LEEP: Losartan Effects on Emphysema Progression

• Sponsor: JHSPH Center for Clinical Trials (Other)
• Overall Status: Completed
• CT.gov ID: NCT02696564
• Collaborator: University of Pittsburgh (Other)
• Enrollment: 220
• Locations: 28
• Arms: 2
• Actual Duration (Months): 49.2
• Patients Per Site: 7.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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

.

Condition or Disease	Intervention/Treatment	Phase
Emphysema	Drug: Losartan; Drug: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 220 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Losartan Effects on Emphysema Progression
• Actual Study Start Date: May 23, 2017
• Actual Primary Completion Date: Mar 31, 2021
• Actual Study Completion Date: Jun 30, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Losartan 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.	Drug: Losartan; 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated
Placebo Comparator: placebo 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.	Drug: Placebo; one capsule per day for two weeks, followed by two capsules per day for 46 weeks

Outcome Measures

Primary Outcome Measures

1. Change in Mean pct950 [48 weeks]

   change in percentage of voxels with density less than -950 Hounsfield Units

Secondary Outcome Measures

1. Change From Baseline in Pre-bronchodilator FEV1 Percent Predicted [48 weeks]

   Change from the first visit to the final visit in a spirometry (breathing test) measure: forced expiratory volume in one second (FEV1). The test is administered without the participant taking any bronchodilator medication. The FEV1 is compared to standard predicted values in the US population for each individual based on their height, gender, and ethnic group; the result is given as percent of predicted value.

2. Change From Baseline in Post-bronchodilator FEV1 Percent Predicted [48 weeks]

   Change from the first visit to the final visit in a spirometry (breathing test) measure: forced expiratory volume in one second (FEV1). This test is performed after the participant is given bronchodilator medications. The FEV1 is compared to standard predicted values in the US population for each individual based on their height, gender, and ethnic group; the result is given as percent of predicted value.

3. Change From Baseline in CAT Score [48 weeks]

   Change from the first visit to the final visit in the participant's COPD Assessment Test (CAT) score. The CAT is an 8-item questionnaire assessing the impact of COPD on health status. CAT scores range from 0 to 40, with higher scores indicating a more severe impact of COPD on a patient's life.

4. Change From Baseline in SGRQ Score: Total [48 weeks]

   Change from the first visit to the final visit in participants' score on the St George's Respiratory Questionnaire - COPD. The St George's Respiratory Questionnaire for COPD patients (SGRQ-C) is a 40-item questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with COPD. The SGRQ-C includes three categories: Symptoms (frequency and severity), Activities caused or limited by breathlessness, and Impacts on social and psychological functioning caused by airways disease. The total score and scores for each category range from 0 to 100, with higher scores indicating more limitations.

5. Change From Baseline in SGRQ Score: Symptoms [48 weeks]

   Change from the first visit to the final visit in participants' scores on the symptom-related questions on the St Georges Respiratory Questionnaire-COPD. The St George's Respiratory Questionnaire for COPD patients (SGRQ-C) is a 40-item questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with COPD. The SGRQ-C includes three categories: Symptoms (frequency and severity), Activities caused or limited by breathlessness, and Impacts on social and psychological functioning caused by airways disease. The total score and scores for each category range from 0 to 100, with higher scores indicating more limitations.

6. Change From Baseline in SGRQ Score: Activity [48 weeks]

   Change from the first visit to the final visit in participants' scores on the activity-related questions on the St Georges Respiratory Questionnaire-COPD. The St George's Respiratory Questionnaire for COPD patients (SGRQ-C) is a 40-item questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with COPD. The SGRQ-C includes three categories: Symptoms (frequency and severity), Activities caused or limited by breathlessness, and Impacts on social and psychological functioning caused by airways disease. The total score and scores for each category range from 0 to 100, with higher scores indicating more limitations.

