed mice develop TGFb mediated emphysema that can be inhibited or 
reversed by losartan12. We conducted a placebo-controlled proof of concept study in COPD 
patients that showed that losartan was well-tolerated and was associated with lack of 
progression of emphysema in the subgroup of patients who had High Resolution Computed 
Tomography (HRCT) evidence of emphysema at baseline (p = 0.06). Therefore, there is a need 
to conduct a definitive clinical trial of losartan to determine whether re-purposing this well-
tolerated and widely available drug can modify disease progression in COPD patients with 
emphysema. 
Emphysema as a COPD subtype and outcome measure for clinical trials  
The widespread adoption of quantitative HRCT scans in clinical research has established 
emphysema as an important sub-type of COPD that correlates with severity of airflow limitation, 
symptoms, and longitudinal decline in lung function13 14 15 16 17 18 19. It is reasonable, therefore, to 
target such patients for treatments that modify disease progression, and to use emphysema 
progression as a primary outcome measure in clinical trials.  
 
Traditionally, the accepted metric for progression of COPD has been FEV1 decline. However 
clinical trials that evaluate this measure require 4,000 – 5,000 patients over 4-5 years20 21 22. 
Because of its greater precision, quantitative HRCT measures of lung density have been 
proposed as a primary outcome for progression of emphysema and has been estimated to be 
2.5 times more sensitive for change than pulmonary function23. In support of this, investigators 
were able to demonstrate significant benefit for alpha-1 anti-protease replacement with a pooled 
study of only 119 patients, and were able to rule out the benefit of retinoic acid therapy in a trial 
of 260 patients over 1 year24 25 26.  
 
Although quantitative HRCT has been considered an expensive and technologically complex 
measure for clinical trials, recent advances in technology have made this a highly tractable 
research tool. The use of multi-detector scanners with reduced scanning times, increased 
computer storage capacity and processing speed, use of preset scanning parameters, and 
commercially available computer-assisted analysis programs have reduced the cost and 
complexity of HRCT. Therefore, quantitative HRCT is now a mature, cost-effective, and clinically 
relevant outcome measure for community-based multicenter clinical trials. 


LEEP Protocol Version 2.2 
Study design │ 8
 
 
Confidential, not for attribution or citation. 
 
2. Study design 
 
This is a pragmatic, randomized, blinded placebo-controlled multi-site clinical trial that will enroll 
220 patients with emphysema to receive either losartan or placebo for 48 weeks.  
 
2.1. Hypotheses 
Administration of losartan at 100 mg/day for 48 weeks will decrease the rate of progression of 
emphysema as measured by quantitative HRCT compared to placebo. 
 
2.2. Study aims 
 
To measure the effect of losartan on HRCT-measured emphysema progression at 48 
weeks 
 
To measure the effect of losartan on lung function (spirometry and HRCT-measured lung 
volumes) 
 
To explore sub-groups of interest for heterogeneity of treatment effects 
 
To determine the safety and tolerability of losartan in emphysema patients  
 
2.3. Trial design /Schema  
The trial is a parallel, randomized, placebo-controlled trial with two treatment groups, losartan at 
100 mg/day and placebo. Participants will be randomly assigned in equal allocation to one of 
two treatments. The treatment period is 48 weeks with follow-up visits at 12-week intervals. 
Participants assigned to losartan will start with a dose of 50 mg/day; participants assigned to 
placebo will start with one capsule per day. A titration visit will be done at 2 weeks; if the systolic 
BP is >90 mm Hg and the diastolic BP is >60 mm Hg, the drug dose will be increased to 100 mg 
per day or matching placebo will be increased to two capsules per day. Symptoms, lung 
function, and specimens are collected at baseline and select follow-up visits. HRCT will be done 
at baseline and 48 weeks. 


LEEP Protocol Version 2.2 
Study design │ 9
 
 
Confidential, not for attribution or citation. 
 
 
Figure 1: LEEP Trial design - schema 
PFT: Pulmonary Function Test; HRCT: High Resolution Computed Tomography 
 
 


LEEP Protocol Version 2.2 
Eligibility criteria │ 10
 
 
Confidential, not for attribution or citation. 
 
3. Eligibility criteria 
 
Participants with mild to severe COPD will be screened using the criteria below.  Participants 
will be asked to sign informed consent before any screening procedures are performed. 
 
3.1. Inclusion criteria:  
• 
Age of 40 years or older at V1, either gender  
• 
Mild to severe COPD (post-BD FEV1/FVC ratio ≤ 0.70 and FEV1 20-80% predicted) at 
V1 
• 
Current or former smoker (≥ 10 pack-year history at V1)  
• 
HRCT Scan with 5-35% of voxels with density < -950 Hounsfield Units (HU) at V1  
• 
Ability to understand and willingness to sign consent documents  
 
3.2. Exclusion criteria: 
• 
Current therapy with angiotensin converting enzyme (ACE) inhibitor or angiotensin 
receptor blocker (ARB)  
• 
Known intolerance to ACE inhibitor or ARB 
• 
History of angioedema 
• 
Conventional indication for ACE inhibitor or ARB (including history of myocardial 
infarction, known cardiomyopathy 
• 
Renal insufficiency (GFR <30 mL/min by Cockcroft-Gault calculation) 
• 
Current regular use of NSAIDs defined as daily use 5 or more days of the week for more 
than one month 
• 
Current treatment with a potassium sparing diuretic 
• 
Potassium supplementation or serum potassium level of ≥ 5.0 mEq/L at V1  
• 
COPD exacerbation requiring treatment within 6 weeks at V1 
• 
Chronic systemic corticosteroid use > 10mg/day of prednisone  
• 
Resting SpO2 <89% on 2L nasal cannula continuous flow; unless at altitude > 4,000 
feet, then resting SpO2 <89% on 4L NC continuous flow 
• 
Untreated arterial hypertension (systolic blood pressure >140 mm Hg, diastolic blood 
pressure > 90 mm Hg)  
• 
Blood pressure less than 90 mm Hg systolic or 60 mm Hg diastolic while standing or 
sitting 
• 
Known unilateral or bilateral renal artery stenosis >70%  
• 
Previous lung resection surgery  
• 
Evidence of interstitial, occupational or chronic infectious lung disease  
• 
Changes to chest that preclude adequate HRCT imaging (e.g. Metallic objects in the 
chest such as shrapnel or pacemaker leads)  
• 
For women of child bearing potential, positive pregnancy test or unwillingness to use two 
methods of birth control or abstinence for the duration of the study 
• 
Major chronic illnesses which in the judgment of the study physician would interfere with 
participation in the study e.g. including but not limited to: cardiac, renal, hepatic 


LEEP Protocol Version 2.2 
Eligibility criteria │ 11
 
 
Confidential, not for attribution or citation. 
 
(LFTs>2.5x normal upper limit), neurological, psychiatric, endocrine or neoplastic 
diseases, uncontrolled diabetes, uncontrolled HIV infection or other immune system 
disorder, hyperthyroidism, seizure disorders, non–skin cancer, rheumatic diseases 
• 
Failure to keep screening appointments or other indicators of non-adherence  
• 
Inability to be contacted by telephone 
• 
Intention to leave area within 12 months  
 
 


LEEP Protocol Version 2.2 
Summary of study visits │ 12
 
 
Confidential, not for attribution or citation. 
 
