Data Analysis for Drug Repurposing for Effective Alzheimer's Medicines (DREAM) - Montelukast vs Fluticasone
Conditions: Asthma
Sponsor: Brigham and Women's Hospital

Data Analysis for Drug Repurposing for Effective 
Alzheimer’s Medicines – Montelukast vs Fluticasone 
 
 
 
NCT05457855 
 
 
July 10, 2023 
 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
1 
1. Comparison Details 
 
a. Intended aim(s) 
 
To evaluate the comparative risk of dementia onset between patients treated with Montelukast versus Fluticasone 
for asthma. 
 
b. Primary endpoint  
Incident dementia (i.e., Alzheimer’s disease, vascular dementia, senile, presenile, or unspecified dementia, or 
dementia in other diseases classified elsewhere). 
 
2. Person responsible for implementation 
Seanna Vine 
 
3. Data Source(s) 
Medicare, 2008-2018  
 
 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
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4. Study Design Diagrams 
 

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DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
4 
5. Cohort Identification  
 
a. Cohort Summary 
This study will employ a new user, active comparator, observational cohort study design comparing Montelukast 
versus Fluticasone. The patients will be required to have continuous enrollment during the baseline period of 365 days 
before initiation of study drugs (cohort entry/index date). Follow-up for the outcome (dementia) differs between 
analyses. Follow-up begins the day after drug initiation (analysis 1, 3, 4); 180 days after drug initiation (analysis 2). 
 
b. Key details regarding cohort creation 
 
Index date: 
• Day of initiation of new Montelukast versus Fluticasone use 
 
Inclusion criteria for analyses 1, 3, 4: 
• Aged > 65 years on the index date 
• 365 days enrollment in Medicare Parts A, B, and D with no HMO coverage  
• No use of Montelukast versus Fluticasone, any time prior to index date (all available lookback approach with a 
minimum of 365 days) 
• No diagnosis of dementia any time prior to and including index date 
• No history of nursing home admission recorded in any time prior to and including index date 
• At least two claims with asthma diagnosis recorded in 365 days prior to index date (ICD-9 493.0x, 493.1, 
493.2x, 493.8x, 493.9x or ICD-10 J44.0, J44.1, J44.9, J45.2x, J45.3x, J45.4x, J45.5x, J45.9x) 
 
Inclusion criteria for analysis 2: 
• Aged > 65 years on the index date 
• 365 days enrollment in Medicare Parts A, B, and D with no HMO coverage or 365 days registration with a 
practice contributing data to CPRD prior to index date 
• No use of Montelukast versus Fluticasone, any time prior to index date (all available lookback approach with a 
minimum of 365 days) 
• No diagnosis of dementia any time prior to and including index date 
• No history of nursing home admission recorded in any time prior to and including index date 
• At least two claims with asthma diagnosis recorded in 365 days prior to index date (ICD-9 493.0x, 493.1, 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
5 
493.2x, 493.8x, 493.9x or ICD-10 J44.0, J44.1, J44.9, J45.2x, J45.3x, J45.4x, J45.5x, J45.9x) 
• 180-day continuous use of Montelukast versus Fluticasone starting on the index date 
 
 
c. Flowchart of the study cohort assembly 
 
  
Less Excluded Patients 
Remaining Patients 
All patients 
  
23,466,175 
Did not meet cohort entry criteria 
-21,749,739 
1,716,436 
Excluded due to insufficient enrollment 
-1,010,844 
705,592 
Excluded based on Dementia Exclusion 
-113,159 
592,433 
Excluded based on Nursing Home Admission 
-62,588 
529,845 
Excluded based on Peripheral artery disease 
Diagnosis 
-454,167 
75,678 
Excluded anyone aged <65 at index 
-24,145 
51,533 
Patients in Montelukast group 
  
12,575 
Patients in Fluticasone group 
  
38,958 
Final cohort 
  
51,533 
 
 
 
 
 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
6 
6. Variables  
 
a. Exposure-related variables:  
 
Study drug:  
The study exposure of interest is initiation of Montelukast 
Comparator: 
Fluticasone 
 
b. Covariates: 
 
Demographics 
Age 
Region 
Gender 
Calendar year of index date 
Race 
Low income subsidy 
 
