Clinical trial NCT03532490
Conditions: Asthma Obesity
Sponsor: Johns Hopkins University
Start date: 2018-08-03; Completion date: 2021-07-30
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
There are currently no treatments to specifically target asthma in obese adults. This pilot study is being conducted to investigate how effective roflumilast is in treating asthma in participants that have a higher BMI. Roflumilast can induce weight loss, which may lead to improved asthma control.

The primary objective of TRIM is to perform a pilot placebo-controlled trial of roflumilast for the treatment of poorly controlled obese asthmatics.

Detailed description:
TRIM is a 24 week, randomized, double-masked, placebo controlled trial that will enroll 38 participants.

This study will be take place in seven centers of the American Lung Association- Airways Clinical Research Centers (ALA-ACRC). The centers include: Northwestern University Feinberg School of Medicine, Mount Sinai Icahn School of Medicine, Duke University, University of Arizona, the University of Vermont, The University of Alabama Lung Health Center, and University of Illinois Breathe Chicago Center. Johns Hopkins University will be the Data Coordinating Center (DCC) for the trial.

Arms: arm 1: 500 mcg roflumilast oral tablets will be taken every other day for the first two weeks. If participant tolerates the drug, the tablet will be taken once daily. arm 2: 500 mcg placebo oral tablets will be taken every other day for the first two weeks. If participant tolerates the drug, the tablet will be taken once daily.
Interventions: intervention 1: Roflumilast 500 Mcg Oral Tablet intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: The first two weeks the participant will take one tablet every other day. If well tolerated, participant will take one tablet every day. intervention 2: The first two weeks the participant will take one tablet every other day. If well tolerated, participant will take one tablet every day.

Protocol documents:
Prot_SAP_002.pdf: 
10 July 2020 
American Lung Association 
Airways Clinical Research Centers 
Trial of Roflumilast in Asthma Management 
(TRIM) 
Protocol 
Version 1.8
NCT #03532490 
Supported by NIH grants: R34 HL135361 


TRIM protocol Version 1.8 
   Contents|2 
Confidential, not for attribution or citation. 
Contents 
1. Introduction .............................................................................................................................................. 4
1.1. Background ........................................................................................................................................ 4 
1.2. Primary objective ............................................................................................................................... 4 
1.3. Study design ....................................................................................................................................... 5 
2. Methods .................................................................................................................................................... 6
2.1. Eligibility criteria................................................................................................................................. 6 
2.1.1. Inclusion criteria .......................................................................................................................... 6 
2.1.2. Exclusion criteria ......................................................................................................................... 6 
2.2. Rationale for study duration .............................................................................................................. 7 
2.3. Rationale for dose of active drug ....................................................................................................... 7 
2.4. Rationale for the seven centers ......................................................................................................... 7 
2.5. Background asthma care ................................................................................................................... 7 
2.6. Randomization and drug distribution ................................................................................................ 7 
2.7. Source of study medication ............................................................................................................... 8 
2.8. Randomization and blinding .............................................................................................................. 8 
2.9. Procedures ......................................................................................................................................... 9 
2.10. Rationale for outcome measurements .......................................................................................... 10 
2.11. Modifications due to COVID-19 pandemic .................................................................................... 11 
3. Data analysis ........................................................................................................................................... 12
3.1. Primary analysis ............................................................................................................................... 12 
3.2. Secondary outcomes ........................................................................................................................ 12 
3.3. Sample size ....................................................................................................................................... 12 
3.4. Data confidentiality .......................................................................................................................... 13 
4. Human subjects ....................................................................................................................................... 14
4.1. Risks of Individual Procedures ......................................................................................................... 14 
4.1.1. Roflumilast ................................................................................................................................ 14 
4.1.2. Venipuncture ............................................................................................................................ 15 
4.2. Handling elevated symptoms: Depression, anxiety, and self-harm ................................................ 16 
4.2.1. Protocol for participant with elevated depression and anxiety symptoms .............................. 16 
4.2.2. Protocol for participants exhibiting potential for self-harm ..................................................... 18 
4.3. Management of GI side effects ........................................................................................................ 20 
4.4. Potential benefits of the proposed research to human subjects and others .................................. 20 
4.4.1. Importance of the knowledge to be gained ............................................................................. 20 


TRIM protocol Version 1.8 
   Contents|3 
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4.4.2. Financial considerations ............................................................................................................ 20 
5. Data safety monitoring plan ................................................................................................................... 21
5.1. Composition of the DSMB ................................................................................................................ 22 
5.2. Adverse events and unanticipated problem reporting .................................................................... 23 
6. Drug ......................................................................................................................................................... 24
6.1. FDA considerations .......................................................................................................................... 24 
7. Special populations ................................................................................................................................. 25
7.1. Inclusion of women .......................................................................................................................... 25 
7.2. Women of childbearing potential .................................................................................................... 25 
7.3. Inclusion of minorities...................................................................................................................... 25 
7.4. Inclusion of children ......................................................................................................................... 25 
7.5. Vulnerable populations .................................................................................................................... 25 
8. References .............................................................................................................................................. 26
9. Appendix ................................................................................................................................................. 28
A. Changes log ......................................................................................................................................... 29 


TRIM protocol Version 1.8                                                                                                                  Introduction|4 
Confidential, not for attribution or citation. 
1. Introduction 
1.1. Background 
Obesity is a risk factor for the development of asthma (approximately 250,000 cases per year of asthma 
in the U.S. are related to obesity).1  These patients have poorly controlled asthma (with a nearly 5-fold 
risk of hospitalization) and do not respond as well to conventional controller therapy as lean 
asthmatics.2-6  Obesity particularly affects minority populations:7 non-Hispanic blacks have the highest 
age-adjusted rates of obesity (47.8%) followed by Hispanics (42.5%), non-Hispanic whites (32.6%), and 
non-Hispanic Asians (10.8%).  This is thought to account in part for the disparities of asthma in minority 
populations; there is a pressing public health need to develop interventions specifically for obese 
asthmatics. 
One medication that might be particularly useful for the treatment of asthma in obesity is roflumilast, a 
medication currently used in the treatment of chronic obstructive pulmonary disease.  Data in clinical 
trials support efficacy of this medication in the treatment of asthma,8 though it has never been 
approved for treating asthma in the general population, likely because of concern about side-effects; 
but these “side-effects” may actually contribute to efficacy in the treatment of asthma in obesity.    
Roflumilast has efficacy in mouse-models of asthma and obesity: roflumilast reduced airway remodeling 
and reactivity in a non-allergic mouse model of obese asthma, and also airway reactivity, inflammation 
and remodeling in an allergic mouse model of obese asthma.9 These effects are likely related both to 
direct effects on inflammatory cells and cells resident in the airway, and also to the beneficial metabolic 
effects of roflumilast.  Roflumilast has significant beneficial incretin-like metabolic effects in patients 
with the metabolic syndrome,10 and so might be helpful to mitigate the metabolic dysfunction 
associated with asthma in obese patients.11  In addition, roflumilast promotes weight loss, especially in 
the obese,12-15 and significant weight loss may improve asthma control in obesity.   These direct effects 
of roflumilast in the airway, and “side-effects” on metabolism and weight loss, make this medication a 
particularly exciting candidate to treat asthma in obese patients. 
1.2. Primary objective 
The primary objective of this proposal is to perform a pilot placebo controlled trial of roflumilast for the 
treatment of poorly controlled obese asthmatics in select centers of the ALA-ACRC to determine the 
effectiveness and tolerability of our intervention in obese asthma.       
The current proposal comprises a pilot randomized, placebo-controlled trial of roflumilast in obese 
patients with poorly controlled asthma in five centers of the American Lung Association-Airways Clinical 
Research Centers (ALA-ACRC).   
The results of this trial will lay the groundwork for a definitive multicenter clinical trial of roflumilast for 
the treatment of poorly controlled asthma in obese patients.   If ultimately successful roflumilast would 
represent a new treatment for obese patients with asthma, a patient population refractory to current 
therapies that represents the majority of poorly controlled asthmatics in the United States. 
 
 


TRIM protocol Version 1.8                                                                                                                  Introduction|5 
Confidential, not for attribution or citation. 
1.3. Study design 
A 24 week, randomized, double-masked, placebo controlled trial in 38 participants. 
 