4. Summary of study visits 
 
V1: Screening visit (Week – 4) 
The initial visit is to determine eligibility, obtain informed consent, and acquire baseline data. It 
will include: 
• 
Obtaining informed consent  
• 
Baseline medical history 
• 
Vital signs including pulse oximetry  
• 
Anthropometrics (height and weight) 
• 
Physical examination  
• 
Orthostatic blood pressure check 
• 
Spirometry pre- and post-bronchodilator (2 inhalations of albuterol MDI)  
• 
Blood draw, venous blood will be obtained to assess hepatic, renal, electrolyte, 
hematological measures 
• 
Pregnancy test for all female participants of childbearing potential  
• 
Administration of questionnaires (ATS-DLD, SGRQ-C, mMRC, CAT, PROMIS -20a) 
• 
HRCT scan (may be scheduled on a different day) 
 
 
V2: Randomization visit (Week 0)  
The purpose of this visit is to confirm eligibility and acquire baseline data and randomly assign 
and distribute a treatment. It will include: 
• 
Interval medical history, adverse events  
• 
Vital signs including pulse oximetry  
• 
Anthropometrics (height and weight) 
• 
Collection of blood and urine for biorepository 
• 
Pregnancy test for all female participants of childbearing potential  
• 
Administration of questionnaires (SGRQ-C, mMRC, CAT, PROMIS -20a) 
• 
Treatment assignment  
• 
Drug administration (50mg losartan or placebo)  
• 
Orthostatic blood pressure check. A two-hour observation of participants in clinic with 
blood pressure check for hypotension (systolic blood pressure <90 mm Hg or diastolic 
blood pressure < 60 or symptoms of lightheadedness or dizziness)  
• 
Drug distribution 
 
V3: Treatment titration (Week 2)  
The purpose of this visit is to titrate drug and ensure the participant can tolerate it. It will include: 
• 
Interval medical history, adverse events   
• 
Vital signs including pulse oximetry  
• 
Anthropometrics (height, weight) 
• 
Orthostatic blood pressure check. If the systolic BP is >90 mm Hg and the diastolic BP is 
>60 mm Hg, the drug dose will be increased to 100 mg per day or the matching placebo 
will be increased to 2 capsules per day 


LEEP Protocol Version 2.2 
Summary of study visits │ 13
 
 
Confidential, not for attribution or citation. 
 
• 
Pregnancy test for all female participants of childbearing potential  
 
V4: Follow-up (Week 12)  
This visit is to obtain follow-up data and screen for adverse events. It will include: 
• 
Interval medical history, adverse events  
• 
Vital signs including pulse oximetry 
• 
Anthropometrics (height and weight) 
• 
Orthostatic blood pressure check 
• 
Blood draw, venous blood will be obtained to assess hepatic, renal, electrolyte, 
hematological measures 
• 
Pregnancy test for all female participants of childbearing potential  
• 
Administration of questionnaires (SGRQ-C, mMRC, CAT, PROMIS -20a)  
• 
Drug distribution and return/capsule count 
 
V5: Follow-up (Week 24)  
This visit is to obtain follow-up data and screen for adverse events. It will include: 
• 
Interval medical history, adverse events  
• 
Vital signs including pulse oximetry 
• 
Anthropometrics (height and weight) 
• 
Physical examination 
• 
Orthostatic blood pressure check 
• 
Spirometry pre- and post-bronchodilator (2 inhalations of albuterol MDI) 
• 
Collection of blood and urine specimens for biorepository 
• 
Pregnancy test for all female participants of childbearing potential  
• 
Administration of questionnaires (SGRQ-C, mMRC, CAT, PROMIS -20a)  
• 
Drug distribution and return/capsule count 
 
V6: Follow-up (Week 36) 
This visit is to obtain follow-up data and screen for adverse events. It will include:  
• 
Interval medical history, adverse events  
• 
Vital signs including pulse oximetry  
• 
Anthropometrics (height and weight) 
• 
Orthostatic blood pressure check 
• 
Pregnancy test for all female participants of childbearing potential  
• 
Administration of questionnaires (SGRQ-C, mMRC, CAT, PROMIS -20a)  
• 
Drug distribution and return/capsule count 
 
V7: Final visit (Week 48)  
This is the final study visit to obtain follow-up data and complete exit tasks. It will include: 
• 
Interval medical history, adverse events  
• 
Vital signs including pulse oximetry 
• 
Anthropometrics (height and weight) 
• 
Physical examination 
• 
Orthostatic blood pressure check 
• 
Spirometry pre- and post-bronchodilator (2 inhalations of albuterol MDI) 


LEEP Protocol Version 2.2 
Summary of study visits │ 14
 
 
Confidential, not for attribution or citation. 
 
• 
Blood draw, venous blood will be obtained to assess hepatic, renal, electrolyte, 
hematological measures  
• 
Collection of blood and urine specimens for biorepository 
• 
Pregnancy test for all female participants of childbearing potential  
• 
Administration of questionnaires (SGRQ-C, mMRC, CAT, PROMIS -20a)  
• 
HRCT scan (may be scheduled on a different day) 
• 
Drug return/capsule count 
• 
Exit interview 
 
 
 
 
 
 
 
 
 
 
 


LEEP Protocol Version 2.2 
Summary of study visits │ 15
 
 
Confidential, not for attribution or citation. 
 
4.1. Study data collection schedule 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Target (weeks) 
-4 
0 
2 
12 
24 
36 
48 
Visit window (weeks) 
-4 to 0 
0 
2-4 
10-14 
22-26 
34-38 
46-50 
Informed consent, eligibility evaluation 
● 
 
 
 
 
 
 
Baseline medical history 
● 
 
 
 
 
 
Adverse events/Interval health history 
 
● 
● 
● 
● 
● 
● 
Pregnancy testing as indicated 
● 
● 
● 
● 
● 
● 
● 
Spirometry (pre and post BD) 
● 
 
 
 
● 
 
● 
Anthropometrics (height & weight) 
● 
● 
● 
● 
● 
● 
● 
ATS-DLD 
● 
 
 
 
 
 
 
SGRQ-C mMRC 
●* 
● 
 
    ● 
● 
● 
● 
CAT 
● 
● 
 
● 
● 
● 
● 
PROMIS-20a 
● 
● 
 
● 
● 
● 
● 
Vital signs, Orthostatic blood pressure 
check, SpO2 
● 
● 
● 
● 
● 
● 
● 
Physical examination 
● 
 
 
 
● 
 
● 
CBC, CMP 
● 
 
 
● 
 
 
● 
Collect blood & urine for biorespository 
 
● 
 
 
● 
 
● 
HRCT 
● 
 
 
 
 
 
● 
Treatment assignment 
 
● 
 
 
 
 
 
Drug distribution 
 
● 
 
● 
● 
● 
 
Drug titration  
 
 
● 
 
 
 
 
Drug return/capsule count 
 
 
● 
● 
● 
● 
Exit interview 
 
 
 
 
 
● 
* mMRC included in ATS-DLD at V1 
 
(V#) Visit Number 
(ATS-DLD) modified American Thoracic Society     
Division of Lung Disease Questionnaire 
(BD) Bronchodilator 
(CAT) COPD Assessment Test 
(CBC) Complete blood count 
(CMP) Comprehensive metabolic panel 
(HRCT) High resolution computed tomography 
 
(mMRC) modified Medical Research Council Dyspnea 
score 
(PROMIS-20a) Patient Reported Outcomes Measurement 
Information System: Physical Function – Short Form 20a 
(SGRQ-C) St. George’s Respiratory Questionnaire for 
COPD Patients 
(SpO2) peripheral capillary oxygen saturation 
 
 
 


LEEP Protocol Version 2.2 
Outcomes │ 16
 
 
Confidential, not for attribution or citation. 
 