 
Dementia risk factors 
Diabetes 
Depression 
Obesity 
Anxiety 
Hypertension 
Bipolar disorder 
Coronary artery disease 
Schizophrenia 
 
Markers for healthy behavior, frailty, healthcare use 
Smoking 
Number of outpatient visits 
Mammography 
Number of hospitalizations 
Colonoscopy 
Number of serum creatinine tests ordered 
Fecal occult blood test 
Composite frailty score 
Influenza vaccination 
Number of C-reactive protein tests ordered 
Pneumococcal vaccination 
Osteoporosis 
Herpes zoster vaccination 
Fractures 
Bone mineral density test 
Falls 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
7 
Number of distinct generic agents 
Use of supplemental oxygen 
Number of emergency room visits 
Combined comorbidity score 
 
Other Asthma treatments and Asthma severity indicators 
Respiratory failure 
LABA 
Asthma exacerbation 
SABA 
Tuberculosis 
SAMA 
Lung Cancer 
LAMA 
Bronchiectasis 
ICS (excluding Fluticasone) 
Sarcoidosis 
Omalizumab, Mepolizumab, Reslizumab, 
Benralizumab, Dupilumab 
Pulmonary Hypertension 
Leukotriene receptor antagonist (excluding 
Montelukast) 
Interstitial lung disease, lung fibrosis, ARDS 
Number of Pulmonologist visits 
Acute Upper/ Lower Respiratory Tract infection 
Pulmonary function test 
Pneumonia 
Antibiotics  
Corticosteroids 
 
 
Comedication use 
Lithium 
Diuretics 
Anti-epileptic mood stabilizers 
Nitrates 
Anti-epileptics (other than mood stabilizers) 
Lipid lowering drugs 
Atypical antipsychotics 
Non-insulin diabetes medications 
Benzodiazepines 
Insulin 
Serotonin-norepinephrine reuptake Inhibitors 
Antidepressants 
Selective serotonin reuptake inhibitors 
Angiotensin II receptor blockers (ARBs) 
Tricyclic antidepressants (TCAs) 
Angiotensin converting enzyme inhibitors (ACEi) 
Typical antipsychotics 
Calcium channel blockers 
Anticoagulants 
Beta blockers 
Antiplatelet agents 
Disease-modifying antirheumatic drugs (DMARDs) 
 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
8 
Comorbid conditions 
Atrial fibrillation 
Ischemic heart disease 
Coronary artery disease 
Chronic obstructive pulmonary disease 
Heart failure 
Malignancy 
Stroke or transient ischemic attack 
Drug or alcohol abuse or dependence 
Peripheral vascular disease 
Venous thromboembolism 
Hyperlipidemia 
Chronic liver disease  
Renal dysfunction 
Rheumatoid Arthritis 
 
ICD-9, ICD-10, HCPCS, and NDC codes used to define the covariates listed above are available in Appendix A. 
 
c. Outcome variables and study follow-up:  
 
• Primary outcome: incident dementia, i.e., Alzheimer’s disease, vascular dementia, senile, presenile, or 
unspecified dementia, or dementia in other diseases classified elsewhere. Outcome will be defined by 1 inpatient 
claim or 2 outpatient claims in analysis 1, 2, 3. In analysis 4, the outcome will be defined by 1 inpatient or 1 
outpatient claims and 1 prescription claim for a symptomatic treatment [donepezil, galantamine, rivastigmine, and 
memantine] within 6 months of each other with outcome date assigned to second event in the sequence.  
• Secondary outcomes: Individual component: 
Alzheimer’s disease 
 
Condition 
ICD-9 and ICD-10 codes 
Alzheimer’s disease 
331.0*, F00*, G30* 
Vascular dementia 
290.4*, F01* 
Senile, presenile, or unspecified dementia 
290.0*, 290.1*. 290.3*, 797*, F03* 
Dementia in other diseases classified elsewhere 
331.1*, 331.2*, 331.7*, 294.1*, F02* 
 
For analysis 1,3, and 4 the follow-up will start the day after initiation of Montelukast and Fluticasone and will continue 
until the earliest date of the following events: 
• The first occurrence of the outcome of interest  
• The date of end of continuous registration in the database, 
• End of the study period, 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
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• Measured death event occurs, 
• The date of drug discontinuation, defined as the date of the last continuous treatment episode of the index drug 
(Montelukast and Fluticasone) plus a defined grace period (i.e., 90 days after the end of the last prescription’s 
days’ supply in main analyses). 
 