TRIM protocol Version 1.8                                                                                                                      Methods|6 
Confidential, not for attribution or citation. 
2. Methods 
2.1. Eligibility criteria 
2.1.1. Inclusion criteria   
• 
Physician diagnosis of asthma and on regular prescribed controller therapy for at least 3 months 
• 
Previous (within five years) evidence of at least a 12% increase in FEV1 after inhaling 2-4 puffs of 
albuterol or a positive methacholine challenge or patient reported history of improvement of 
asthma exacerbation after a course of systemic or inhaled corticosteroids.  
• 
Age: ≥18 years of age 
• 
Obese: BMI > 30 kg/m2 
• 
Poorly controlled asthma: Asthma Control Test Score < 20, or use of rescue inhaler, on an 
average of> 2 uses/week for preceding month, or nocturnal asthma awakening, on an average 
of 1 or more times / week in preceding month, or ED/hospital visit or prednisone course for 
asthma in past six months. 
• 
Ability and willingness to provide informed consent 
2.1.2. Exclusion criteria  
• 
Participation in an investigational study within the past 4 weeks 
• 
Physician diagnosis of chronic obstructive pulmonary disease 
• 
Any condition that puts the participant at risk from weight loss as judged by the site physician 
• 
Liver cirrhosis 
• 
Major psychiatric disorders such as generalized anxiety disorder, major depressive disorder, 
history of suicidal ideation/ attempt, panic disorder, post-traumatic stress disorder, 
schizophrenia, schizoaffective, substance abuse or other disorders that in the opinion of the 
study physician that would affect study participation  
• 
> 0 time use of illicit drugs in the past 12 months  
• 
> 0 time use of cannabis in the past 12 months 
• 
Uncontrolled depression as defined by a score of 15 or greater on the depression questions of 
the PHQ-9  
• 
Suicidal ideation (a score of greater than 0 on Question 9 on the PHQ-9)  
• 
Uncontrolled anxiety as defined by a score of 10 or greater on the anxiety questions of the GAD-
7 
• 
Pregnancy/lactation  
• 
Females of childbearing age who do not agree to practice an adequate birth control method 
(abstinence, combination barrier and spermicide, or hormonal) for the duration of the study. 
• 
Greater than 20 pack year smoking history, or smoking within the last 6 months. 
• 
History of bariatric surgery 
• 
Drugs metabolized by cytochrome P450 (rifampicin, phenobarbital, carbamazepine, phenytoin, 
erythromycin, ketoconazole, cimetidine, fluvoxamine, enoxacin, oral contraceptives containing 
ethinyl estradiol with gestodene). 
• 
Currently on roflumilast or theophylline (patient may wash out of these medications for 4 weeks 
prior to visit 1). 
• 
Intention to move out of area within the next 6 months  


TRIM protocol Version 1.8                                                                                                                      Methods|7 
Confidential, not for attribution or citation. 
2.2. Rationale for study duration 
We base the duration of the study on the likely time needed to induce weight loss, as well as to improve 
metabolic control.8,10,16 We anticipate that this will be the duration of the definitive clinical trial, and so it 
will be important to ascertain the feasibility of a trial of this duration in our patient population of 
interest. 
2.3. Rationale for dose of active drug 
We base the dose of active drug on the dose that is FDA approved for use in COPD in this country, and 
has also shown efficacy in the treatment of asthma8 and metabolic disorders:10 this will be 500 µg, once 
per day.  For the first two weeks we will treat with 500 µg every other day to increase tolerability of the 
medication. 
2.4. Rationale for the seven centers 
Collaborating sites: Northwestern University Feinberg School of Medicine, Mount Sinai Icahn School of 
Medicine, Duke University, University of Arizona, University of Alabama Lung Health Center, University 
of Illinois – Chicago, and the University of Vermont. Johns Hopkins University will be the Data 
Coordinating Center (DCC) for the trial.  
We will perform this study in seven centers that have a strong record of recruitment and working 
together as part of the ALA-ACRC, and that represent diverse populations within the network.  We will 
need to recruit 5-6 patients per site within an approximate 12 month period to complete all procedures 
and study analysis within the time-frame of this proposal, and this is a reasonable recruitment target for 
these centers.  These centers represent diverse patient population, and so if successful, this will likely 
predict success in the multi-center trial.  Many of these centers have established research programs on 
obesity in asthma. 
2.5. Background asthma care 
Participants will be treated in accordance with asthma guidelines and best practices using materials that 
have been already developed by the ALA-ACRC. This includes a written asthma action plan based on 
peak flow, and instruction on inhaler technique and avoidance of asthma triggers. All participants will be 
prescribed controller medication that includes medium dose inhaled corticosteroids and additional add-
on treatments as needed. Participants who have a regular asthma care provider will continue to receive 
care from that source. If not, they will be referred to an asthma care provider associated with the study 
site. All participants will be provided with an asthma action plan, but we will not provide routine asthma 
care. 
2.6. Randomization and drug distribution  
Participants will be randomly assigned with an equal allocation to receive either active treatment or 
matching placebo for 6 months.  The treatment assignment will be double-masked, neither the 
participant nor the clinical center investigators will be informed of the treatment group.  Randomization 
will be accomplished with an auditable, documented generation scheme that produces a reproducible 
order of assignment, this schema will be generated by the DCC.  Randomization will be stratified by 
center and age and each clinical center randomization schedule will be based on randomly permuted 
blocks of varying size to ensure appropriate balance between the treatment groups within a center.  


TRIM protocol Version 1.8                                                                                                                      Methods|8 
Confidential, not for attribution or citation. 
Drug bottles will be shipped to the centers from Temple University. These bottles will be identified by a 
number to maintain masking of the study site.  Upon randomization, the site will be advised of the 
bottle number to issue a particular participant. 
2.7. Source of study medication  
We will purchase drug, and arrange for matching active drug and placebo through Temple University 
Research Pharmacy.  Drug will be distributed from Temple University to the individual sites. DCC will 
instruct Temple University on the set of bottle numbers to dispense.  
2.8. Randomization and blinding  
Treatment assignments will be stratified by clinic and the allocation ratio will be (1:1). Randomization 
will be accomplished by keying eligibility data into the data system; after verification of eligibility, a 
treatment assignment number corresponding to unique study kit will be assigned. Study kits will be 
labeled with two-part tear-off labels with unique identifiers. The tear-off label is affixed to a study form 
when the kit is assigned to a participant and the information is keyed into data system to verify that 
assigned treatment was given to the participant.  
 
 


TRIM protocol Version 1.8                                                                                                                      Methods|9 
Confidential, not for attribution or citation. 
2.9. Procedures 
 Sites conducting remote follow up visits must use a secure (password protected) zoom link or other 
secure online communication method. Participants who are followed up remotely, will complete some 
questionnaires over the phone and mail back the rest of the questionnaires to the site. 
Outline of Study Visits 
Week 
-1 
0 
2 
6 
12 
18 
24 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Consent 
• 
  
  
 
  
 
  
Baseline/interim history 
• 
• 
• 
• 
• 
• 
• 
Randomization 
 
• 
 
 
 
 
 
Pill distribution† 
 
• 
 
• 
• 
 
 
Pill distribution‡ 
 
• 
 
 
• 
 
 
Review of paper/electronic diary cards 
  
• 
• 
• 
• 
• 
• 
Pill Counts 
 
 
• 
• 
• 
• 
• 
Asthma Control 
• 
• 
• 
• 
• 
• 
• 
Anxiety/depression questionnaires 
• 
• 
• 
• 
• 
• 
• 
GSRS 
• 
• 
• 
• 
• 
• 
• 
QOL  
• 
• 
• 
• 
• 
• 
• 
Anthropometrics 
• 
• 
• 
• 
• 
• 
• 
Fasting Blood draw¥ 
 
• 
 
 
 
 
• 
Pregnancy test* 
• 
• 
• 
• 
• 
• 
• 
End of study questionnaire 
  
  
  
 
  
  
• 
† if dose frequency is every day since V3 
‡ if dose frequency is every other day since V3 
¥ conduct blood draw only if site permits it 
*for women of child-bearing potential and participating in remote follow up participants will be mailed 
testing kit, and asked to send photo of result to coordinator  
• 
Participants will be trained on how to perform peak expiratory flow at the study visit and sent 
home with asthma action plan.  
• 
Asthma paper/electronic diary cards will be completed by participants throughout the study to 
record daily morning peak expiratory flow (PEF), daily asthma symptom scores, beta-agonist 
use, nocturnal asthma awakenings, and health care use.17,18   Diary data are used to identify 
episodes of poor asthma control and days with no asthma symptoms (asthma-free days). 
• 
The Asthma Control Test (ACT) is a 4-week recall questionnaire that measures asthma control.19   
• 
The Marks Asthma Quality of Life Questionnaire (Marks AQLQ) assesses asthma specific quality 
of life.20  
• 
The Asthma Symptom Utility Index (ASUI) is a 2-week utility-weighted asthma symptom 
questionnaire.21   
• 
GI side effects will be assessed with the Gastrointestinal Symptom Rating Scale.  This is a 15-
item instrument with five subscales (reflux, diarrhea, constipation, abdominal pain and 
indigestion) that was originally developed to assess the symptoms associated with the most 
common GI disorders, and has previously been used to assess tolerability of medications.  The 
five subscales of the questionnaire produce a mean score ranging from 1 (no discomfort) to 7 
(very severe discomfort).22 
• 
Medical Outcomes Study (SF36) is a measure of general health related quality of life which 
correlates with asthma outcomes.23,24   