7. Change in SGRQ Score: Impact [48 weeks]

   Change from the first visit to the final visit in participants' scores on the impact-related questions on the St Georges Respiratory Questionnaire-COPD. The St George's Respiratory Questionnaire for COPD patients (SGRQ-C) is a 40-item questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with COPD. The SGRQ-C includes three categories: Symptoms (frequency and severity), Activities caused or limited by breathlessness, and Impacts on social and psychological functioning caused by airways disease. The total score and scores for each category range from 0 to 100, with higher scores indicating more limitations.

8. Change From Baseline in mMRC Dyspnea Scale [48 weeks]

   Change from the first visit to the final visit in participants' scores on the modified Medical Research Council dyspnea scale. The modified Medical Research Council dyspnea scale (mMRC) is a self-rating tool to measure how much breathlessness affects someone's day to day activities. Scores are between 0 and 4, with higher scores indicating more severe breathlessness.

9. Change From Baseline in PROMIS-20a T-score [48 weeks]

   Change from the first visit to the final visit in participants' scores on the Patient-Reported Outcome Measures Information System (PROMIS) Physical Function assessment. The Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 20a is a 20-item questionnaire used to indicate a patient's ability to perform activities of daily living, such as bathing, dressing, and commuting. Raw scores from this questionnaire are compared to a reference population to create a "T-score". The general US population is the reference population. In this T-score metric, 50 indicates the population mean with a standard deviation of 10. Higher scores mean better outcomes (more ability to do activities of daily living)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Mild to severe COPD: Ratio of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) less than or equal to 0.70, FEV1 20-80% of predicted

• Current or former smoker

• HRCT scan with 5-35% of voxels with density less than -950 Hounsfield Units (HU)

• Ability to understand and willingness to sign consent documents

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 (e.g., 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

• Potassium supplementation or serum potassium level of 5.0 milliequivalents (mEq)/dL or higher at V1

• Current use of a potassium sparing diuretic

• COPD exacerbation requiring treatment within 6 weeks at V1

• Chronic systemic corticosteroid use of more than 10mg/day of prednisone

• Resting SpO2 <89% on 2 L nasal cannula continuous flow; unless at altitude > 4,000 feet, then resting oxygen saturation (SpO2) <89% on 4 L N C continuous flow

• Untreated arterial hypertension (systolic blood pressure greater than140 mm Hg, diastolic blood pressure greater than 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 higher than 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 (LFTs more than 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35249
2	University of Arizona	Tucson	Arizona	United States	85724
3	University of California at San Diego	San Diego	California	United States	92103
4	University of California at San Francisco	San Francisco	California	United States	94143
5	National Jewish Medical and Research Center	Denver	Colorado	United States	80206
6	Western Connecticut Health Network	Danbury	Connecticut	United States	06810
7	University of Florida College of Medicine	Jacksonville	Florida	United States	32209
8	University of South Florida	Tampa	Florida	United States	33613
9	University of Illinois at Chicago	Chicago	Illinois	United States	60608
10	Northwestern University	Chicago	Illinois	United States	60611
11	Rush University Medical Center	Chicago	Illinois	United States	60612
12	University of Chicago Hospitals	Chicago	Illinois	United States	60637
13	St. Vincent Hospital and Health Care Center, Inc.	Indianapolis	Indiana	United States	46260
14	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
15	Louisiana State University	New Orleans	Louisiana	United States	70112
16	University of Michigan	Ann Arbor	Michigan	United States	48109-5360
17	St. Louis University School of Medicine	Saint Louis	Missouri	United States	63104
18	St. Louis Asthma Clinical Research Center - Washington University School of Medicine	Saint Louis	Missouri	United States	63110
19	New York University School of Medicine	New York	New York	United States	10016
20	Weill Cornell Medicine	New York	New York	United States	10021
21	Mount Sinai National Jewish Health Respiratory Institute; Icahn School of Medicine	New York	New York	United States	10029
22	Columbia University Medical Center	New York	New York	United States	10032
23	Duke University Medical Center	Durham	North Carolina	United States	27710
24	Temple University	Philadelphia	Pennsylvania	United States	19140
25	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
26	Baylor College of Medicine	Houston	Texas	United States	77030
27	Vermont Lung Center at The University of Vermont	Colchester	Vermont	United States	05466
28	Pacific Northwest Airways - VA Puget Sound Healthcare System	Seattle	Washington	United States	98108

Sponsors and Collaborators

• JHSPH Center for Clinical Trials
• University of Pittsburgh

Investigators

• Principal Investigator: Robert Wise, MD, Johns Hopkins University
• Principal Investigator: Janet Holbrook, PhD, Johns Hopkins University Bloomberg School of Public Health

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 17, 2018

More Information

Publications

None provided.