For analysis 2, the follow-up will start 180 days after initiation of Montelukast and Fluticasone and will continue until the 
earliest date of the following events: 
• The first occurrence of the outcome of interest, unless otherwise specified for selected outcomes,  
• The date of end of continuous registration in the database, 
• End of the study period, 
• Measured death event occurs, 
• 
Maximum allowed follow-up time (1095 days) reached 
 
 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
10 
7. Propensity score analysis  
We will use a propensity-score (PS)1-based approach to account for measured confounding in this study. The PS 
will be calculated as the predicted probability of initiating the exposure of interest (i.e., the repurposing candidate) 
versus the reference drug conditional on baseline covariates using multivariable logistic regression constructed 
separately in each data source. On average, patients with similar PSs have similar distribution of potential 
confounders used to estimate the PS. Therefore, analyses conditioned on the PS provide effect estimates that are 
free from measured confounding. For all our analyses, initiators of each exposure of interest will be matched with 
initiators of the reference exposure based on their PS within each data source.2 Pair matching will be conducted 
using a nearest-neighbor algorithm, which seeks to minimize the distance between propensity scores in each pair 
of treated and reference patients,3 and a caliper of 0.025 on the natural scale of the PS will be used to ensure 
similarity between the matched patients.4  
 
We report multiple diagnostics for PS analysis in this protocol. First, the PS distributional overlap is provided 
between two groups before and after matching to ensure comparability of these groups.5 Next, balance in each 
individual covariate between two treatment groups is reported using standardized differences.6 
 
 
 
 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
11 
8. Table for covariate balance 
  
Unmatched 
PS-Matched 
Variable 
Montelukast 
Fluticasone 
St. Diff 
Montelukast 
Fluticasone 
St. Diff 
  
(N = 12,575) 
(N = 38,958) 
  
(N = 12,572) 
(N = 12,572) 
  
Demographics 
  
  
  
  
  
  
 Age, mean (SD)  
72.8 (6.1) 
73.3 (6.4) 
-8.20 
72.8 (6.1) 
72.8 (6.1) 
-0.30 
 Gender, n (%)  
  
  
  
  
  
  
 Male  
3694 (29.4) 
12706 (32.6) 
-7.00 
3694 (29.4) 
3764 (29.9) 
-1.20 
 Female  
8881 (70.6) 
26252 (67.4) 
7.00 
8878 (70.6) 
8808 (70.1) 
1.20 
 Race, n (%)  
  
  
  
  
  
  
 White  
10614 (84.4) 
33028 (84.8) 
-1.00 
10613 (84.4) 
10650 (84.7) 
-0.80 
 Black  
831 (6.6) 
3055 (7.8) 
-4.80 
831 (6.6) 
881 (7) 
-1.60 
 Hispanic  
218 (1.7) 
639 (1.6) 
0.70 
218 (1.7) 
203 (1.6) 
0.90 
Other 
912 (7.3) 
2236 (5.7) 
6.10 
910 (7.2) 
838 (6.7) 
2.30 
 Region, n (%)  
  
  
  
  
  
  
 Northeast; n (%)  
2271 (18.1) 
8670 (22.3) 
##### 
2271 (18.1) 
2335 (18.6) 
-1.30 
 South; n (%)  
5310 (42.2) 
13528 (34.7) 
15.50 
5307 (42.2) 
5179 (41.2) 
2.10 
 Midwest; n (%)  
2498 (19.9) 
8288 (21.3) 
-3.50 
2498 (19.9) 
2546 (20.3) 
-1.00 
 West; n (%)  
2484 (19.8) 
8431 (21.6) 
-4.70 
2484 (19.8) 
2501 (19.9) 
-0.30 
 Other; n (%)  
12 (0.1) 
41 (0.1) 
-0.30 
12 (0.1) 
11 (0.1) 
0.30 
Calendar year of index date, n (%) 
  
  
  
  
  