5. Outcomes 
5.1. Primary outcome measures 
The primary outcome measure is quantitative HRCT measurement of emphysema as indicated 
by the percent of lung voxels with a density less than – 950 Hounsfield Units (HU), measured 
using commercially available software (Slicer, NIH developed, open source).  
 
5.2. Secondary outcome measures 
 
Spirometry. FEV1 and FVC are measured before and after 2 inhalations of albuterol in 
accordance with ATS/ERS standards and using NHANES reference values27 28.  
 
Other HRCT measures. Emphysema (pct950) will be measured in each of the lobes of 
the lung separately. Other measures include TLC29, mean lung density, 15th percentile 
density, and airway lumen and wall thickness will be measured for small, medium, and 
large airways30.  
 
Respiratory questionnaires. The St. George’s Respiratory Questionnaire for COPD 
Patients (SGRQ-C) is a widely used measure of disease impact as an indicator of 
disease-specific quality of life. The mMRC dyspnea scale (mMRC) will serve as our 
primary measure of dyspnea and be used for risk stratification31 The COPD Assessment 
Test (CAT) is designed to quantify the impact of COPD symptoms on the health status of 
participants32.  
 
Patient reported outcomes. The Patient Reported Outcomes Measurement Information 
System Questionnaire: Physical Function – Short Form 20a (PROMIS-20a) is used to 
indicate patients' state of wellbeing or suffering as well as their ability or lack of ability to 
function33. 
 
Laboratory testing. Complete Blood Count (CBC) and Comprehensive Metabolic Panel 
(CMP) of blood chemistries will be obtained at local labs to detect hematologic, 
electrolyte, renal, or hepatic abnormalities that indicate exclusion from treatment or 
adverse events. Pregnancy tests will be done on women of child-bearing potential at 
each visit and prior to performing a HRCT scan  
 
Adverse effects to assess safety and tolerability are assessed by open-ended questions 
at each visit and rated in severity. Targeted symptoms, e.g. orthostasis, cough, and 
angioedema will be asked directly.  
 
Interval health history is recorded at each clinic visit. With participant permission, records 
of hospitalizations and deaths are obtained for verification of diagnoses and assessment 
of safety.  
 
Adherence is recorded at each visit by self-report and by capsule counts from returned 
containers. 
 
5.3. Other data 
 
General health history: Questionnaires to collect demographic and general information 
(including race, gender, COPD history) as well as information about COPD symptoms, 


LEEP Protocol Version 2.2 
Outcomes │ 17
 
 
Confidential, not for attribution or citation. 
 
medication use, other diseases and illnesses that affect eligibility for the trial. These data 
along with clinical measures such as height and weight will be used to characterize the 
population and allow for analysis of subgroups.  
 
Respiratory questionnaires:  The ATS-DLD questionnaire is a general respiratory 
symptom questionnaire. We will use the LHS-III modified version that includes 
information regarding occupational exposures and asthma. 
 
An exit interview is administered at the last visit to determine global assessments of 
treatment, adequacy of informed consent procedures, satisfaction with study procedures 
and personnel, and effectiveness of the blinding procedures.  
 
Biospecimens: Blood and urine will be drawn for future studies and will stored in the 
American Lung Association Airways Clinical Research Center (ALA ACRC) biorepository 
at Nemours Children’s Health System, Jacksonville, FL.  Although it is beyond the scope 
of this study, ancillary studies may be done to measure elastin fragments, inflammatory 
biomarkers, or measures of oxidative stress.  
 
 


LEEP Protocol Version 2.2 
Study treatments │ 18
 
 
Confidential, not for attribution or citation. 
 
 
6. Study treatments 
6.1. Description of study treatments  
 
V2 – V3 
- 
Losartan 50 mg per day (one capsule) OR placebo (one capsule) 
 
V3 – V7 
o If well tolerated and systolic BP is >90 mm Hg and the diastolic BP is >60 mm Hg 
blood pressure is above at V3: Losartan 100mg once per day (two capsules of 50 
mg each) OR placebo (two capsules per day) 
o If not tolerated at V3: Losartan 50 mg per day (one capsule) OR placebo (one 
capsule) 
 
Drug titration  
Participants will receive their first dose of drug in the clinic under observation for at least two 
hours to ensure that there are no immediate adverse effects. Participants will take 50 mg/day 
(one capsule) or one capsule of placebo for the first two weeks. If well tolerated and systolic BP 
is >90 mm Hg and the diastolic BP is >60 mm Hg will be increased to 100 mg/day (two 
capsules) or two capsules of placebo, which will be taken in clinic under observation for at least 
one hour. 
 
 
6.2. Side effects of drug 
Losartan is an FDA-approved angiotensin receptor blocker that is widely prescribed for 
treatment of hypertension, heart failure, and for renal protective effects in diabetics. The dose 
proposed in this study is 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, blood dyscrasias, 
hepatitis or rhabdomyolysis. According to the FDA-approved prescribing information, the 
adverse event profile is as follows:  
 
“Cozaar has been evaluated for safety in more than 3300 adult patients treated for essential 
hypertension and 4058 patients/subjects overall. Over 1200 patients were treated for over six 
months and more than 800 for over one year. In general, treatment with Cozaar was well 
tolerated. The overall incidence of adverse experiences reported with Cozaar was similar to 
placebo. In controlled clinical trials, discontinuation of therapy due to clinical adverse 
experiences was required in 2.3 percent of patients treated with Cozaar and 3.7 percent of 
patients given placebo.”34  
 
“In the RENAAL study involving 1513 [Type II Diabetic Patients with Nephropathy] patients 
treated with Cozaar or placebo, the overall incidences of reported adverse experiences were 
similar for the two groups. Cozaar was generally well tolerated as evidenced by a similar 
incidence of discontinuations due to side effects compared to placebo (19% for Cozaar, 24% for 


LEEP Protocol Version 2.2 
Study treatments │ 19
 
 
Confidential, not for attribution or citation. 
 
placebo). The adverse experiences, regardless of drug relationship, reported with an incidence 
of ≥ 4% of patients treated with Cozaar and occurring more commonly than placebo, on a 
background of conventional antihypertensive therapy are shown in the table below.” 35 
 
 


LEEP Protocol Version 2.2 
Study treatments │ 20
 
 
Confidential, not for attribution or citation. 
 
 
Figure 2: Adverse events in the RENAAL study 
 


LEEP Protocol Version 2.2 
Study treatments │ 21
 
 
Confidential, not for attribution or citation. 
 
6.3. Handling of drug 
Study drugs will be supplied by a central drug distribution center and shipped to the 
investigators from a central drug repository. The study drug will be kept in a secure, limited 
access, storage area within a controlled, appropriate temperature range (room temperature). 
Each container of study medication will be identified by protocol name and labeled as required 
by federal law. Study drug receipt, distribution, and destruction will be documented in the drug 
accountability log. Adherence will be monitored by capsule count at follow-up visits. Unused 
study drug distributed to participants enrolled in the study should be returned to the clinic site. 
Unused drug will be destroyed at the clinical sites in accordance with the local policy and 
procedures. 
6.4. COPD treatment 
All participants enrolled in this study will continue to have their usual care for COPD as 
determined by their primary care provider or their usual COPD caregiver. No treatments will be 
discontinued. Study physicians will render emergency care for participants, refer to appropriate 
treating sources, and confer with treating sources, but will not provide comprehensive medical 
care to participants. With permission of the participant, treating physicians will be notified of the 
participant's enrollment in the study and results of study evaluations, e.g., spirometry, as 
appropriate.  
 