TRIM protocol Version 1.8                                                                                                                      Methods|10 
Confidential, not for attribution or citation. 
• 
The Patient Health Questionnaire for Depression and Anxiety (PHQ9 and GAD7) will be used. 
The Patient Health Questionnaire is a diagnostic tool for mental health disorders used by health 
care professionals that is quick and easy for patients to complete.  We have used this 
questionnaire in prior ALA-ACRC studies, and so the centers are familiar with its use.  We will 
use sections specific to mood (PHQ-9) and anxiety (GAD-7). The PHQ-9, a tool specific to 
depression, scores each of the 9 DSM-IV criteria based on the mood module from the original 
PRIME-MD. The GAD-7 was subsequently developed as a brief scale for anxiety and scores seven 
common anxiety symptoms.25,26 
• 
Anthropometrics will include blood pressure, height and weight, and waist and hip 
circumference per NHANES III.27 Digital scales will be given to participants at visit 2 to take home 
to measure weight. Participants will be asked to send a photo of the weight shown on the scale 
along with their feet to the coordinator.  
• 
Adverse effects will be assessed by open-ended questions at each visit and rated in severity.  
• 
Interval health history will be recorded at each clinic visit. Records of all hospitalizations and, if 
necessary, deaths are obtained for verification of diagnoses and assessment of safety issues.  
• 
Baseline questionnaires and exam will be administered to ascertain demographics including self-
reported ethnicity and race, general health, co-morbid conditions, asthma symptoms, and 
medication use.   
• 
Assessment of Adherence: adherence will be assessed from pill counts when participant returns 
pills  at each study visit after randomization. If only remote visits are permitted, then pill count 
will be completed when participant mails back drug bottles at the end of the study.  
• 
Exit questionnaires will be administered at the last visit to determine global assessments of 
treatment, adequacy of informed consent procedures, satisfaction with study procedures and 
personnel, and opinions about the intervention. 
• 
Blood specimens will be collected for fasting blood glucose and analysis of metabolic and 
oxidative markers related to asthma if a site permits this. Excess blood specimens will be used 
for future asthma research with the patient’s consent. Fasting blood draw may take place within 
7 days of rest of the procedures scheduled for visit 2 or visit 7. 
2.10. Rationale for outcome measurements  
Our outcome measures are all well validated clinical outcomes for use in studies of asthma, and 
validated questionnaires for assessing likely side effects.  We are including a number of feasibility 
outcomes that will inform the decision to proceed with a definitive multi-center clinical trial: these 
include assessment of recruitment and retention, adherence and non-compliance (from pill counts, 
diary cards, missed visits) and side-effects (from GSRS, PHQ-9 and GAD-7).  Participants with scores on 
the PHQ-9 or GAD-7 that reach the thresholds for exclusion outlined in the eligibility criteria will be 
discontinued from study drug, the site specific plan for caring for these participants will be instituted, 
and they will be followed for the rest of the study off of study drug. 
Baseline medical and asthma control questionnaires will take 20-30 minutes to complete, will be 
completed at the Medical Office Building, in a private office.  Questionnaires are in paper format, and 
will be completed by the participant. 
 
 


TRIM protocol Version 1.8                                                                                                                      Methods|11 
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2.11. Modifications due to COVID-19 pandemic  
Due to the COVID-19 public health emergency, TRIM, will permit remote follow up of enrolled 
participants as of April, 6, 2020.  Participants enrolled after re-opening of the study should be seen at in-
person visit for V2 (randomization visit) and V7 (24 weeks), other visits can be conducted in-part or fully 
remotely. It is possible that research activities will face restrictions in the future or that a participant will 
prefer to do the V4-V6 remotely, so we will provide participants with a scale and tape measure to collect 
data for remote visits. All questionnaires can be conducted remotely prior to in-person visits for all 
visits. Participants who are followed up remotely, will complete some questionnaires over the phone 
and mail back the rest of the questionnaires to the site. Methacholine challenge tests and spirometry 
should not be conducted. Women of child-bearing potential and participating in remote follow up will 
be mailed testing kit, and asked to send photo of result to coordinator


TRIM protocol Version 1.8                                                                                                               Data analysis|12 
Confidential, not for attribution or citation. 
3. Data analysis 
The appropriateness of the human, technological and systems components of the data acquisition and 
management procedures will be analyzed including practicality of data acquisition, estimation of likely 
participant characteristic and outcome distributions, suitability and functionality of paper and electronic 
forms, and resources required for participants contact and follow up, and to anticipate rates for missing 
data.  
 
3.1. Primary analysis 
The primary statistical analysis will be an unadjusted comparison of 24-wk change in ACT between 
treatment groups. A linear mixed effects model will be used to model the change in ACT over time.  A 
saturated means model, including indicators for each time point, treatment and treatment by time 
interaction, will be specified and a random effect for individual will be used to account for the repeated 
measurements over time.  The 24-week treatment by time interaction term represents the difference in 
change in ACT between the treatment groups, i.e. the primary outcome. If the data are non-normal, 
then transformations and non-parametric alternatives (e.g. Wilcoxon Rank-Sum test comparing the raw 
differences from baseline to 24-weeks between treatment groups) will be explored.  If imbalances in 
influential baseline variables are present, then secondary analyses using appropriate stratification or 
adjustments will be done.  Sensitivity analyses using alternate mean and covariance structures will also 
be performed.  Analyses will be done based upon principles of intention to treat, i.e. all data from all 
randomized participants will be included in the analysis. 
Secondary analyses will focus on the effects of additional covariates including age, gender, site, BMI >40, 
baseline ACT score, and adherence with treatment.  These models will build on primary analysis 
described above. Potentials risk factors will be added as a main effect to reduce variability and 
interaction effect to identify potential subgroup effects. Analyses using adherence measures will be 
performed to explore dose-response relationships.   
3.2. Secondary outcomes  
Secondary outcomes include ASUI, mAQLQ, and GSRS scores, lung function, weight loss and adverse 
events.  Continuous outcomes, scores and lung function, will be analyzed similarly to the primary 
outcome. Event outcomes will be analyzed in two ways: negative binomial regression to estimate rates 
and Kaplan-Meier curves and Cox proportional hazard models for time-to-first event. 
3.3. Sample size  
The sample size for this pilot is based on the confidence interval approach recommended by Cocks and 
Torgerson for pilot clinical trials.29 For the definitive trial, the planned sample size is 190 (95 participants 
on active drug, 95 on placebo), to provide 90% power to detect a difference of 2.8 in the changes in ACT 
score from baseline to 24 weeks for the roflumilast versus placebo, with a type 1 error rate of 5%, and a 
standard deviation (SD) of 5. The SD is based on prior data from studies by our research network, and 
previous publications.30,31 A pilot study of 28 to 34 participants provides 90% one-sided confidence limit 
to exclude a clinical important effect in a definitive trial if we see no effect in the pilot study, and so 
could inform the decision as to whether to proceed to the full definitive trial.  We will inflate this to 38 
participants to allow for possible loss to follow up. 
 


TRIM protocol Version 1.8                                                                                                               Data analysis|13 
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Table: Recommended pilot sample size for continuous outcome measures* 
Standardized effect 
size for main trial 
Pilot Sample size (90% 
level) 
Upper 90% one-sided 
confidence limit 
0.5 
28 
0.4844 
0.45 
34 
0.4397 
0.4 
42 
0.3955 
0.35 
54 
0.3488 
0.3 
74 
0.298 
* Adapted from Cocks & Torgerson (2013)29 
 
3.4. Data confidentiality 
Data which includes identifiable personal health information (PHI) are collected at each of the clinical 
sites. PHI is 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 participating study personnel, password protection for electronic medical 
records, and explanation of HIPAA regulations on the study consent form. 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 are informed in the consent that PHI may 
also be disclosed for auditing purposes by the FDA or other regulatory bodies and is subject to 
subpoena.  
Information transmitted to the coordinating center is identified by an anonymous study ID, and other 
identifying information such as birthdate, visit dates, and study site is removed from limited use 
datasets. Source records that are transmitted to the coordinating center for data quality audits have 
identifying information redacted.  
 