  
2014 
3143 (25) 
10567 (27.1) 
-4.90 
3142 (25) 
3037 (24.2) 
1.90 
2015 
2585 (20.6) 
8299 (21.3) 
-1.80 
2585 (20.6) 
2519 (20) 
1.30 
2016 
2396 (19.1) 
7305 (18.8) 
0.80 
2394 (19) 
2425 (19.3) 
-0.60 
2017 
2330 (18.5) 
6986 (17.9) 
1.50 
2330 (18.5) 
2408 (19.2) 
-1.60 
2018 
2121 (16.9) 
5801 (14.9) 
5.40 
2121 (16.9) 
2183 (17.4) 
-1.30 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
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Low income subsidy, n (%) 
1824 (14.5) 
6953 (17.8) 
-9.10 
1823 (14.5) 
1859 (14.8) 
-0.80 
Dementia risk factors, n (%) 
  
  
  
  
  
  
Diabetes 
4101 (32.6) 
13257 (34) 
-3.00 
4098 (32.6) 
4087 (32.5) 
0.20 
Obesity 
2804 (22.3) 
9138 (23.5) 
-2.80 
2804 (22.3) 
2808 (22.3) 
-0.10 
Coronary artery disease 
3338 (26.5) 
11429 (29.3) 
-6.20 
3338 (26.6) 
3264 (26) 
1.30 
Hypertension 
9870 (78.5) 
30962 (79.5) 
-2.40 
9867 (78.5) 
9909 (78.8) 
-0.80 
Depression 
2029 (16.1) 
6989 (17.9) 
-4.80 
2029 (16.1) 
2013 (16) 
0.30 
Anxiety 
2235 (17.8) 
6921 (17.8) 
0.00 
2235 (17.8) 
2234 (17.8) 
0.00 
Bipolar disorder 
126 (1) 
555 (1.4) 
-3.90 
126 (1) 
120 (1) 
0.50 
Schizophrenia 
8 (0.1) 
70 (0.2) 
-3.30 
8 (0.1) 
3 (0) 
1.90 
Markers for healthy behavior, frailty, 
healthcare use 
  
  
  
  
  
  
Smoking, n (%) 
2803 (22.3) 
10651 (27.3) 
##### 
2803 (22.3) 
2833 (22.5) 
-0.60 
Mammography, n (%) 
4285 (34.1) 
12152 (31.2) 
6.20 
4283 (34.1) 
4262 (33.9) 
0.40 
Colonoscopy, n (%) 
1465 (11.7) 
4797 (12.3) 
-2.00 
1464 (11.6) 
1465 (11.7) 
0.00 
Fecal occult blood test, n (%) 
1172 (9.3) 
3374 (8.7) 
2.30 
1172 (9.3) 
1172 (9.3) 
0.00 
Influenza vaccination, n (%) 
8417 (66.9) 
26819 (68.8) 
-4.10 
8416 (66.9) 
8463 (67.3) 
-0.80 
Herpes zoster vaccination, n (%) 
3 (0) 
11 (0) 
-0.30 
3 (0) 
2 (0) 
0.60 
Pneumococcal vaccination, n (%) 
5584 (44.4) 
17347 (44.5) 
-0.20 
5583 (44.4) 
5680 (45.2) 
-1.60 
Bone mineral density test, n (%) 
1743 (13.9) 
5139 (13.2) 
2.00 
1743 (13.9) 
1732 (13.8) 
0.30 
Number of distinct prescriptions, mean 
(SD) 
12.3 (5.8) 
12.5 (5.8) 
-2.30 
12.3 (5.8) 
12.2 (5.7) 
2.00 
Number of emergency room visits, mean 
(SD) 
0.7 (1.4) 
0.8 (1.6) 
-8.80 
0.7 (1.4) 
0.7 (1.2) 
1.20 
Number of outpatient visits, mean (SD) 
12.5 (8.4) 
12.4 (8.6) 
1.10 
12.5 (8.4) 
12.5 (8.6) 
0.90 
Number of hospitalizations, mean (SD) 
0.2 (0.6) 
0.2 (0.6) 
-6.60 
0.2 (0.6) 
0.2 (0.5) 
1.40 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
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Number of C-reactive protein tests 
ordered, mean (SD) 
0.2 (0.8) 
0.2 (0.9) 
-1.20 
0.2 (0.8) 
0.2 (0.8) 
0.40 
Number of serum creatinine tests 
ordered, mean (SD) 
0.9 (1.6) 
1.1 (2) 
##### 
0.9 (1.6) 
0.9 (1.5) 
1.60 
Composite frailty score, mean (SD) 
0.2 (0.1) 
0.2 (0.1) 
##### 
0.2 (0.1) 
0.2 (0.1) 
1.40 
Osteoporosis, n (%) 
1911 (15.2) 
5814 (14.9) 
0.80 
1911 (15.2) 
1912 (15.2) 
0.00 
Fractures, n (%) 
877 (7) 
2787 (7.2) 
-0.70 
877 (7) 
893 (7.1) 
-0.50 
Falls, n (%) 
641 (5.1) 
2326 (6) 
-3.80 
641 (5.1) 
656 (5.2) 
-0.50 
Use of supplemental oxygen, n (%) 
260 (2.1) 
1091 (2.8) 
-4.80 
260 (2.1) 
279 (2.2) 
-1.00 
Combined comorbidity score, mean (SD) 
2.2 (2.2) 
2.4 (2.4) 
##### 
2.2 (2.2) 
2.2 (2.2) 
0.50 
Comedication use, n (%) 
  