 


LEEP Protocol Version 2.2 
Specific procedures │ 22
 
 
Confidential, not for attribution or citation. 
 
 
7. Specific procedures  
7.1. HRCT scans 
HRCT scans of the lung will be acquired from individuals with COPD at V1 to confirm 
emphysema, and if eligible and randomized, at V7 (total of two scans). These data will be 
obtained specifically for research purposes using standardized protocols for different model 
scanners. Variation between scanners is minimized by designating the same scanner to be 
used for all scans on an individual before and after study treatment. The participant should have 
taken 2 puffs of albuterol within 6 hours of the HRCT scan.  
For the HRCT scans:  
 
A pregnancy test will be administered at each visit before imaging for women of child 
bearing potential   
 
The lungs and trachea will be included 
 
The scanning protocol will begin below the lung bases and end above the lung apexes at 
the mandible 
 
Scans will be performed with the subjects in the supine position  
 
Each participant will have one standard scout (AP/PA) scan over the chest at Total Lung 
Capacity (TLC). Then a complete chest HRCT will be done at Total Lung Capacity (TLC) 
 
Since the scans will be done at TLC, it is important for the coordinators and radiology 
technologists to ensure that the participant is appropriately coached prior to performing the 
actual scanning procedures. Study coordinators will be provided with a script to coach 
participants in the appropriate breathing technique to take and hold a TLC breath during 
spirometry prior to the HRCT exam. They will also provide the script for the radiology 
technologist to coach participants in the breathing technique. The scan will take about one hour 
including preparation and coaching. In order to minimize errors in scan acquisition, we will ask 
coordinators to accompany the participants to the HRCT scanner and provide the radiology 
technologist with the LEEP HRCT protocol including the proper acquisition parameters to 
program into the HRCT scanner. The model and serial identification number of the scanner will 
be recorded so that the same scanner is used for the second scan.  
 
7.2. Pulmonary Function Testing 
Spirometry before and after 2 inhalations of albuterol will be performed in accordance with 
ATS/ERS recommendations and PTC procedures. Spirometry is a common clinical test used to 
diagnose asthma, COPD, and certain other conditions that affect breathing. It measures how 
much and how fast air is inhaled and exhaled. It should be administered at the same time of the 
day. Spirometry reference values will be those of Hankinson et al from NHANES36. 
 


LEEP Protocol Version 2.2 
Specific procedures │ 23
 
 
Confidential, not for attribution or citation. 
 
7.3. Randomization 
Treatment assignment will be randomly allocated in a 1:1 ratio with stratification by clinic using a 
permuted block randomization scheme. Randomization will occur at V2 after the participant 
meets all eligibility criteria. The clinic staff will complete a randomization form for each eligible 
participant and enter it into a web-based randomization system. Eligibility criteria are verified via 
computer program, which then provides a unique study treatment assignment number according 
to an encrypted table on the server; the assignment number will correspond to a specific drug 
bottle. 
The initial drug supply will be dispensed and a tear-off label will be affixed to a study form to 
provide an audit trail for drug distribution. 
 
7.4. Phlebotomy and biospecimens 
Whole blood and serum will be collected for measurement of complete blood counts and serum 
chemistry panels. The purpose of this testing is to monitor for potential adverse events that 
might lead to discontinuation of study treatment. 
For participants willing to provide specimens for future analyses, (e.g. possible biomarker 
analysis), additional blood and urine specimens will be collected and stored at the ALA ACRC 
biospecimen repository. Specimens will be stored at -70 or -80C at the local site and shipped 
periodically in batches on dry ice for storage at the biospecimen repository.  
Approximately 10 mL of blood is collected by venipuncture at V1, V4 and V7. Two 5 mL tubes 
are transmitted to the local hospital laboratory without processing for measurement of CBC and 
chemistries. Also, approximately 20 mL of blood is collected at V2, V5, and V7. This will be 
divided into eight, 1mL aliquots of serum and plasma for freezing and bulk storage pending 
shipping. DNA will be collected at V2. Instructions for processing the blood are provided in the 
manual of operations. Note that the total blood drawn at V7 is approximately 30mL for lab 
testing and for storage.  
Approximately 20 mL of urine is collected by clean catch and is divided into 1.8 mL aliquots for 
freezing and storage pending shipping to the biorepository. 
 
7.5. Unmasking 
Unmasking of treatment assignment before the end of participant’s treatment period is rarely 
necessary. If adverse events occur that may be related to the study treatment, then the study 
treatment is stopped and the participant continues scheduled follow-up.  
Routine unmasking will occur at the end of the participant’s V7 visit. The treatment assignment 
will only be provided to the participant and not the staff at the clinical center. Sealed envelopes 
with treatment assignment are provided to the clinic to provide the participants. In addition, 


LEEP Protocol Version 2.2 
Specific procedures │ 24
 
 
Confidential, not for attribution or citation. 
 
clinics can contact the DCC if necessary for unmasking information. All participants are provided 
with a wallet card that provides information that they are participating in a clinical trial and gives 
the contact numbers of personnel at the clinic.  
7.6. Treatment termination 
Participants may be withdrawn from the treatment if they have a serious adverse event or are 
intolerant of the treatment. All participants will be asked to return for study visits in order to 
maintain the intent to treat paradigm for the primary analysis. Participants will be treated by their 
usual COPD care provider according to best medical judgment regardless of whether they 
continue to use study treatment. Any female participant with a positive pregnancy test at any 
time during the study will be taken off study drug and followed to the outcome of pregnancy.  
 
 


LEEP Protocol Version 2.2 
Analysis plan │ 25
 
 
Confidential, not for attribution or citation. 
 
 
8. Analysis plan 
8.1. Primary analysis  
The primary goal of analysis is to precisely estimate the difference in response between the 
losartan and placebo groups by comparing between-group means of changes from baseline 
pct950 over the time course of treatment. The secondary goals require estimation of analogous 
differences in response trajectories separately for each secondary response variable. For 
analytic methods, we propose a series of generalized linear mixed models (GLMMs) for 
responses (Y) with possibly g-transformed) expected primary or secondary responses, 
g(E(Yij|b0i,βiXij), where 1.) (β0 + b0i ) for the ith patient response is a random intercept (to account 
for serial correlations in the within-patient responses) with fixed mean β0 and random normal 
distributed offsets b0i, with mean zero and standard deviation σb0i and 2.) Xij are fixed values of jth 
covariate for the ith patient and βi is the fixed unknown regression coefficient to be estimated for 
covariate Xj. Covariates will include site (14 binary spline indicator variables for the 15 category 
site stratification), baseline values of the Y response, an indicator variable for treatment group 
(trt = 1 losartan, 0 placebo), and either spline indicators for time or a continuous function for the 
fixed time trend in mean response, and, if needed, interaction terms between the time 
covariates and the (trt) treatment group indicator. The primary outcome is  change in pct950 
from baseline after 48 weeks of treatment ( Y=pct950-pct950bl) and g(.) is the identity function, 
so the above model simplifies to Yi+εi = E(Yi|b0i,Xi)) = β0 + b0i + β1 trt   + β2 pct950i bl   + { βj Xij  j}+ 
εij , where β0 is the intercept for the fixed effects, b0i is the normal (0, σb0i ) random intercept 
offset for each participant, β1 is the primary losartan vs placebo treatment effect = mean 
difference in 48 week change in pct950 from baseline, losartan vs. placebo, {βj} is the set of 
regression coefficients to account for stratification by site, and εi  is a normal (0, σ2) random 
error for the ith change from baseline in pct950. The primary analysis will focus on β1,= mean 
losartan vs. placebo mean change over 48 weeks in pct950. We will estimate a 95% confidence 
interval for the losartan vs placebo mean difference, β1, using the regression estimate and the t-
distribution; we will reject the null that losartan is equivalent to placebo if the 95% interval 
excludes 0.0. A robust variance estimate37 will be used to guard against incorrect inferences 
due to misspecification of the assumed serial correlation structure among repeated observations 
on each subject.  
 