TRIM protocol Version 1.8                                                                                                        Human subjects|14 
Confidential, not for attribution or citation. 
4. Human subjects  
4.1. Risks of Individual Procedures 
4.1.1. Roflumilast 
Roflumilast will be provided to 19 subjects for 24 weeks at the 7 centers. While roflumilast has been 
approved for use in patients with COPD, the label includes warnings about psychiatric events (including 
suicidality), weight loss, and drug interactions. The psychiatric adverse reactions included insomnia, 
anxiety and depression (rate of psychiatric adverse reactions was 2.6% higher in roflumilast group than 
placebo). Instances of suicidal ideation and behavior, including completed suicides, were observed in 
clinical trials and in the post-marketing surveillance of the drug, in individuals with and without any prior 
history of depression. Of note, the safety data for roflumilast were based on 4438 patients between the 
ages of 40-91 years, 73% of whom were male and 92.9% were Caucasian. Given these limitations (in 
comparison to the planned trial in patients with asthma), the safety risks are taken from a pooled 
analysis of asthma patients receiving the 500 mcg dose of roflumilast to be used in the current trial 
(n=1567; Chervinsky, P et al Pulmonary Pharmacology and Therapeutics 2015 (35):S28-34).  (This asthma 
population was 42.2% male, 80.2% white, and had a mean BMI of 27.47 as well as including 96.7 % of 
subjects between the ages of 12-65 years. Treatment duration varied between 4-24 weeks.)  In these 
studies of patients with asthma, the risks that occurred with more than 5 events per 100 patient years 
follow up in excess of the control group included: 
Excess incidence rate of adverse events for roflumilast compared to placebo by System Organ Class 
(SOC)*:  
• 
Gastrointestinal disorders (61.7 cases per 100 patient years) 
o Diarrhea (21.0 cases per 100 patient years) 
o Nausea (24.0 cases per 100 patient years) 
• 
Psychiatric disorders (7.1 cases per 100 patient years) 
o Insomnia (6.0 cases per 100 patient year) 
• 
Nervous system disorders (33.7 cases per 100 patient years) 
o Headache (20.8 cases per 100 patient year) 
o Dizziness (6.2 cases per 100 patient years) 
• 
Musculoskeletal and connective tissue (19.8 cases per 100 patient years) 
• 
Infections and infestations (19.2 cases per 100 patient years) 
*Includes SOCs and the associated preferred terms for events with an excess of >5.0 cases per 100 
patient years for the difference between roflumilast and placebo where 95% confidence interval does 
not include 0. 
Anticipated % patients experiencing an event compared to placebo if treated for 24 weeks with 
roflumilast 500 mcg per day (based on data above): 
• 
diarrhea (9.7%)   
• 
nausea (11.1%)  
• 
insomnia (2.8%)   
• 
headache (9.6%)  
• 
dizziness (2.9%)   


TRIM protocol Version 1.8                                                                                                        Human subjects|15 
Confidential, not for attribution or citation. 
The psychiatric risks of roflumilast treatment are mitigated through the monitoring and management of 
symptoms as described below.  
Weight loss is considered to be an advantageous outcome in the population being studied. If a 
participant loses ≥ 10% of baseline weight during the course of the trial, this will be discussed with the 
study physician (preferably the study PI) as soon as possible.   
The GSRS will be used primarily to monitor GI side-effects, if a participant scores ≥ 6 on any item 
(indicative of severe or very severe discomfort), this will be discussed with the study doctor 
immediately, and the study PI as soon as possible. 
The potential for drug interactions with roflumilast is mitigated through excluding participants on 
medications known to interact with roflumilast.  We will exclude participants with uncontrolled anxiety 
and depression, and suicidal ideation, and screen for these at every visit, we will discontinue the patient 
from drug treatment if they develop these symptoms (threshold as defined in eligibility criteria).  Plans 
for dealing with elevated symptoms of depression, anxiety and self-harm are outlined below.  
4.1.2. Venipuncture 
The main risk of this is bruising and minor discomfort.  We may find elevated fasting blood glucose, 
which requires clinical follow up.  Our plan is as follows: 
< 100: no action 
100-125: notify participant and PCP within 3 months 
126-199: notify participant and PCP within 5 working days 
200-299: notify participant and PCP within 24 hours 
≥ 300: contact participant immediately, and advise to go to PCP/ ED/ urgent care 
 
 


TRIM protocol Version 1.8                                                                                                        Human subjects|16 
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4.2. Handling elevated symptoms: Depression, anxiety, and self-harm  
This proposed plan will be subject to DSMB review. 
We will ask all patients if they have a mental health care provider at the beginning of the study. 
The questionnaires used in this study include questions regarding the participant’s health - both physical 
and mental.  If a participant is experiencing a mental health crisis, we will provide them with additional 
support and referrals as needed. Information provided will include the following:- 
• 
The National Strategy for Suicide Prevention, 1-800-273-TALK (8255) 24 hour hotline 
• 
Howard Center 300 Flynn Ave. Burlington, VT 802-488-6400 local Crisis 24 hour hotline 
• 
Seneca Center 1 South Prospect, St Burlington VT 802-847-3333  
• 
Northeastern Family Institute 30 Airport Rd. South Burlington VT 802-657-8890 
• 
UVMMC Psychiatry:  111 Colchester Ave. Burlington VT 802-847-4727 
In addition, each site will identify a psychiatrist or licensed psychologist to be available to discuss any 
issues related to depression/anxiety with the PI. 
4.2.1. Protocol for participant with elevated depression and anxiety symptoms  
The PHQ-9/ GAD-7 captures the presence and severity of depression and anxiety symptoms. Scores 
above the specified thresholds suggest a clinically significant level of psychological distress. It does not 
necessarily mean that the participant has a clinical diagnosis of depression or anxiety but may indicate 
the need for appropriate care. Study personnel will be instructed to tabulate and review the scores for 
these instruments before the participant is released from the study visit. 
Participants with scores on the PHQ-9 or GAD-7 (including those being screened for the eligibility who 
do not qualify for the study) that reach or exceed the thresholds for exclusion outlined in the study 
eligibility criteria will be discontinued from study drug under the supervision of the site PI (if on study 
drug), and the site PI will ensure that the site specific plan for managing these participants is instituted.  
Participants already randomized into the study will continue to be followed for the rest of the study off 
of study drug (unless they decide to withdraw). Subsequent scores exceeding the threshold score, or the 
minimally clinically important difference for the questionnaires when compared to Visit 2 (≥ 5) will be 
considered an adverse event, and, as such, followed until resolution or a plan for care under the 
supervision of another medical provider is established. This will be considered an adverse event, and, as 
such, followed until resolution or a plan for care under the supervision of another medical provider is 
established. Participants will be informed that the elevated score could be related to the study drug, 
though investigators and subjects will not be unblinded to treatment assignment. 
 
 


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4.2.1.1. Elevated depression scores  
Elevated depression scores are defined as:  
• 
Total score of 15 or greater on the depression questions of the PHQ-9 or an increase of 5 points 
or more from score at Visit 2. 
If depression score is elevated, we will tell the participant the following:  
• 
“It seems that you are “down” or somewhat distressed. I would like to give you a few names and 
numbers of people in the community you can contact for assistance.” OR “Your score is a bit 
high. Are you feeling “down” or upset? Would you like to have some names and numbers to 
contact for help?”  
• 
Offer patient the mental health resource information  
• 
We will follow up with participants who have elevated depression by phone within 7 days to 
check on follow up with mental health care resources, or mail them a letter with resources if we 
are unable to reach them by phone. 
4.2.1.2. Elevated anxiety scores  
Elevated anxiety scores are defined as:  
• 
Total score of 10 or greater on the anxiety questions of the GAD-7 or an increase of 5 points or 
more from score at Visit 2. 
If anxiety score is elevated, we will tell the participant the following:  
• 
“It seems that your anxiety may be causing you a lot of stress. I would like to give you a few 
names and numbers of people in the community you can contact for assistance.” OR “Your score 
is a bit high. Are you feeling anxious or ‘on edge’ a lot? Would you like to have some names and 
numbers to contact for help?”  
• 
Offer patient the mental health resource information  
• 
We will follow up with participants who have elevated anxiety scores by phone within 7 days to 
check on follow up with mental health care resources, or mail them a letter with resources if we 
are unable to reach them by phone. 
 
 


TRIM protocol Version 1.8                                                                                                        Human subjects|18 
Confidential, not for attribution or citation. 
4.2.2. Protocol for participants exhibiting potential for self-harm  
If a participant discloses that they may do harm to themselves, we will follow up with the participant 
and report to PI.   This will be indicated with a score of greater than 0 on Question 9 on the PHQ-9.  We 
will then administer the Suicidality Severity Screener (SSW form), adapted from the Columbia-Suicide 
Severity Rating Scale (C-SSRS), by Posner, K., et al, and used in prior ALA-ACRC studies.   
We will proceed as follows  
Suicidal Severity Screener  
You mentioned on some of the questions that you have thought about killing yourself. Tell me about 
those thoughts.  
1. Have you been thinking about how you might kill yourself?  
YES /NO  
2. Have you had these thoughts and had some intention of acting on them?  
YES /NO 
3. Have you started to work out or worked out the details of how to kill yourself?  
YES/ NO  
4. Do you intend to carry out any plans you have?  
YES/ NO  
5. Do you have a current mental health provider?  
If yes- when is your next appointment?  
 