  
  
  
  
  
Lithium 
17 (0.1) 
50 (0.1) 
0.20 
17 (0.1) 
12 (0.1) 
1.20 
Anti-epileptic mood stabilizers 
142 (1.1) 
562 (1.4) 
-2.80 
142 (1.1) 
149 (1.2) 
-0.50 
Anti-epileptics (other than mood 
stabilizers) 
1839 (14.6) 
6087 (15.6) 
-2.80 
1837 (14.6) 
1778 (14.1) 
1.30 
Atypical antipsychotics 
170 (1.4) 
719 (1.8) 
-3.90 
170 (1.4) 
158 (1.3) 
0.80 
Benzodiazepines 
2537 (20.2) 
7878 (20.2) 
-0.10 
2537 (20.2) 
2523 (20.1) 
0.30 
Serotonin-norepinephrine reuptake 
inhibitors 
715 (5.7) 
2343 (6) 
-1.40 
715 (5.7) 
721 (5.7) 
-0.20 
Selective serotonin reuptake inhibitors 
2265 (18) 
7367 (18.9) 
-2.30 
2265 (18) 
2205 (17.5) 
1.20 
Tricyclic antidepressants (TCAs) 
434 (3.5) 
1548 (4) 
-2.80 
434 (3.5) 
425 (3.4) 
0.40 
Typical antipsychotics 
20 (0.2) 
105 (0.3) 
-2.40 
20 (0.2) 
24 (0.2) 
-0.80 
Anticoagulants 
1163 (9.2) 
4342 (11.1) 
-6.30 
1163 (9.3) 
1217 (9.7) 
-1.50 
Antiplatelet agents 
947 (7.5) 
3416 (8.8) 
-4.50 
947 (7.5) 
916 (7.3) 
0.90 
Nitrates 
915 (7.3) 
3131 (8) 
-2.90 
915 (7.3) 
881 (7) 
1.10 
Lipid lowering drugs 
6790 (54) 
22232 (57.1) 
-6.20 
6789 (54) 
6819 (54.2) 
-0.50 
Non-insulin diabetes medications 
2391 (19) 
7537 (19.3) 
-0.80 
2388 (19) 
2415 (19.2) 
-0.50 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
14 
Insulin 
725 (5.8) 
2740 (7) 
-5.20 
725 (5.8) 
705 (5.6) 
0.70 
Antidepressants 
3634 (28.9) 
11842 (30.4) 
-3.30 
3634 (28.9) 
3557 (28.3) 
1.40 
Angiotensin converting enzyme 
inhibitors (ACEi) 
3269 (26) 
10938 (28.1) 
-4.70 
3268 (26) 
3300 (26.2) 
-0.60 
Angiotensin II receptor blockers (ARBs) 
3599 (28.6) 
10554 (27.1) 
3.40 
3598 (28.6) 
3563 (28.3) 
0.60 
Beta blockers 
4312 (34.3) 
14499 (37.2) 
-6.10 
4312 (34.3) 
4274 (34) 
0.60 
Calcium channel blockers 
3182 (25.3) 
10328 (26.5) 
-2.80 
3181 (25.3) 
3192 (25.4) 
-0.20 
Disease-modifying antirheumatic drugs 
(DMARDs) 
457 (3.6) 
1522 (3.9) 
-1.40 
457 (3.6) 
452 (3.6) 
0.20 
Diuretics 
5260 (41.8) 
17028 (43.7) 
-3.80 
5259 (41.8) 
5306 (42.2) 
-0.80 
Biologics (Omalizumab, Mepolizumab, 
Reslizumab, Benralizumab, Dupilumab) 
89 (0.7) 
218 (0.6) 
1.90 
89 (0.7) 
77 (0.6) 
1.20 
Comorbid conditions, n (%) 
  