The primary analysis will be intention-to-treat so that the indicator trt is the group to which the 
person is randomized without regard to whether they complied with the treatment assignment or 
not. We anticipate some degree of loss-to-follow-up (less than 10%) that will not affect our 
analyses. However, the regression model above will be estimated using the method of 
maximum likelihood so that missing data will effectively be imputed by their expected values 
given the other measurements. If the loss-to-follow is 10% or greater, then multiple imputation 
will be used to construct the 95% confidence limits for β1 estimated across 50 imputations of the 
dataset. 
 


LEEP Protocol Version 2.2 
Analysis plan │ 26
 
 
Confidential, not for attribution or citation. 
 
8.2. Secondary analyses  
As indicated above, the same basic model specified above can be used for the secondary 
outcomes, most of which are continuous. For a binary secondary outcome, we will use the 
logistic regression analog in which g() above is the logistic function, g(u)=log{u/(1-u)}. Since the 
strict interpretation of odds ratios from mixed models with the logistic link is dependent on the 
value of the random effect variable (participant), we will also use maximum likelihood estimation 
and robust variance estimation described for the primary analysis above. The same 
assumptions and methods for missing data for the primary outcome will also be used in the 
secondary analyses.  
 
In particular, we seek to estimate the treatment effect for each of 5 lobes of the lung. A simple 
approach is to use the basic change-from-baseline model described above separately for data 
from each lobe and then use a gate-keeper Chi-square test and Bonferroni correction to 
account for the multiplicity of tests. This method, while valid, does not provide evidence about 
the correlation among the estimates from the 5 lobes that is itself of scientific interest. 
Therefore, we will use a multivariate version of the GLMM from Section 8.1 that simultaneously 
estimates the treatment effect for the 5 lobes and produces both the 5 estimates of treatment 
effect as well as their covariance matrix38. We will use these results to conduct gate-keeper Chi-
square test of the null hypothesis that the 5 treatment effects are all the same across lobes and 
if this null is rejected, provide lobe-specific treatment effect estimates with 99% Bonferonni-
corrected confidence limits to ensure that the joint coverage probability is 95%. In addition, we 
will also show estimates and 95% confidences limits for the between lobes correlations. 
8.3. Exploratory analyses  
Preliminary to the main analyses, the data will be checked for obvious errors that cause outliers 
and for systematic errors due to improper coding at one or a few centers. For each time x trt 
cell, the distribution of outcome values will be summarized by its mean, standard deviation, and 
five number summary. Boxplots of the cell-specific distributions will be made to see the basic 
patterns of change over time and to detect outlying values. The autocorrelation matrix of 
repeated measures on the individual will be estimated separately for each treatment group.  
After the main analyses, numerous exploratory analyses will be conduct using variants of the 
model above to generate hypotheses for future research. 
8.4. Subgroups of interest 
We will quantify the evidence in the study data in support of the possibility that the treatment 
effect differs between persons with (Z=1) versus those without (Z=0) pre-specified 
characteristics. Subgroups of interest include: Current vs. Former smokers; severe emphysema 
(pct950 >15) vs mild emphysema (pct950 <15); severity of airflow limitation (FEV1 < 50% 
predicted vs FEV1 > 50% predicted); and men vs women. In addition, other baseline 
characteristics may be explored. The model above will be extended to include the variables Z 


LEEP Protocol Version 2.2 
Analysis plan │ 27
 
 
Confidential, not for attribution or citation. 
 
and Z*trt. The coefficient for the 2-way interaction is the difference in the treatment group effects 
(losartan vs placebo) between the Z=1 and Z=0 subgroups. We will reject the null of no 
difference in treatment effects between the subgroups if the 95% confidence interval for this 3-
way interaction coefficient excludes 0.  
Other subgroups may be identified post hoc. The same model can be used to quantify the 
evidence for a difference in treatment effect for these subgroups. However, we view such 
analyses as hypothesis generating, not hypothesis testing. 
8.5. Sample size 
To estimate the sample size for a given power, we note that the variance of the change in mean 
for one of the two groups is given by V=SD2/n where SD is the standard deviation of the 
changes across people within a group and n is the number of subjects in each group. Then, the 
main hypothesis that the two treatment groups change an equal amount is just a two sample 
comparison for which the sample size is given V*{Z(1-β) + Z(1-α/2)}2 / δ2 where Z(1-β), (1-α/2), 
are the 1-β and 1-α/2 quantiles for the standard normal distribution, and δ is the anticipated 
difference in change from baseline between the two groups39. Figure 3 shows the requisite 
sample size per group to attain 80% and 90% power respectively for varying values of the 
difference in change denoted δ on the horizontal axis. For the estimated minimally important 
difference (MID) of pct950, (delta = 2%/year), SD = 4%/year, alpha = 0.05 two-sided, and power 
= 90%, the required sample size is 88 participants per group which is inflated 20% (110 per 
group) to account for poor adherence, missing data, or to have adequate power to detect 
smaller treatment effects.  
 


LEEP Protocol Version 2.2 
Analysis plan │ 28
 
 
Confidential, not for attribution or citation. 
 
 
Figure 3: Sample size required for indicated power and difference (Delta) between change for 
losartan and placebo groups, assuming alpha=0.05, and standard deviation of the change 
within a group of 4.0 
 


LEEP Protocol Version 2.2 
Protection of human subjects │ 29
 
 
Confidential, not for attribution or citation. 
 
9. Protection of human subjects 
9.1.  Recruitment and consent procedures 
 
Participants will be recruited by each participating clinic by their own methods. These methods 
may include social media campaigns, solicitation in physician offices, clinics, workplaces, and 
public media advertisements, patient and research subject registries and electronic medical 
records. All public advertisements are subject to approval by the local Institutional Review Board 
(IRB) and must indicate that it is a research study. The NEMO will help coordinate recruitment 
among clinics and promote sharing of effective recruitment strategies within the network. The 
study encourages prescreening of participants for prior HRCT evidence of emphysema, 
presence of comorbidities, and concurrent medications. 
 
Potential enrollees will be approached either in person, by telephone or by mail to establish 
general eligibility criteria.  A general description will be provided prior to their initial visit. If the 
potential enrollees are interested in participating, they will meet with the study coordinator and 
local physician co-investigators to review the study and to ask questions. They will be asked to 
sign consent, and if appropriate provide assent, and undergo the screening procedures.   
The consent form will be subject to approval by the clinical center IRB. A copy of the consent 
form will be given to each participant, and the signed original will be kept in the participant’s 
research chart. 
9.2. Potential risks and procedures to minimize risk to the 
participants 
 
During this study, participants will continue to receive their usual care for COPD as per their 
treating physician. If any medical illness requiring treatment is discovered during the collection 
of data for the course of this study protocol, individuals will be referred to their primary care 
providers for further evaluation and treatment. 
 