Risk will be determined as outlined below: 
Mild Risk  
If participant answers NO to questions 1, 2, 3, AND 4 of the SSW:  
• 
Notify PI  
• 
Provide resource guide, including suicide hotline number, with statement: “It sounds like 
currently you have some thoughts about suicide but do not plan to go through with it. If you 
notice the thoughts become more frequent, or you want to talk with someone, please call this 
number.”  
• 
If they have a provider, make sure there is an upcoming appointment scheduled to talk about 
their concerns. If they do not have a provider, indicate possible providers on resource sheet.  
• 
Complete an adverse Event Report (UE) form documenting the outcome of this questionnaire 
and subsequent action taken. 
• 
Contact the participant by phone 7 days after visit to confirm they are receiving follow up care. 
Update AE form with results of phone call.  
• 
A letter will be mailed with resources if we are unable to reach them by phone, and this will be 
discussed with the study physician 
 
 


TRIM protocol Version 1.8                                                                                                        Human subjects|19 
Confidential, not for attribution or citation. 
Moderate Risk  
If participant answers YES to questions 1 or 2 but not to questions 3 or 4 of the SSW:  
• 
Notify study physician immediately  
• 
Provide resource guide, including suicide hotline number, with statement: “It sounds like 
currently you have some thoughts about suicide but do not plan to go through with it. If you 
notice the thoughts become more frequent, or you want to talk with someone, please call this 
number.”  
• 
If they have a provider, make sure there is an upcoming appointment scheduled to talk about 
their concerns. If they do not have a provider, staff should strongly encourage them to contact 
the suicide hotline and/or one of the local providers listed to schedule a follow up call or 
appointment.  
• 
Staff should encourage participants to contact the hotline or schedule an appointment before 
concluding the study visit.  
• 
Complete an Adverse Event Report (AE) form documenting the outcome of the questionnaire 
and subsequent action taken.  
• 
Contact the participant by phone 7 days after visit to confirm they are receiving follow up care. 
Update AE form with results of phone call.  
• 
A letter will be mailed with resources if we are unable to reach them by phone, and this will be 
discussed with the study physician 
Immediate Risk  
If participant answers YES to questions 3 or 4 of the SSW: 
• 
Notify study physician immediately 
• 
Instruct participant to call PCP, 911, or appropriate crisis number and give participant resource 
guide highlighting 24-hr help lines.  
- 
If participant does not call for assistance, let them know you are obligated to report this 
to emergency services; walk participant to ER or call 911  
• 
If concerned there is an immediate risk, walk the participant to the ER or call 911  
• 
Complete a Serious Adverse Event Report (SR) form documenting the outcome of this 
questionnaire and subsequent action taken.  
• 
Contact the participant by phone 7 days after visit to confirm they are receiving follow up care. 
Update SR form with results of phone call.  
If unsure about the patient’s risk, contact a study physician (preferably the PI) to notify them 
immediately and discuss action to take. 
If patient is contacted and it is determined that they are not receiving follow up care/ it is not possible to 
reach the patient, contact the study physician immediately, who will contact their site’s psychiatrist or 
licensed psychologist to discuss appropriate next steps. 
FOR ALL SUICIDALITY RISK ASSESSMENTS:  
Speak with a study doctor immediately and the study PI as soon as possible.  


TRIM protocol Version 1.8                                                                                                        Human subjects|20 
Confidential, not for attribution or citation. 
Assessment of Insomnia: sleep difficulties will be assessed by response to PHQ9 questions #3, if a 
participant scores > 2 this will be discussed with the study physician (preferably the study PI) as soon as 
possible. 
4.3. Management of GI side effects 
If a participant loses ≥ 10% of baseline weight during the course of the trial, this will be discussed with 
the study physician (preferably the study PI) as soon as possible. 
The GSRS will be used primarily to monitor GI side-effects, if a participant scores ≥ 6 on any item 
(indicative of severe or very severe discomfort), this will be discussed with the study doctor 
immediately, and the study PI as soon as possible. 
4.4. Potential benefits of the proposed research to human subjects 
and others 
Patients assigned to either treatment group will benefit from asthma education and attention to their 
asthma care program. Moreover, some participants in research studies report that they enjoy 
participation because they have the opportunity to assist in the development of new knowledge that 
may be helpful to others and that the relationship with the research staff is rewarding.  If this study 
shows that participants assigned to roflumilast experience improved asthma control, this might lead to a 
specific therapy to treat asthma in obese patients. 
4.4.1. Importance of the knowledge to be gained  
If this study shows that participants assigned to roflumilast experience improved asthma control, this 
might lead to a specific therapy to treat asthma in obese patients.  This patient population currently 
suffers with poor asthma control, and do not respond as well to standard therapies, so this would be a 
very important finding. 
4.4.2. Financial considerations 
At the University of Vermont, participants will receive a stipend of $50 per visit, for a total of $350 for 
completion of the study. 
We will also reimburse for mileage at standard UVM rates if participants pick up/drop off study supplies. 


TRIM protocol Version 1.8                                                                                   Data safety monitoring plan |21 
Confidential, not for attribution or citation. 
5. Data safety monitoring plan 
• 
Significant changes or amendments to the protocol or consent form will be submitted to the 
DSMB, and included in the DSMB reports. 
• 
We will follow the ALA ACRC annual reporting requirements for management of conflict of 
interest. 
• 
There are no plans for interim data analysis for this pilot study. 
• 
The American Lung Association appoints a DSMB to oversee trials conducted by the ACRC. 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 risk-benefit ratio 
for participants. The DSMB is typically composed of a pulmonary specialist, an ethicist, a 
statistician, a patient representative, and specific content experts, in this case a psychiatrist. 
Typically, the DSMB would have an initial meeting to review and approve the protocol, and then 
meet every six months or more frequently to review the progress of the trial. The investigators 
present the DSMB study performance data including screening and enrollment data, and 
measures of data quality and 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.  
• 
Dr. Wise of the DCC at Johns Hopkins serves as the medical monitor for the research group and 
reviews all serious adverse event or unusual event reports to determine whether any immediate 
local or study-wide actions are indicated. Interim serious adverse events or adverse events 
related to study procedures are transmitted to the DSMB by the DCC with concurrent 
notification of the clinical site IRBs and, if appropriate, NIH.  
• 
At the end of each DSMB meeting, the board will vote whether to continue the study as planned 
or whether to recommend changes to the study. The DSMB may recommend that the study be 
stopped early if there is evidence that the risk-benefit ratio does not warrant continuation of the 
trial. 
 
 


TRIM protocol Version 1.8                                                                                   Data safety monitoring plan |22 
Confidential, not for attribution or citation. 
5.1. Composition of the DSMB 
We will use the ALA-ACRC standing DSMB, and in addition a psychiatrist and patient representative. 
Vernon M. Chinchilli, PhD, CHAIR (statistician) 
Distinguished Professor and Chair 
Department of Public Health Sciences, A210 
Penn State Hershey College of Medicine 
600 Centerview Drive, Suite 2200 
Hershey, PA 17033-0855 
 
James Donohue, MD 
Chair and Professor of Medicine 
Chief of the Division of Pulmonary and Critical Care Medicine 
University of North Carolina at Chapel Hill 
Chapel Hill, NC 
Paul N. Lanken, MD  
Professor of Medicine 
Associate Dean, Ethics and Humanities 
Hospital of University of Pennsylvania 
5048 A Gates Pavilion 
3400 Spruce St 
Philadelphia, PA, 19104-4283 
 
Cristine E. Oropez, MD MHS 
Regional Medical Officer, Pima County Market 
CareMore Health  
4821 N. Stone Avenue 
Tucson, AZ 85704 
 
Jess G. Fiedorowicz, M.D., Ph.D. 
Department of Psychiatry 
University of Iowa 
 
 
 


TRIM protocol Version 1.8                                                                                   Data safety monitoring plan |23 
Confidential, not for attribution or citation. 
5.2. Adverse events and unanticipated problem reporting 
The PI will submit a completed serious adverse event report to the DCC and the IRB, and then the DCC 
will report to the NIH, FDA and Chair of the DSMB within 7 calendar days after initial receipt of 
information pertaining to any potentially life-threatening (grade 4) unexpected, suspected serious 
adverse reactions.  
The PI will submit a completed serious adverse event report to the DCC and the IRB, and then the DCC 
will report to the NIH, FDA and Chair of the DSMB within 15 calendar days after initial receipt of 
information pertaining to any non-fatal, non-life-threatening unexpected, suspected serious adverse. 
Unanticipated Problems that are not SAE’S will be reported to the NIH, FDA and DSMB within 14 days of 
the investigator becoming aware of the problem. 
All unanticipated problems will be reported to OHRP and external IRB’s within 30 days of the IRB’s 
receipt of the report of the UP from the investigator. 
A summary of all adverse events will be reported to the DSMB, NIH, FDA and IRB at least annually. 
 