  
  
  
  
  
Atrial fibrillation 
1527 (12.1) 
5492 (14.1) 
-5.80 
1527 (12.1) 
1543 (12.3) 
-0.40 
Heart failure 
1397 (11.1) 
5145 (13.2) 
-6.40 
1397 (11.1) 
1352 (10.8) 
1.10 
Stroke or transient ischemic attack 
858 (6.8) 
3209 (8.2) 
-5.40 
858 (6.8) 
867 (6.9) 
-0.30 
Peripheral vascular disease 
1056 (8.4) 
3915 (10) 
-5.70 
1055 (8.4) 
1055 (8.4) 
0.00 
Hyperlipidemia 
8900 (70.8) 
27637 (70.9) 
-0.40 
8898 (70.8) 
8820 (70.2) 
1.40 
Renal dysfunction 
1706 (13.6) 
6279 (16.1) 
-7.20 
1705 (13.6) 
1704 (13.6) 
0.00 
Chronic liver disease 
810 (6.4) 
2628 (6.7) 
-1.20 
809 (6.4) 
807 (6.4) 
0.10 
Ischemic heart disease 
3250 (25.8) 
11107 (28.5) 
-6.00 
3250 (25.9) 
3170 (25.2) 
1.50 
Chronic obstructive pulmonary disease 
5222 (41.5) 
16890 (43.4) 
-3.70 
5220 (41.5) 
5213 (41.5) 
0.10 
Malignancy 
3369 (26.8) 
11073 (28.4) 
-3.70 
3369 (26.8) 
3411 (27.1) 
-0.80 
Drug or alcohol abuse or dependence 
944 (7.5) 
4336 (11.1) 
##### 
944 (7.5) 
936 (7.4) 
0.20 
Venous thromboembolism 
425 (3.4) 
1565 (4) 
-3.40 
425 (3.4) 
423 (3.4) 
0.10 
Rheumatoid Arthritis 
595 (4.7) 
1994 (5.1) 
-1.80 
595 (4.7) 
592 (4.7) 
0.10 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
15 
Other Asthma treatments and Asthma 
severity indicators 
  
  
  
  
  