Potential risks associated with this study are outlined below. In order to minimize risk to 
participants, the following actions will be taken. 
 
 
Treatment with losartan: Losartan is an FDA-approved angiotensin receptor blocker that 
is widely prescribed for treatment of hypertension, heart failure, and for renal protective 
effects in diabetics. The dose proposed in this study is 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. In order to minimize risk to participants, the following actions will be 
taken. The first dose of medication will be administered in the clinic (50mg/placebo) and 
the participant observed for two hours thereafter with a blood pressure check for 


LEEP Protocol Version 2.2 
Protection of human subjects │ 30
 
 
Confidential, not for attribution or citation. 
 
hypotension. Participants with hyperkalemia, significant renal dysfunction, or who are 
taking potassium supplements will not be enrolled into the study. Participants are given 
written descriptions of potential side-effects and appropriate means of dealing with them. 
For example, mild postural hypotension can often be minimized by arising slowly and 
maintaining adequate hydration. Skin rashes, palpitations or other moderate or severe 
(defined as those that interfere with usual daily activities) adverse events without other 
clear explanation should warrant immediate cessation of treatment and notification of 
study personnel. If the study physician warrants that it is unlikely that the event is related 
to the medication, then it may be restarted after resolution or stabilization of the adverse 
event.  
 
After the initial two weeks of treatment, subjects will return for titration up to 100mg of 
losartan or two placebo capsules. They will be observed for one hour thereafter with a 
blood pressure check for hypotension. Adverse events will be monitored at each of the 
study visits by specific and open-ended questions. Losartan is a potential human 
teratogen particularly in the second trimester of pregnancy. Therefore, pregnancy testing 
will be performed prior to randomization and at each visit for persons of child bearing 
potential. As well, participants of child-bearing age will be counseled on the risk of 
pregnancy as delineated in the consent form. 
 
 
High Resolution Computed: Tomography: HRCT is a standard medical procedure for 
imaging of the lung, is widely used in research and clinical care of patients with COPD, 
and is recommended by the US Preventive Services Task Force for annual lung cancer 
screening. Risks to the volunteers are minimal. This will involve a small amount of 
radiation exposure to our subjects. The HRCT Dose is standardized so each 
manufacturer and model are matched within ± 3% of the Target CTDIvol. For the current 
proposal, to limit the risk of radiation exposure, we have determined what we consider 
the best balance between high quality data and minimal radiation exposure. We intend 
to perform two high-resolution chest HRCT scans of the subjects over 48 weeks. The 
chest HRCT protocol will be adjusted; based on the weight of the subjects. For average-
weight adults of 80 kg, the effective dose estimation for each CT scan, is 4 mSv. The 
total effective dose for the study protocol will be 8 mSv. This compares to the annual 
allowed limit on radiation workers is 50 mSv in the US. The risk of radiation 
overexposure will be mitigated by ensuring that all centers are certified for performance 
of the tests in an ACR accredited facility that performs the required daily calibration of 
instrumentation.  Moreover, prior to participant enrollment and regularly during the trial, 
HRCT scanners at each site will be calibrated using a Lung Phantom (e.g. CPT674, The 
Phantom Lab, Salem, NY) and reviewed by the HRCT reading center. While there are 
some variations between HRCT scanners, a standardization of the parameters and 
exposure levels has been developed to allow multiple scanners to output reliable 
quantitative measures and minimize risk across a given patient population. 
 
There is risk of discomfort while lying in the scanner, or cough with breath holding, and 
participants will be continuously supervised by radiology staff during the procedure.  


LEEP Protocol Version 2.2 
Protection of human subjects │ 31
 
 
Confidential, not for attribution or citation. 
 
 
Although the scans are done only for research purposes, we are requiring that all HRCT 
scans be interpreted by a certified radiologist on site. The scans will be inspected for 
adequate inspiration, absence of motion artifact and inclusion of all parts of the chest. It 
may occur that other findings are found on these images that may represent clinically 
significant findings (e.g. lung nodules). If any incidental findings are discovered during 
study, the clinical site study physician will be notified, the information will be given to the 
participant and, with their permission, the information will also be transmitted to the 
participant’s usual care-giver for appropriate medical care or follow-up. 
 
 
Pulmonary Function Testing: Spirometry is a routine clinical procedure that entails little 
risk. Participants are coached to make repeated forceful breathing efforts that 
sometimes makes their chest sore for a day or so. In some unusual cases participants 
may become light-headed during these efforts. The risk to the participant is minimized by 
having these procedures done with the participant seated during the testing. 
 
 
Phlebotomy: This may cause pain during the insertion of the needle or slight bruising 
afterward. This risk is minimized by the use of disposable single use needles, trained 
personnel, and application of pressure after the blood draw.  
 
 
Questionnaires: Health History acquires information that is routinely collected in the 
process of medical care of patients with COPD. There are no significant physical risks 
from these procedures. As with all medical information, there is always the risk of 
psychological distress if personal health information is not held confidential within the 
wishes of the participant. 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. Medical 
information is provided to treating sources consistent with HIPAA guidelines. 
 
 
Physical examination: Physical examinations and the collection of vital sign including 
pulse oximetry are usual medical procedures for patients with COPD. There are no 
significant physical risks from these procedures. 
 
9.3. Data and safety monitoring plan 
 
A Data and Safety Monitoring Board (DSMB) will be appointed by NHLBI to monitor the entire 
PTC and will be chartered and managed by the NEMO. The DSMB will serve in a consultative 
capacity to NHLBI and will make recommendations regarding the initiation and conduct of the 
study to the institute. The primary responsibility of the DSMB is to protect participants but may 
also have recommendations regarding the scientific conduct of the study to optimize the 
information gained from the study. Typically, the DSMB would meet every six months or more 
frequently to review the progress of the trial. The investigators will present the DSMB with study 
performance data including screening and enrollment data, and measures of data quality and 


LEEP Protocol Version 2.2 
Protection of human subjects │ 32
 
 
Confidential, not for attribution or citation. 
 
timeliness. Safety data will include reporting of adverse events, protocol deviations, and 
unexpected or unusual events that may affect the safety or scientific validity of the study; these 
will be reported by treatment group. After sufficient data are acquired, the DSMB may request to 
see outcome data, although for this type of translational study, it is unlikely that any finding 
would be sufficiently clinically directive to use for interim recommendations. Accordingly, we are 
not proposing formal interim efficacy analyses or stopping guidelines. 
 
Reporting of Serious Adverse Events 
A serious adverse event (SAE) is an adverse event that results in one of the following 
outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or 
congenital anomaly/birth defect. Also, important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention (treatment) to prevent any of the outcomes previously 
listed in this definition. When an investigator or clinical center staff member becomes aware of 
an SAE, it should be reported to the DCC within 72 hours with follow up reporting until the event 
is terminated. The DCC will send these reports to the DSMB, the network coordinating center, 
and NHLBI representatives; these reports will be distributed with a ballot for DSMC members to 
indicate whether an ad hoc meeting should be convened to discuss the SAE, The DCC will 
distribute reports of SAEs that are possibly related to the study treatment or study participation 
all centers for review by their local IRBs and to the DSMB in a timely fashion. 
 