• Responsible Party: JHSPH Center for Clinical Trials
• ClinicalTrials.gov Identifier: NCT02696564
• Other Study ID Numbers: U01HL128951
• First Posted: Mar 2, 2016
• Last Update Posted: Jun 1, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by JHSPH Center for Clinical Trials: COPD; emphysema; HRCT; losartan
• Additional relevant MeSH terms: Pulmonary Emphysema; Emphysema; Losartan

Study Results

Participant Flow

Recruitment Details	2,779 individuals were screened for this study; of those, 2,028 were determined to be ineligible, and 531 declined to participate.
Pre-assignment Detail	220 individuals were randomized into the study.

Arm/Group Title	Losartan	Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
Period Title: Overall Study
STARTED	108	112
COMPLETED	94	99
NOT COMPLETED	14	13

Baseline Characteristics

Arm/Group Title	Losartan	Placebo	Total
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks	Total of all reporting groups
Overall Participants	108	112	220
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	66	65	65
Sex: Female, Male (Count of Participants)
Female	47 43.5%	46 41.1%	93 42.3%
Male	61 56.5%	66 58.9%	127 57.7%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	19 17.6%	23 20.5%	42 19.1%
White	88 81.5%	88 78.6%	176 80%
Other	1 0.9%	1 0.9%	2 0.9%
Region of Enrollment (participants) [Number]
United States	108 100%	112 100%	220 100%
Body Mass Index (BMI) (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	27	26	26
Current smokers (past month) (Count of Participants)
Count of Participants [Participants]	26 24.1%	26 23.2%	52 23.6%
Smoking history (Pack-years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Pack-years]	46	42	44
Spirometry percent predicted (Percent predicted) [Median (Inter-Quartile Range) ]
Pre-bronchodilator % predicted FEV1	43	43	43
Post-bronchodilator % predicted FEV1	48	48	48
Spirometry pre-bronchodilator FEV1 (Liters) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Liters]	1.1	1.1	1.1
Sitting Blood Pressure (Millimeters of mercury (mmHg)) [Median (Inter-Quartile Range) ]
Systolic	125	123	124
Diastolic	77	75	76
St. George's Respiratory Questionnaire for chronic obstructive pulmonary disease (COPD) score (units on a scale) [Median (Inter-Quartile Range) ]
Total	42	40	42
Symptoms	55	56	55
Activity	59	59	59
Impact	28	26	27
COPD Assessment Test (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	17	16	17
COPD Assessment Test impact level (Count of Participants)
Mild	21 19.4%	26 23.2%	47 21.4%
Moderate	52 48.1%	45 40.2%	97 44.1%
Severe	35 32.4%	33 29.5%	68 30.9%
Very severe	0 0%	8 7.1%	8 3.6%
Modified Medical Research Council dyspnea scale (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	1	1	1
PROMIS Physical Function-20a (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	40	40	40

Outcome Measures

1. Primary Outcome

Title	Change in Mean pct950
Description	change in percentage of voxels with density less than -950 Hounsfield Units
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Losartan	Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
Measure Participants	94	99
Least Squares Mean (95% Confidence Interval) [percentage of voxels]	1.35	0.66

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	We will estimate a 95% confidence interval for the losartan vs placebo mean difference, 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.
Statistical Test of Hypothesis	p-Value	0.133
	Comments
	Method	Mixed Models Analysis
	Comments	P-value based on generalized linear mixed models with covariates for site, baseline value, and for treatment group.