  
Asthma exacerbation, n (%) 
213 (1.7) 
478 (1.2) 
3.90 
211 (1.7) 
174 (1.4) 
2.40 
Bronchiectasis, n (%) 
347 (2.8) 
1006 (2.6) 
1.10 
346 (2.8) 
357 (2.8) 
-0.50 
Interstitial lung disease, lung fibrosis, 
ARDS, n (%) 
1220 (9.7) 
3941 (10.1) 
-1.40 
1219 (9.7) 
1205 (9.6) 
0.40 
Lung Cancer, n (%) 
144 (1.1) 
674 (1.7) 
-4.90 
144 (1.1) 
137 (1.1) 
0.50 
Pneumonia, n (%) 
694 (5.5) 
2455 (6.3) 
-3.30 
693 (5.5) 
670 (5.3) 
0.80 
Pulmonary Hypertension, n (%) 
194 (1.5) 
691 (1.8) 
-1.80 
194 (1.5) 
182 (1.4) 
0.80 
Respiratory failure, n (%) 
723 (5.7) 
2725 (7) 
-5.10 
722 (5.7) 
704 (5.6) 
0.60 
Sarcoidosis, n (%) 
60 (0.5) 
259 (0.7) 
-2.50 
60 (0.5) 
68 (0.5) 
-0.90 
Tuberculosis, n (%) 
2157 (17.2) 
7552 (19.4) 
-5.80 
2155 (17.1) 
2177 (17.3) 
-0.50 
Acute Upper/ Lower Respiratory Tract 
infection, n (%) 
4789 (38.1) 
14315 (36.7) 
2.80 
4788 (38.1) 
4850 (38.6) 
-1.00 
Pulmonary function test, n (%) 
4989 (39.7) 
13566 (34.8) 
10.00 
4988 (39.7) 
4943 (39.3) 
0.70 
Number of Pulmonologist visits, mean 
(SD) 
1.1 (2.4) 
1 (2.5) 
3.50 
1.1 (2.4) 
1.1 (2.5) 
0.90 
Antibiotics, n (%) 
9638 (76.6) 
29724 (76.3) 
0.80 
9636 (76.6) 
9601 (76.4) 
0.70 
Corticosteroids, n (%) 
6750 (53.7) 
18540 (47.6) 
12.20 
6748 (53.7) 
6551 (52.1) 
3.10 
ICS (excluding Fluticasone), n (%) 
3647 (29) 
8369 (21.5) 
17.40 
3644 (29) 
3386 (26.9) 
4.60 
LAMA, n (%) 
884 (7) 
3315 (8.5) 
-5.50 
884 (7) 
883 (7) 
0.00 
LABA, n (%) 
2532 (20.1) 
12953 (33.2) 
##### 
2532 (20.1) 
2143 (17) 
8.00 
Leukotriene receptor antagonist 
(excluding Montelukast), n (%) 
93 (0.7) 
150 (0.4) 
4.70 
91 (0.7) 
68 (0.5) 
2.30 
SABA, n (%) 
6687 (53.2) 
21764 (55.9) 
-5.40 
6684 (53.2) 
6657 (53) 
0.40 
SAMA, n (%) 
656 (5.2) 
2193 (5.6) 
-1.80 
656 (5.2) 
629 (5) 
1.00 
 
 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
16 
9. Statistical analysis plans 
Incidence rates for the outcome will be estimated for the treatment and reference groups before and after PS 
matching. The competing risk of death could be of concern for the current set of analyses if mortality is frequent 
among patients included in the cohort and if differences in the risk of mortality between treatment and reference 
groups are substantial. In the PS-matched sample, we will use cause-specific hazard models7 to provide hazard 
ratios averaged over the entire follow-up period as well as interval specific hazard ratios (1, 2, and 3 years) for the 
association between the treatment of interest and risk of ADRD after considering all-cause mortality as a competing 
event. Pre-specified subgroup analyses will be conducted based on age, sex, and baseline cardiovascular disease.  
 
 
 

DREAM study protocol - Comparison 10 Montelukast vs Fluticasone 
 
 
17 
10. References 
 
1. 
Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. 
Biometrika. 1983;70(1):41-55. 
2. 
Rassen JA, Avorn J, Schneeweiss S. Multivariate-adjusted pharmacoepidemiologic analyses of confidential 
information pooled from multiple health care utilization databases. Pharmacoepidemiology and drug safety. 
2010;19(8):848-857. 
3. 
Rassen JA, Shelat AA, Myers J, Glynn RJ, Rothman KJ, Schneeweiss S. One-to-many propensity score matching 
in cohort studies. Pharmacoepidemiol Drug Saf. May 2012;21 Suppl 2:69-80. 
4. 
Austin PC. Some Methods of Propensity-Score Matching had Superior Performance to Others: Results of an 
Empirical Investigation and Monte Carlo simulations. Biometrical Journal. 2009;51(1):171-184. 
5. 
AM Walker AM, Patrick A, Lauer M, et al. Tool for Assessing the Feasibility of Comparative Effectiveness 
Research. Comp Effect Res 2013;3:11-20. 
6. 
Franklin JM, Rassen JA, Ackermann D, Bartels DB, Schneeweiss S. Metrics for covariate balance in cohort studies 
of causal effects. Statistics in medicine. May 10 2014;33(10):1685-1699. 
7. 
Austin PC, Lee DS, Fine JP. Introduction to the analysis of survival data in the presence of competing risks. 
Circulation. 2016;133(6):601-609.