Interim Analysis for Safety 
The DSMB will evaluate reported adverse events and treatment-emergent symptoms by 
treatment group at each meeting. These analyses will review both expected and unexpected 
events by severity and treatment-emergent symptoms reported by participants at follow-up 
visits.  A standard set of symptoms will be queried at each visits along with an open-ended 
question about other symptoms.  Analysis of treatment effects on adverse events and 
treatment-emergent symptoms will include cumulative percentages of participants with events 
by severity. While no formal stopping guidelines for safety are planned, the DSMB will evaluate 
whether the burden of treatment exceeds the potential benefits of treatment at each meeting 
and be responsible for making a recommendation to the NHLBI regarding continuation of the 
trial.   
 
9.4. Data confidentiality 
 
Participant data, which includes identifiable personal health information (PHI), are collected at 
each of the clinical sites. PHI will be stored at each of the clinical sites in accordance with 
HIPAA regulations and local university and hospital policies. This includes the storage of PHI in 
locked cabinets or rooms, limited access to secure data areas by certified study personnel, 
password protection for electronic medical records, and explanation of HIPAA regulations on the 
study consent form. Analytic files will not contain personal identifiers (e.g. name, address). All 


LEEP Protocol Version 2.2 
Protection of human subjects │ 33
 
 
Confidential, not for attribution or citation. 
 
reports/manuscripts will be prepared in such a way that individual participants cannot be 
identifiable. 
 
Data such as lung function or laboratory tests that are collected as part of this study may be 
transmitted to the participants treating physicians with the consent of the participant. 
Participants will be informed in the consent that PHI may also be disclosed for auditing 
purposes by the NIH or other regulatory bodies and is subject to subpoena.  
 
All HRCT scans will be de-identified at the scanning institution and a unique study ID will be 
assigned by the DCC. De-identified HRCT scans are transmitted electronically to the NEMO, 
then to the DCC and are logged, quality-controlled, and analyzed in a blinded fashion by a 
trained technician using a semi-automated Slicer workstation at the HRCT reading center 
supervised by Dr. Brown. HRCT scans and other data will also be transmitted to the NEMO at 
University of Pittsburgh for the purposes of ensuring quality control.  
 
Personal identifiers (e.g. name, address, EMR number) are not transmitted to the DCC or 
central laboratory in that all biospecimens and records are identified by a study ID, and other 
identifying information such as names are not entered into the central study database. Source 
records that are transmitted to the DCC for data quality audits have identifying information 
redacted. No highly confidential information is routinely collected, although the data collection 
does include PHI, so a breach of confidentiality would constitute a HIPAA violation. If a 
participant is harmed from this study as a consequence of negligence, then the investigators or 
University might be liable for damages.  
 
We will advise participants that the U.S. Department of Health and Human Services has the 
right to inspect medical records relating to this research for the purposes of verifying data. 
Where data are shared with other research entities, it will comply with the HIPAA definition of a 
limited dataset, and appropriate IRB approvals and waivers will be obtained. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


LEEP Protocol Version 2.2 
Acronyms │ 34
 
 
Confidential, not for attribution or citation. 
 
10. Acronyms 
 
ACE 
Angiotensin converting enzyme 
ACR 
American College of Radiology 
ARB 
Angiotensin receptor blocker 
AT1 
Angiotensin 1 
ATS 
American Thoracic Society 
ATS-DLD 
modified American Thoracic Society - Division of Lung Disease questionnaire 
BD 
Bronchodilator 
BMI 
Body Mass Index 
BP 
Blood pressure 
CAT 
COPD Assessment Test 
CBC 
Complete blood count 
CMP 
Comprehensive metabolic panel 
COPD 
Chronic Obstructive Pulmonary Disease 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
ERS 
European Respiratory Society 
FDA 
US Food and Drug Administration 
FEV1 
Forced Expiratory Volume in one second 
FVC 
Forced Vital Capacity 
GFR 
Glomerular Filtration Rate 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HRCT 
High resolution computed tomography 
HU 
Hounsfield Units 
IRB 
Institutional Review Board 
LEEP 
Losartan Effects on Emphysema Progression 
LFT 
Liver Function Test 
MDI 
Metered dose inhaler 
mEq/L 
Milliequivalent/ iliter 
MID 
Minimal important difference 
mMRC 
Modified Medical Research Council 
mSv 
millisievert 
NHANES 
National Health and Nutrition Examination Survey 
NHLBI 
National Heart, Lung, and Blood Institute 
NSAID 
Non-steroidal anti-inflammatory drug 
OC 
Operations Committee 
PFT 
Pulmonary Function Test 
PHI 
Protected health information 
PROMIS-20a 
Patient Reported Outcomes Measurement Information System: Physical Function – 
Short Form 20a 
RENAAL 
Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study 
SAE 
Serious adverse event 
SD 
Standard deviation 
SpO2 
Peripheral capillary oxygen saturation 
TGFb 
Transforming Growth Factor Beta 
SGRQ-C 
St. George’s Respiratory Questionnaire for COPD Patients 
TLC 
Total Lung Capacity 


LEEP Protocol Version 2.2 
Literature cited │ 35
 
 
Confidential, not for attribution or citation. 
 
11. Literature cited 
1    US Burden of Disease Collaborators. The state of US health, 1990-2010: burden of   
diseases, injuries, and risk factors. JAMA. 2013 Aug 14;310(6):591-608.   
2    Anthonisen NR, Connett JE, Murray RP. Smoking and lung function of Lung Health Study 
participants after 11 years. Am J Respir Crit Care Med. 2002;166(5):675-9.   
3    Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE; Lung Health 
Study Research Group. The effects of a smoking cessation intervention on 14.5-year 
mortality: a randomized clinical trial. Ann Intern Med. 2005;142(4):233-9   
4    Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM, Brophy JM. Reduction of 
morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin 
receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol. 
2006 Jun 20;47(12):2554-60   
5    Mancini GB. The 'double dip' hypothesis: simultaneous prevention of cardiovascular and 
pulmonary morbidity and mortality using angiotensin II type 1 receptor blockers. Can J 
Cardiol. 2005; 21(6):519-23   
6    Andreas S, Herrmann-Lingen C, Raupach T, Lüthje L, Fabricius JA, Hruska N, Körber W, 
Büchner B, Criée CP, Hasenfuss G, Calverley P. Angiotensin II blockers in obstructive 
pulmonary disease: a randomised controlled trial. Eur Respir J. 2006;27(5):972-9   
7    Wang R, Alam G, Zagariya A, Gidea C, Pinillos H, Lalude O, Choudhary G, Oezatalay D, 
Uhal BD. Apoptosis of lung epithelial cells in response to TNF-alpha requires angiotensin II 
generation de novo. J Cell Physiol. 2000;185(2):253-9   
8    Papp M, Li X, Zhuang J, Wang R, Uhal BD. Angiotensin receptor subtype AT(1) mediates 
alveolar epithelial cell apoptosis in response to ANG II. Am J Physiol Lung Cell Mol Physiol. 
2002;282(4):L713-8   
9    Yoshida T, Tuder RM. Pathobiology of cigarette smoke-induced chronic obstructive 
pulmonary disease. Physiol Rev. 2007 Jul;87(3):1047-82   
10  Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, Ramirez F, 
Sakai LY, Dietz HC. Dysregulation of TGF-beta activation contributes to pathogenesis in 
Marfan syndrome. Nat Genet. 2003; 33(3):407-11   
11  Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu 
G, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, 
Carta L, Ramirez F, Huso DL, Dietz HC. Losartan, an AT1 antagonist, prevents aortic 
aneurysm in a mouse model of Marfan syndrome. Science. 2006; 312(5770):117-21   
12  Podowski M, Calvi C, Metzger S, Misono K, Poonyagariyagorn H, Lopez-Mercado A, Ku T, 
Lauer T, McGrath-Morrow S, Berger A, Cheadle C, Tuder R, Dietz HC, Mitzner W, Wise R, 
Neptune E. Angiotensin receptor blockade attenuates cigarettesmoke-induced lung injury 
and rescues lung architecture in mice. J Clin Invest. 2012;122:229-40   
13  Schroeder JD, McKenzie AS, Zach JA, Wilson CG, Curran-Everett D, Stinson DS, Newell 
JD Jr, Lynch DA. Relationships between airflow obstruction and quantitative CT 
measurements of emphysema, air trapping, and airways in subjects with and without chronic 
obstructive pulmonary disease. AJR Am J Roentgenol. 2013;201:W460-70   
                                                     
 


LEEP Protocol Version 2.2 
Literature cited │ 36
 
 
Confidential, not for attribution or citation. 
 