2. Secondary Outcome

Title	Change From Baseline in Pre-bronchodilator FEV1 Percent Predicted
Description	Change from the first visit to the final visit in a spirometry (breathing test) measure: forced expiratory volume in one second (FEV1). The test is administered without the participant taking any bronchodilator medication. The FEV1 is compared to standard predicted values in the US population for each individual based on their height, gender, and ethnic group; the result is given as percent of predicted value.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

Pre-bronchodilator results were not available at the baseline and/or final visit for 57 participants in the Losartan group and 56 participants in the placebo group. This was due in part to the elimination of all non-medically necessary spirometry testing during the COVID-19 pandemic.

Arm/Group Title	Losartan	Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
Measure Participants	51	56
Least Squares Mean (95% Confidence Interval) [percentage of predicted value]	-0.99	-0.54

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Statistical differences were inferred if the 95% confidence intervals (CI) did not include zero.
Statistical Test of Hypothesis	p-Value	0.762
	Comments	P-value based on generalized linear mixed models with covariates for site, baseline value, and for treatment group.
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Change From Baseline in Post-bronchodilator FEV1 Percent Predicted
Description	Change from the first visit to the final visit in a spirometry (breathing test) measure: forced expiratory volume in one second (FEV1). This test is performed after the participant is given bronchodilator medications. The FEV1 is compared to standard predicted values in the US population for each individual based on their height, gender, and ethnic group; the result is given as percent of predicted value.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

Post-bronchodilator results were not available at the baseline and/or final visit for 35 participants in the Losartan group and 39 participants in the placebo group. This was due in part to the elimination of all non-medically necessary spirometry testing during the COVID-19 pandemic.

Arm/Group Title	Losartan	Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
Measure Participants	73	73
Least Squares Mean (95% Confidence Interval) [percentage of predicted value]	-2.60	-2.37

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Statistical differences were inferred if the 95% confidence intervals (CI) did not include zero.
Statistical Test of Hypothesis	p-Value	0.834
	Comments	P-value based on generalized linear mixed models with covariates for site, baseline value, and for treatment group.
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Change From Baseline in CAT Score
Description	Change from the first visit to the final visit in the participant's COPD Assessment Test (CAT) score. The CAT is an 8-item questionnaire assessing the impact of COPD on health status. CAT scores range from 0 to 40, with higher scores indicating a more severe impact of COPD on a patient's life.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

CAT results were not available at the baseline and/or final visit for 9 participants in the Losartan group and 8 participants in the placebo group.

Arm/Group Title	Losartan	Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
Measure Participants	99	104
Least Squares Mean (95% Confidence Interval) [score on a scale]	-0.18	0.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Statistical differences were inferred if the 95% confidence intervals (CI) did not include zero.
Statistical Test of Hypothesis	p-Value	0.783
	Comments	P-value based on generalized linear mixed models with covariates for site, baseline value, and for treatment group.
	Method	Mixed Models Analysis
	Comments

5. Secondary Outcome

Title	Change From Baseline in SGRQ Score: Total
Description	Change from the first visit to the final visit in participants' score on the St George's Respiratory Questionnaire - COPD. The St George's Respiratory Questionnaire for COPD patients (SGRQ-C) is a 40-item questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with COPD. The SGRQ-C includes three categories: Symptoms (frequency and severity), Activities caused or limited by breathlessness, and Impacts on social and psychological functioning caused by airways disease. The total score and scores for each category range from 0 to 100, with higher scores indicating more limitations.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

Total SGRQ results were not available at the baseline and/or final visit for 9 participants in the Losartan group and 9 participants in the placebo group.

Arm/Group Title	Losartan	Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
Measure Participants	99	103
Least Squares Mean (95% Confidence Interval) [score on a scale]	-1.31	1.20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Statistical differences were inferred if the 95% confidence intervals (CI) did not include zero.
Statistical Test of Hypothesis	p-Value	0.053
	Comments	P-value based on generalized linear mixed models with covariates for site, baseline value, and for treatment group.
	Method	Mixed Models Analysis
	Comments

6. Secondary Outcome

Title	Change From Baseline in SGRQ Score: Symptoms
Description	Change from the first visit to the final visit in participants' scores on the symptom-related questions on the St Georges Respiratory Questionnaire-COPD. The St George's Respiratory Questionnaire for COPD patients (SGRQ-C) is a 40-item questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with COPD. The SGRQ-C includes three categories: Symptoms (frequency and severity), Activities caused or limited by breathlessness, and Impacts on social and psychological functioning caused by airways disease. The total score and scores for each category range from 0 to 100, with higher scores indicating more limitations.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

SGRQ results were not available at the baseline and/or final visit for 9 participants in the Losartan group and 9 participants in the placebo group.