TRIM protocol Version 1.8                                                                                                                             Drug |24 
Confidential, not for attribution or citation. 
6. Drug 
• 
Roflumilast (Daliresp®), 500 mcg tablets, will be obtained from a commercial vendor, and 
supplied to Temple University Research Pharmacy.  Temple will also supply matching placebo. 
• 
Temple will provide bottles with a 6 week supply of study drug or placebo.  This will be shipped 
to the study sites. 
• 
Storage and stability 
• 
Capsules will be stored at room temperature (20-25oC), excursions permitted to 15-30oC, per 
labeling standards for this medication. 
• 
Administration: oral administration 
6.1. FDA considerations 
This medication is FDA approved for the treatment of recurrent exacerbations of COPD.  It has not been 
approved for the treatment of asthma.  This study has been deemed exempt from requiring an IND by 
the FDA. 
 
 
 
 


TRIM protocol Version 1.8                                                                                                  Special populations |25 
Confidential, not for attribution or citation. 
7. Special populations 
7.1. Inclusion of women 
Both women and men will be enrolled in these studies. Asthma is more prevalent among female adults, 
and so we anticipate a slight majority of participants will be women. 
7.2. Women of childbearing potential 
Women of childbearing potential have been included, but women of childbearing age who do not agree 
to practice an adequate birth control method (abstinence, combination barrier and spermicide, or 
hormonal) for the duration of the study will be excluded. 
Pregnant women will not be enrolled in the trial, as the safety of roflumilast in pregnancy is not known. 
Women of child-bearing potential will be required to use adequate contraception, and undergo a 
pregnancy test at every visit in SA1. Any pregnancy that might occur would be followed to term if 
patient consents.  
7.3. Inclusion of minorities 
We anticipate minority enrollment will reflect prior enrollment in ALA-ACRC studies, with approximately 
50% Caucasian, 40% African American, and 15% Hispanic in the study overall.  We anticipate that 
minority enrollment at UVM will reflect the demographics of Vermont.  
7.4. Inclusion of children  
We will not include children as the phenotype of asthma in obese children is likely to be different 
that in obese adults. 
7.5. Vulnerable populations 
None 
 


TRIM protocol Version 1.8                                                                                                                 References |26 
Confidential, not for attribution or citation. 
8. References 
1. Beuther DA, Sutherland ER. Overweight, obesity, and incident asthma: a meta-analysis of 
prospective epidemiologic studies. American journal of respiratory and critical care medicine. 
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2. Taylor B, Mannino D, Brown C, Crocker D, Twum-Baah N, Holguin F. Body mass index and 
asthma severity in the National Asthma Survey. Thorax. 2008;63(1):14-20. 
3. Vortmann M, Eisner MD. BMI and health status among adults with asthma. Obesity. 
2008;16(1):146-152. 
4. Mosen DM, Schatz M, Magid DJ, Camargo CA, Jr. The relationship between obesity and asthma 
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5. Peters-Golden M, Swern A, Bird SS, Hustad CM, Grant E, Edelman JM. Influence of body mass 
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6. Boulet LP, Franssen E. Influence of obesity on response to fluticasone with or without salmeterol 
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7. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United 
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8. Meltzer EO, Chervinsky P, Busse W, et al. Roflumilast for asthma: Efficacy findings in placebo-
controlled studies. Pulmonary pharmacology & therapeutics. 2015. 
9. Park HJ, Lee JH, Park YH, et al. Roflumilast Ameliorates Airway Hyper-responsiveness Caused by 
Diet-induced Obesity in a Murine Model. American journal of respiratory cell and molecular 
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10. Wouters EF, Bredenbroker D, Teichmann P, et al. Effect of the phosphodiesterase 4 inhibitor 
roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 
diabetes mellitus. The Journal of clinical endocrinology and metabolism. 2012;97(9):E1720-1725. 
11. Sideleva O, Suratt BT, Black KE, et al. Obesity and asthma: an inflammatory disease of adipose 
tissue not the airway. American journal of respiratory and critical care medicine. 
2012;186(7):598-605. 
12. Dixon AE, Gerald LB. Promoting weight loss in asthma. Respirology. 2015;20(2):179-180. 
13. Dixon AE, Pratley RE, Forgione PM, et al. Effects of obesity and bariatric surgery on airway 
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14. Scott HA, Gibson PG, Garg ML, et al. Dietary restriction and exercise improve airway 
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15. Ma J, Strub P, Xiao L, et al. Behavioral weight loss and physical activity intervention in obese 
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16. Calverley PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive 
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17. American Lung Association Asthma Clinical Research C. Clinical trial of low-dose theophylline 
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Efficacy of esomeprazole for treatment of poorly controlled asthma. The New England journal of 
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19. Schatz M, Sorkness CA, Li JT, et al. Asthma Control Test: reliability, validity, and responsiveness 
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20. Marks GB, Dunn SM, Woolcock AJ. An evaluation of an asthma quality of life questionnaire as a 
measure of change in adults with asthma. Journal of clinical epidemiology. 1993;46(10):1103-
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21. Revicki DA, Leidy NK, Brennan-Diemer F, Sorensen S, Togias A. Integrating patient preferences 
into health outcomes assessment: the multiattribute Asthma Symptom Utility Index. Chest. 
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22. Svedlund J, Sjodin I, Dotevall G. GSRS--a clinical rating scale for gastrointestinal symptoms in 
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24. Mancuso CA, Peterson MG, Charlson ME. Comparing discriminative validity between a disease-
specific and a general health scale in patients with moderate asthma. Journal of clinical 
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25. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J 
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27. Inc W. Anthropometry Manual. In: (NCHS) NCfHCS, ed: Centers for Disease Control an 
Prevention (CDC); 1998. 
28. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. The European 
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approach. Journal of clinical epidemiology. 2013;66(2):197-201. 
30. American Lung Association-Asthma Clinical Research Centers' Writing C, Dixon AE, Castro M, et 
al. Efficacy of nasal mometasone for the treatment of chronic sinonasal disease in patients with 
inadequately controlled asthma. The Journal of allergy and clinical immunology. 
2015;135(3):701-709 e705. 
31. Schatz M, Kosinski M, Yarlas AS, Hanlon J, Watson ME, Jhingran P. The minimally important 
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TRIM protocol Version 1.8                                                                                                                    Appendix |28 
Confidential, not for attribution or citation. 
 
 
 
 
 
 
 
 
 
 
 
9. Appendix  


TRIM protocol Version 1.8                                                                                                                    Appendix |29 
Confidential, not for attribution or citation. 
A. Changes log 
 
Protocol 
section 
Version 1.6 
Version 1.7 
Version 1.8 
2.1.1. 
Inclusion 
criteria  
Physician diagnosis of asthma on 
regular prescribed controller 
therapy for at least 3 months 
 
Current or previous (within five 
years) evidence of at least a 12% 
increase in FEV1 after inhaling 2-4 
puffs of albuterol or a positive 
methacholine challenge test 
Same as Version 1.6  
Physician diagnosis of 
asthma and on regular 
prescribed controller 
therapy for at least 3 
months 
 
Previous (within five 
years) evidence of at 
least a 12% increase in 
FEV1 after inhaling 2-4 
puffs of albuterol or a 
positive methacholine 
challenge or patient 
reported history of 
patient reported 
improvement of asthma 
exacerbation after a 
course of systemic or 
inhaled corticosteroids 
2.4.  
2.4. Rationale for the five centers 
Collaborating sites: Northwestern 
University Feinberg School of 
Medicine, Mount Sinai Icahn School 
of Medicine, Duke University, 
University of Arizona, and the 
University of Vermont. Johns 
Hopkins University will be the Data 
Coordinating Center (DCC) for the 
trial. 
 
We will perform this study in five 
centers that have a strong record 
of recruitment and working 
together as part of the ALA-ACRC, 
and that represent diverse 
populations within the network.  
We will need to recruit 7-8 patients 
per site within an approximate 12 
month period to complete all 
procedures and study analysis 
within the time-frame of this 
proposal, and this is a reasonable 
recruitment target for these 
centers.   
2.4. Rationale for the seven centers 
Collaborating sites: Northwestern 
University Feinberg School of Medicine, 
Mount Sinai Icahn School of Medicine, 
Duke University, University of Arizona, 
University of Alabama Lung Health 
Center, University of Illinois – Chicago, 
and the University of Vermont. Johns 
Hopkins University will be the Data 
Coordinating Center (DCC) for the trial. 
 