                                                                                                                                                                           
 
14  Hansel NN, Washko GR, Foreman MG, Han MK, Hoffman EA, DeMeo DL, Barr RG, Van 
Beek EJ, Kazerooni EA, Wise RA, Brown RH, Black-Shinn J, Hokanson JE, Hanania NA, 
Make B, Silverman EK, Crapo JD, Dransfield MT; COPDGene Investigators. Racial 
differences in CT phenotypes in COPD. COPD. 2013;10(1):20-7   
15  Cerveri I, Corsico AG, Grosso A, Albicini F, Ronzoni V, Tripon B, Imberti F, Galasso T, 
Klersy C, Luisetti M, Pistolesi M. The rapid FEV(1) decline in chronic obstructive pulmonary 
disease is associated with predominant emphysema: a longitudinal study. COPD. 
2013;10(1):55-61   
16  Parr, D.G., Stoel, B.C., Stolk, J. and Stockley, R.A. Validation of computed tomographic lung 
densitometry for monitoring emphysema progression in alpha-1 antitrypsin deficiency. 
Thorax 2006; 61: 485-90. 
17  Newell JD Jr, Hogg JC, Snider GL. Report of a workshop: quantitative computed tomography 
scanning in longitudinal studies of emphysema. Eur Respir J. 2004;23:769-75   
18  Nishimura M, Makita H, Nagai K, Konno S, Nasuhara Y, Hasegawa M, Shimizu K, Betsuyaku 
T, Ito YM, Fuke S, Igarashi T, Akiyama Y, Ogura S; Hokkaido COPD Cohort Study 
Investigators. Annual change in pulmonary function and clinical phenotype in chronic 
obstructive pulmonary disease. Am J Respir Crit Care Med. 2012 Jan1;185(1):44-52   
19  McAllister DA, Ahmed FS, Austin JH, Henschke CI, Keller BM, Lemeshow A, Reeves AP, 
Mesia-Vela S, Pearson GD, Shiau MC, Schwartz JE, Yankelevitz DF, Barr RG. Emphysema 
predicts hospitalisation and incident airflow obstruction among older smokers: a prospective 
cohort study. PLoS One. 2014 Apr 3;9(4):e93221   
20  Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, Conway WA Jr, 
Enright PL, Kanner RE, O'Hara P, et al. Effects of smoking intervention and the use of an 
inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. 
JAMA. 1994 Nov 16;272:1497-505   
21  Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M; UPLIFT Study 
Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J 
Med. 2008;359:1543-54   
22  Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in 
pulmonary function in chronic obstructive pulmonary disease. N Engl J Med. 2000 Dec 
28;343(26):1902-9   
23  Stolk J, Putter H, Bakker EM, Shaker SB, Parr DG, Piitulainen E, Russi EW, Grebski E, 
Dirksen A, Stockley RA, Reiber JH, Stoel BC. Progression parameters for emphysema: a 
clinical investigation. Respir Med. 2007;101(9):1924-30   
24  Stockley RA, Parr DG, Piitulainen E, Stolk J, Stoel BC, Dirksen A. Therapeutic efficacy of α-
1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 
randomised clinical trials using computed tomography densitometry. Respir Res. 2010 Oct 
5;11:136   
25  Stolk J, Cooper BG, Stoel B, Rames A, Rutman O, Soliman S, Stockley R.Retinoid treatment 
of Emphysema in Patients on the Alpha-1 International Registry. The REPAIR study: study 
design, methodology and quality control of study assessments. Ther Adv Respir Dis. 
2010;4:319-32   
26  Roth MD, Connett JE, D'Armiento JM, Foronjy RF, Friedman PJ, Goldin JG, Louis TA, Mao 
JT, Muindi JR, O'Connor GT, Ramsdell JW, Ries AL, Scharf SM, Schluger NW, Sciurba FC, 
Skeans MA, Walter RE, Wendt CH, Wise RA; FORTE Study Investigators.  Feasibility of 
retinoids for the treatment of emphysema study. Chest. 2006;130:1334-45 
27  Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, 
van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas 


LEEP Protocol Version 2.2 
Literature cited │ 37
 
 
Confidential, not for attribution or citation. 
 
                                                                                                                                                                           
 
D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. Standardisation of 
spirometry. Eur Respir J. 2005 Aug;26(2):319-38   
28  Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the 
general U.S. population. Am J Respir Crit Care Med. 1999;159:179-87  
29  Garfield JL, Marchetti N, Gaughan JP, Steiner RM, Criner GJ. Total lung capacity by 
plethysmography and high-resolution computed tomography in COPD. Int J Chron Obstruct 
Pulmon Dis. 2012;7:119-26   
30  Martinez CH, Chen YH, Westgate PM, Liu LX, Murray S, Curtis JL, Make BJ, Kazerooni EA, 
Lynch DA, Marchetti N, Washko GR, Martinez FJ, Han MK; COPDGene Investigators. 
Relationship between quantitative CT metrics and health status and BODE in chronic 
obstructive pulmonary disease. Thorax. 2012 May;67(5):399-406 
31  Mahler DA, Waterman LA, Ward J, McCusker C, ZuWallack R,Baird JC. Validity and 
responsiveness of the self-administered computerized versions of the baseline and transition 
dyspnea indexes. Chest, 2007. 132(4): p. 1283-90 
32  Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first 
validation of the COPD assessment test. Eur Respir J. 2009 Sep;34(3):648-54 
33  Aletaha, D. (2010). From the item to the outcome: the promising prospects of PROMIS. 
Arthritis Research & Therapy, 12(1), 104 
34  COZAAR – Losartan potassium tablets [package insert]. Whitehouse Station. NJ: Merck & 
Co, Inc; 2014 
35  COZAAR – Losartan potassium tablets [package insert]. Whitehouse Station. NJ: Merck & 
Co, Inc; 2014 
36   Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the 
general U.S. population. Am J Respir Crit Care Med. 1999;159:179-87  
37  Diggle PJ, Heagerty P, Liang K-Y, Zeger SL. “Analysis of Longitudinal Data 2nd ed.” Oxford 
University Press, 2002; Chapter 7:126-137 
38  Chi, Yueh‐Yun, and Joseph G. Ibrahim. "Joint models for multivariate longitudinal and 
multivariate survival data." Biometrics 62.2 (2006): 432-445 
39  Rosner, B. Fundamentals of Biostatistics, Sixth Edition, page 335