Arm/Group Title	Losartan	Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
Measure Participants	99	103
Least Squares Mean (95% Confidence Interval) [score on a scale]	-6.19	-1.78

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Statistical differences were inferred if the 95% confidence intervals (CI) did not include zero.
Statistical Test of Hypothesis	p-Value	0.016
	Comments	P-value based on generalized linear mixed models with covariates for site, baseline value, and for treatment group.
	Method	Mixed Models Analysis
	Comments

7. Secondary Outcome

Title	Change From Baseline in SGRQ Score: Activity
Description	Change from the first visit to the final visit in participants' scores on the activity-related questions on the St Georges Respiratory Questionnaire-COPD. The St George's Respiratory Questionnaire for COPD patients (SGRQ-C) is a 40-item questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with COPD. The SGRQ-C includes three categories: Symptoms (frequency and severity), Activities caused or limited by breathlessness, and Impacts on social and psychological functioning caused by airways disease. The total score and scores for each category range from 0 to 100, with higher scores indicating more limitations.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

SGRQ results were not available at the baseline and/or final visit for 9 participants in the Losartan group and 9 participants in the placebo group.

Arm/Group Title	Losartan	Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
Measure Participants	99	103
Least Squares Mean (95% Confidence Interval) [score on a scale]	-0.66	2.45

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Statistical differences were inferred if the 95% confidence intervals (CI) did not include zero.
Statistical Test of Hypothesis	p-Value	0.065
	Comments	P-value based on generalized linear mixed models with covariates for site, baseline value, and for treatment group.
	Method	Mixed Models Analysis
	Comments

8. Secondary Outcome

Title	Change in SGRQ Score: Impact
Description	Change from the first visit to the final visit in participants' scores on the impact-related questions on the St Georges Respiratory Questionnaire-COPD. The St George's Respiratory Questionnaire for COPD patients (SGRQ-C) is a 40-item questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with COPD. The SGRQ-C includes three categories: Symptoms (frequency and severity), Activities caused or limited by breathlessness, and Impacts on social and psychological functioning caused by airways disease. The total score and scores for each category range from 0 to 100, with higher scores indicating more limitations.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

SGRQ results were not available at the baseline and/or final visit for 9 participants in the Losartan group and 9 participants in the placebo group.

Arm/Group Title	Losartan	Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
Measure Participants	99	103
Least Squares Mean (95% Confidence Interval) [score on a scale]	-0.25	1.35

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Statistical differences were inferred if the 95% confidence intervals (CI) did not include zero.
Statistical Test of Hypothesis	p-Value	0.293
	Comments	P-value based on generalized linear mixed models with covariates for site, baseline value, and for treatment group.
	Method	Mixed Models Analysis
	Comments

9. Secondary Outcome

Title	Change From Baseline in mMRC Dyspnea Scale
Description	Change from the first visit to the final visit in participants' scores on the modified Medical Research Council dyspnea scale. The modified Medical Research Council dyspnea scale (mMRC) is a self-rating tool to measure how much breathlessness affects someone's day to day activities. Scores are between 0 and 4, with higher scores indicating more severe breathlessness.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

mMRC dyspnea scale results were not available at the baseline and/or final visit for 9 participants in the Losartan group and 9 participants in the placebo group.