We will perform this study in seven 
centers that have a strong record of 
recruitment and working together as 
part of the ALA-ACRC, and that 
represent diverse populations within 
the network.  We will need to recruit 5-
6 patients per site within an 
approximate 12 month period to 
complete all procedures and study 
analysis within the time-frame of this 
proposal, and this is a reasonable 
recruitment target for these centers.  
 
Same as Version 1.7 


TRIM protocol Version 1.8                                                                                                                    Appendix |30 
Confidential, not for attribution or citation. 
Protocol 
section 
Version 1.6 
Version 1.7 
Version 1.8 
2.9. 
Procedures 
a. All procedures will be performed 
exclusively for study purposes 
b. Old randomization/drug 
distribution with in-person visits  
c. Only paper diary cards 
d. Spirometry and methacholine tests 
for in-person visits  
e. Pregnancy testing in clinic 
f. Peak flow given and demonstrated 
in clinic at V1 
g. Only paper completion of asthma 
diaries 
h. Blood pressure not listed 
i. No scales given 
j. Medicine adherence at each clinic 
visit after V2 
k. Blood draw not optional  
 
Same as Version 1.6  
a. Sites conducting remote 
follow up visits must use a 
secure (password protected) 
zoom link or other secure 
online communication 
method.   Participants who 
are followed up remotely, will 
complete some 
questionnaires over the 
phone and mail back the rest 
of the questionnaires to the 
site.  
b. Clarified when 
randomization/drug 
distribution will occur 
c. Added review of paper or 
electronic diary cards to study 
visit table  
d. Removed spirometry and 
methacholine challenge tests 
from study visit table 
e. Clarified new procedure for 
pregnancy testing 
f. Added when peak 
expiratory flow will be trained  
g. Asthma diaries can be 
completed on paper or 
electronically 
h. Added blood pressure to 
anthropometrics.  
i. Digital scales will be given 
to eligible participants at visit 
2 to take home to measure 
weight. Participants will send 
photo of weight along with 
feet on scale.  
j. Modified when medicine 
adherence will be assessed   
k. Clarified that blood draw is 
optional 


TRIM protocol Version 1.8                                                                                                                    Appendix |31 
Confidential, not for attribution or citation. 
 
 
 
 
Protocol 
section 
Version 1.6 
Version 1.7 
Version 1.8 
2.11. 
Modificatio
ns due to 
COVID-19 
pandemic 
Section not there 
Same as Version 1.6 
New section  
4.1. Risks of 
individual 
procedures 
4.1.1. Pulmonary function testing,  
4.1.2. Methacholine challenge,  
4.1.3. Bronchodilator all present 
Same as Version 1.6 
Old 4.1.1., 4.1.2., and 4.1.3. 
removed  
4.1.1. Roflumilast  
4.1.2. Venipuncture  
No more section 4.1.3. 
4.4.2. 
Financial 
considerati
ons 
We will also reimburse for mileage at 
standard UVM rates. 
Same as Version 1.6 
We will also reimburse for 
mileage at standard UVM 
rates if participants pick 
up/drop off study supplies. 
 
5.1. 
Compositio
n of DSMB 
Vernon Chinchili, Donald Tashkin, Paul 
Lanken, Frederic Wamboldt, Tricia 
Williams  
Same as Version 1.6  
Vernon Chinchili, James 
Donohue, Paul Lanken, 
Cristine Oropez, Jess 
Fiedorowicz  

ICF_003.pdf: 
Protocol: Trial of Roflumilast in Asthma Management 
CHRMS 17-0047 
Site Version: 10 Jul 2020 
Page 1 of 13 
RESEARCH PARTICIPANT INFORMED CONSENT AND 
PRIVACY AUTHORIZATION FORM 
Protocol Title:  
Trial of Roflumilast in Asthma Management (TRIM) 
Application No.: 
Sponsor: 
National Institutes of Health (NIH) and 
American Lung Association (ALA) 
Principal Investigator: 
Anne E. Dixon, MA, BCh 
University of Vermont, Vermont Lung Center 
792 College Parkway, Suite 305 
Colchester, Vermont, 05446 
Phone: (802) 847-2193 
Fax: (802) 656-8926 
1. What you should know about this study:
•
You are being asked to take part in a research study. This consent form explains the research
study and your part in it. Please read it carefully and take as much time as you need.
•
Ask your study doctor or the study team to explain any words or information that you do not
understand.
•
You are a volunteer.  If you join the study, you can change your mind later.  There will be no
penalty or loss of benefits if you decide to quit the study.
•
During the study, we will tell you if we learn any new information that might affect whether you
wish to continue to participate.
•
This study is being conducted by the University of Vermont as part of the American Lung
Association’s Airways Clinical Research Centers network; participants will also be recruited at
six other centers across the United States.
•
Biospecimens will be collected in this study if site policies allow it. Biospecimens may include
any of the following: blood, tissue, saliva, urine, bone marrow, cells, etc. Most biospecimens
contain DNA, which is the genetic code for each person.
NCT03532490


Protocol: Trial of Roflumilast in Asthma Management 
CHRMS 17-0047 
 
 
Site Version: 10 Jul 2020 
 
 
Page 2 of 13 
 
 
• A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you. At most, the web 
site will include a summary of the results. You can search this Web site at any time.  
 
• If you would like to review the information for this study, or a summary of the results, ask the 
study team doctor for the ClinicalTrials.gov study registration number. 
 
• We encourage you to ask questions and take the opportunity to discuss the study with anybody 
you think can help you make this decision.  
 
2. Why is this research being done? 
 
• You are being invited to take part in this research study because you have asthma that is not well 
controlled, and your body mass index (BMI) is greater than 30 kg/m2 (BMI is a person’s weight 
in kilograms (kg) divided by his or her height in meters squared), which may make your asthma 
less responsive to asthma medications.   
 
• People who have a BMI greater than 30 tend to have poor asthma control that does not respond 
well to usual asthma treatments.  In fact there are no treatments specifically targeting asthma in 
patients with a higher BMI.  The purpose of this study is to investigate how effective a 
medication called Roflumilast might work for people with asthma and a BMI greater than 30.  
 
• Roflumilast is available as the medication “Daliresp” in the United States, and has been 
approved by the FDA to treat COPD. Roflumilast has beneficial metabolic effects that may be 
useful in the treatment of asthma in patients with a higher BMI. Roflumilast can induce weight 
loss, which may also lead to improved asthma control.  
 
 
 
How Many People Will Take Part In The Study? 
 
• 38 people will participate in the study nationwide 
 
3. What will happen if you join this study? 
 
• If you agree to be in the study, we will ask you to do the following things: 
 
o This study involves seven study visits over approximately 6 months, and taking study 
medication and keeping a record of your symptoms every day. Essential clinic visits are 
visit 2 (week 2) and 7 (week 24). Study visit 2 is when eligibility is established. This visit 
must be done in the clinic.  All other visits maybe done in the clinic or remotely using a 
secure video conference application. Study medication will be either Roflumilast or a 
placebo (a placebo is a tablet that looks the same as the Roflumilast tablet, but does not 
actually contain any medication).  You will be assigned to either Roflumilast or placebo 
by randomization (a process that assigns people to a specific treatment according to a 
random process like tossing a coin). You will have an equal chance of being assigned to 
either group.  
 


Protocol: Trial of Roflumilast in Asthma Management 
CHRMS 17-0047 
 
 
Site Version: 10 Jul 2020 
 
 
Page 3 of 13 
 
 
o At the first visit you will answer questions to see if you are eligible for the study.  We 
will not be able to determine if you are eligible at the first visit as we reassess at visit 2. 
We will determine your eligibility at the second, in person, study visit. 
 
o If you are eligible at visit 2, you will be assigned the study drug, Roflumilast or placebo.  
 
o When you receive the study drug, you will be instructed to take 1 capsule Every Other 
Day Roflumilast (500 mcg) OR placebo for the First Two Weeks.  
 
o After two weeks, if you tolerate the drug well, you will take 1 capsule Every Day 
(Roflumilast 500 mcg OR placebo), beginning at Visit 3 and continuing for the rest of the 
study. If you do not tolerate the full dose, you will continue to take one capsule Every 
Other Day for the duration of the study.   
 
o You will receive study drug at clinic visits starting at the second visit.  You will be 
expected to return all unused study drug at each follow-up in-person visit after that, or at 
the end of the study if study visits are conducted remotely.   
 