Arm/Group Title	Losartan	Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
Measure Participants	99	103
Least Squares Mean (95% Confidence Interval) [score on a scale]	0.01	0.11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Statistical differences were inferred if the 95% confidence intervals (CI) did not include zero.
Statistical Test of Hypothesis	p-Value	0.356
	Comments	P-value based on generalized linear mixed models with covariates for site, baseline value, and for treatment group.
	Method	Mixed Models Analysis
	Comments

10. Secondary Outcome

Title	Change From Baseline in PROMIS-20a T-score
Description	Change from the first visit to the final visit in participants' scores on the Patient-Reported Outcome Measures Information System (PROMIS) Physical Function assessment. The Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 20a is a 20-item questionnaire used to indicate a patient's ability to perform activities of daily living, such as bathing, dressing, and commuting. Raw scores from this questionnaire are compared to a reference population to create a "T-score". The general US population is the reference population. In this T-score metric, 50 indicates the population mean with a standard deviation of 10. Higher scores mean better outcomes (more ability to do activities of daily living)
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

PROMIS-20a results were not available at the baseline and/or final visit for 9 participants in the Losartan group and 10 participants in the placebo group.

Arm/Group Title	Losartan	Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
Measure Participants	99	102
Least Squares Mean (95% Confidence Interval) [score on a scale]	0.00	-1.04

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Statistical differences were inferred if the 95% confidence intervals (CI) did not include zero.
Statistical Test of Hypothesis	p-Value	0.009
	Comments	P-value based on generalized linear mixed models with covariates for site, baseline value, and for treatment group.
	Method	Mixed Models Analysis
	Comments

11. Post-Hoc Outcome

Title	Number of COPD Exacerbations by Severity and Treatment Assignment
Description	This measure assessed the number of exacerbations of chronic obstructive pulmonary disease in both the losartan and placebo treatment groups. Participants were asked about current and past exacerbations during each study visit. Exacerbations were defined as 2 or more worsening COPD symptoms lasting 3 or more consecutive days that required a new prescribed treatment. Each exacerbation was further classified as "mild" (requiring only a change in existing COPD medications),"moderate" (requiring a new prescription for a steroid and/or antibiotic), or "severe" (requiring a hospitalization for COPD symptoms).
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

The analysis population consists of the number of participants who reported at least one exacerbation in each treatment group. Two participants in the losartan treatment group did not report any COPD exacerbations during the study.

Arm/Group Title	Losartan	Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated	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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
Measure Participants	106	112
Mild exacerbation	3	4
Moderate exacerbation	41	47
Severe exacerbation	7	21

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments	P-value for rate of mild exacerbations between treatment groups (measured in events per 100 person-years).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.892
	Comments
	Method	Negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Relative rate (losartan to placebo)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.03 to 18.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments	P-value for rate of moderate exacerbations between treatment groups (measured in events per 100 person-years).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.946
	Comments
	Method	Negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Relative rate (losartan to placebo)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.05 to 14.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments	P-value for rate of severe exacerbations between treatment groups (measured in events per 100 person-years).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.487
	Comments
	Method	Negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Relative rate (losartan to placebo)
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95%; 0.02 to 6.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Baseline up to 48 weeks
Adverse Event Reporting Description	Adverse events were assessed throughout the study through regular physical exams by a study physician, symptom questionnaires and medical history review at each study visit, and blood testing at the beginning, middle, and end of the study.
Arm/Group Title	Losartan		Placebo
Arm/Group Description	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. Losartan: 50mg once per day for two weeks,followed by 100mg once per day for 46 weeks if increased dose tolerated		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. Placebo: one capsule per day for two weeks, followed by two capsules per day for 46 weeks
All Cause Mortality
	Losartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/108 (0.9%)		2/112 (1.8%)
Serious Adverse Events
	Losartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/108 (16.7%)		25/112 (22.3%)
Cardiac disorders
Myocardial infarction	1/108 (0.9%)	1	1/112 (0.9%)	1
Coronary artery disease	0/108 (0%)	0	3/112 (2.7%)	3
Ear and labyrinth disorders
Vertigo	1/108 (0.9%)	1	0/112 (0%)	0
Gastrointestinal disorders
Gastrointestinal bleeding	0/108 (0%)	0	2/112 (1.8%)	2
General disorders
Dehydration	1/108 (0.9%)	1	0/112 (0%)	0
Infections and infestations
Influenza	0/108 (0%)	0	1/112 (0.9%)	1
Sepsis	0/108 (0%)	0	1/112 (0.9%)	1
Injury, poisoning and procedural complications
Falls	0/108 (0%)	0	1/112 (0.9%)	1
Ankle fracture	0/108 (0%)	0	1/112 (0.9%)	1
Motor vehicle accident	1/108 (0.9%)	1	0/112 (0%)	0
Musculoskeletal and connective tissue disorders
Spinal fusion revision	1/108 (0.9%)	1	0/112 (0%)	0
Pseudogout	0/108 (0%)	0	1/112 (0.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/108 (0.9%)	1	0/112 (0%)	0
Lung cancer	2/108 (1.9%)	2	0/112 (0%)	0
Lymphoma	0/108 (0%)	0	1/112 (0.9%)	1
Prostate cancer	0/108 (0%)	0	1/112 (0.9%)	1
Nervous system disorders
Near syncope	0/108 (0%)	0	1/112 (0.9%)	1
Psychiatric disorders
Panic attack	0/108 (0%)	0	1/112 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
COPD Exacerbation	6/108 (5.6%)	6	15/112 (13.4%)	19
Bronchitis	1/108 (0.9%)	1	0/112 (0%)	0
Pneumonia	0/108 (0%)	0	3/112 (2.7%)	3
Acute respiratory failure secondary to end stage COPD	1/108 (0.9%)	1	1/112 (0.9%)	1
Collapsed lung	1/108 (0.9%)	1	0/112 (0%)	0
Pneumothorax	1/108 (0.9%)	1	0/112 (0%)	0
Radiation pneumonitis	1/108 (0.9%)	1	0/112 (0%)	0
Pleural effusion	0/108 (0%)	0	1/112 (0.9%)	1
Hypercapnic respiratory failure	0/108 (0%)	0	1/112 (0.9%)	1
Pulmonary embolism	0/108 (0%)	0	1/112 (0.9%)	1
Shortness of breath	0/108 (0%)	0	1/112 (0.9%)	1
Other (Not Including Serious) Adverse Events
	Losartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	106/108 (98.1%)		112/112 (100%)
Cardiac disorders
Chest pain	9/108 (8.3%)	10	8/112 (7.1%)	9
Gastrointestinal disorders
Diarrhea	13/108 (12%)	15	12/112 (10.7%)	16
Heartburn/indigestion	11/108 (10.2%)	17	24/112 (21.4%)	36
Nausea/vomiting	7/108 (6.5%)	7	10/112 (8.9%)	11
General disorders
Fatigue	38/108 (35.2%)	71	41/112 (36.6%)	77
Fever	5/108 (4.6%)	5	6/112 (5.4%)	6
Sleep problems	30/108 (27.8%)	46	34/112 (30.4%)	65
Sore throat	8/108 (7.4%)	9	18/112 (16.1%)	24
Musculoskeletal and connective tissue disorders
Back pain	33/108 (30.6%)	57	38/112 (33.9%)	77
Muscle cramps	28/108 (25.9%)	46	30/112 (26.8%)	49
Musculoskeletal pain	30/108 (27.8%)	50	32/112 (28.6%)	63
Weakness	19/108 (17.6%)	36	24/112 (21.4%)	36
Nervous system disorders
Dizziness/lightheadedness	27/108 (25%)	34	16/112 (14.3%)	20
Headache/ head pain	26/108 (24.1%)	38	35/112 (31.3%)	52
Respiratory, thoracic and mediastinal disorders
Congestion	42/108 (38.9%)	73	47/112 (42%)	70
Dry cough	22/108 (20.4%)	26	34/112 (30.4%)	57
Mild COPD exacerbation	3/108 (2.8%)	3	4/112 (3.6%)	4
Moderate COPD exacerbation	25/108 (23.1%)	41	29/112 (25.9%)	47
Severe COPD exacerbation	7/108 (6.5%)	7	14/112 (12.5%)	21
Skin and subcutaneous tissue disorders
Edema	8/108 (7.4%)	9	10/112 (8.9%)	15
Skin rash or hives	9/108 (8.3%)	9	7/112 (6.3%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.