Description of Study Visit Procedures   
 
• Visits 1–7 (each visit estimated time 1-2 hours): 
 
1. Medical History:  We will document your medical history by asking you questions about your 
past and present health status, medical and surgical history, use of medications, and your family 
history. We will measure your height and weight, and your waist circumference and hip 
circumference.  You will be asked to complete questionnaires about your asthma, gastrointestinal 
symptoms, and also anxiety and depression symptoms. If you will be followed up remotely, you 
will complete some questionnaires over the phone and mail back the rest of the questionnaires to 
the site. We will review medical records of any prior lung function tests and allergy tests.  We 
will show you how to fill out the paper or electronic diary cards so you can record your daily 
symptoms at home. A scale and tape measure will be given to you during the second study visit 
so you can record these measurements at home.  
 
2. Urine Pregnancy Test: If you are a female and of childbearing potential, you will be asked to 
provide a urine specimen to test for pregnancy. If you will be followed up remotely, then an at 
home pregnancy test will be provided to you and you will be required to send us a picture of the 
results If you qualify for the study, you will need to use a reliable form of birth control for the 
duration of the study. 
 
 
3. Blood Draw at visits 2 and 7: If the clinic policies permit blood draw we will perform a blood 
draw for analysis of substances in your blood, measuring metabolic and oxidative markers 
related to your asthma – we will need approximately 15 cc (3 teaspoons) of blood. We will ask 
you not to eat or drink anything after midnight the night before this morning blood draw. Blood 
draw is optional.  
 
 


Protocol: Trial of Roflumilast in Asthma Management 
CHRMS 17-0047 
 
 
Site Version: 10 Jul 2020 
 
 
Page 4 of 13 
 
 
4. Diary Cards:  Complete the provided paper or electronic asthma diary cards daily. On the diary 
card you will record your peak flow, your asthma symptoms or other symptoms you might 
experience, and whether you took the study medication or other asthma medication. The diary 
card will take less than 5 minutes a day to complete.  We will ask you to fill out the diary cards 
on paper, your phone, or your computer. An email or text with a link to the asthma diary card 
will be sent to you if they will be completed electronically. The purpose of this diary is to see 
how well your asthma symptoms are being controlled. You will be asked to complete the asthma 
diary card every day after the first visit until the study is completed. You will be given a peak 
flow meter at the second study visit. The coordinator will instruct you on how to use it. You will 
then demonstrate how to use the peak flow meter at home via video conference application. 
Asthma action plan will be provided for guidance as well.  
 
5. Randomization at visit 2: You will be assigned to study medication (roflumilast or placebo). You 
will be taking the study medication for 24 weeks, every other day or every day  depending on 
how well you tolerate it.  
 
A schedule of tests and procedures is outlined in the following table. 
Outline of Study Visits 
Week 
-1 
0 
2 
6 
12 
18 
24 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Consent 
• 
  
  
 
  
 
  
Baseline/interim history 
• 
• 
• 
• 
• 
• 
• 
Randomization 
 
• 
 
 
 
 
 
Pill distribution† 
 
• 
 
• 
• 
 
 
Pill distribution‡ 
 
• 
 
 
• 
 
 
Review of paper/electronic diary 
cards 
  
• 
• 
• 
• 
• 
• 
Pill Counts 
 
 
• 
• 
• 
• 
• 
Asthma Control 
• 
• 
• 
• 
• 
• 
• 
Anxiety/depression questionnaires 
• 
• 
• 
• 
• 
• 
• 
GSRS 
• 
• 
• 
• 
• 
• 
• 
QOL  
• 
• 
• 
• 
• 
• 
• 
Blood draw¥ 
 
• 
 
 
 
 
• 
Anthropometrics 
• 
• 
• 
• 
• 
• 
• 
Pregnancy test* 
• 
• 
• 
• 
• 
• 
• 
End of study questionnaire 
  
  
  
 
  
  
• 
† if dose frequency is every day since V3 
‡ if dose frequency is every other day since V3 
¥ conduct blood draw only if site permits it 
*for women of child-bearing potential and participating in remote follow up participants will be mailed testing 
kit, and asked to send photo of result to coordinator 
 
 


Protocol: Trial of Roflumilast in Asthma Management 
CHRMS 17-0047 
 
 
Site Version: 10 Jul 2020 
 
 
Page 5 of 13 
 
 
Request to collect and store blood samples and data for future research 
 
• Your samples and data will be stored for future use with your consent.  
 
• We have several tests planned for the blood samples and information that we collect from you 
during this study.  We are also hoping to store any leftover blood samples and data you provide 
for future research on obesity and asthma. We will store your samples and data with a code 
number, not your name, so laboratory personnel will not be able to identify you. The list 
connecting your name to this code will be stored separately, in a password protected file within 
the Vermont Lung Center.  
 
Participation in this long-term storage of samples is voluntary, and if you choose not to allow it 
or withdraw later, your participation in the main study will not be affected. You will not be able 
to withdraw specimens already donated.  
 
• Check the box below and place your signature if you give permission for collection of blood 
samples and related data to be stored/used/disclosed/shared for future research projects. 
 
 
 
Yes    
 
 
No    
           ______________________ 
                          Signature of Participant 
 
 
How long will you be in the study? 
 
• You will be in this study for six months. 
 
 
       _____________________  
         Signature of Participant 


Protocol: Trial of Roflumilast in Asthma Management 
CHRMS 17-0047 
 
 
Site Version: 10 Jul 2020 
 
 
Page 6 of 13 
 
 
4. What are the risks or discomforts of the study? 
 
• There are risks involved with taking Roflumilast. However Daliresp® (Roflumilast) is a FDA 
approved drug for COPD in the US. In previous studies the most common side effects were: 
 
o Diarrhea (9.5%), 
 
o Weight decrease (7% to 20%), 
 
o Nausea (4.7%), 
 
o Headache (4.4%), 
 
o Back pain (3.2%), 
 
o Influenza (flu) (2.8%), 
 
o Insomnia (difficulty sleeping) (2.4%), 
 
o Dizziness (dizzy) (2.1%), and 
 
o Decreased appetite (2.1%) 
 
• Most side effects generally happened within the first weeks of starting to take study drug and 
resolved during continued use of roflumilast. As with any drug, you may feel some discomfort or 
side effects associated with the use of the drug that has not already been reported. 
 
• Use of roflumilast has been shown to be associated with an increase in psychiatric side effects 
such as insomnia, anxiety, and depression. There have been subject reported cases of suicidal 
ideation and behavior, including a completed suicide in previous studies. We will ask you to let 
us know the name of your mental health care provider, if you have one.  At each study visit you 
will complete a questionnaire about anxiety, depression and suicidal thoughts, which we will 
check before you leave the clinic.   
 
• If you have symptoms of anxiety/depression/suicidal thoughts, we will provide you with 
information about mental health care resources and/or ask you to schedule an appointment with 
your mental health care provider.  We will check in with you a week later to make sure that you 
have been able to get follow up care.  If we can’t reach you, we will discuss this with the study 
physician (Dr. Dixon, or her designee), who will contact Dr. Desjardins (a psychiatrist at UVM 
Medical Center) to discuss what follow-up care you might need. 
 
• If you are actively suicidal, we will ask you to contact your primary /mental-health care provider 
immediately (from our clinic), but if you are unable to reach your primary /mental-health care 
provider, we will either accompany you to the Emergency Department, or call 911.  
 
• If you have any psychiatric side effects during the study please report the illness to your study 
doctor immediately. 
 


Protocol: Trial of Roflumilast in Asthma Management 
CHRMS 17-0047 
 
 
Site Version: 10 Jul 2020 
 
 
Page 7 of 13 
 
 
• Participants and their families/caregivers should be alert for worsening of difficulty sleeping, 
anxiety, depression, mood changes or suicidal thoughts while on study drug, and should contact 
the study team immediately to discuss. 
 
• Venipuncture: The main risk of this is bruising and minor discomfort. 
 
5. Are there risks related to pregnancy?  
 
• We will not recruit participants who report that they are pregnant. 
 
6. Are there benefits to being in the study? 
 
• 
There may be no direct benefit of participation in this study other than the opportunity to learn more 
about your asthma, and to have your asthma closely monitored.  Your asthma control might improve 
on the study medication. We may learn new information that will help patients in the future who have 
asthma.  
 
7. What are your options if you do not want to be in the study? 
 
• 
The only option is to not participate in this study. The decision not to participate will not affect the 
care you receive. Other potential options to better control your asthma can be discussed with your 
primary care provider or pulmonologist.  
 
8. Will it cost you anything to be in this study?  
 
• The only cost to you for participating in this study is your time. 
 
9. Will you be paid if you join this study? 
 
• You will receive $50 at visit 2 for a total of $350 for completion of the study.  Subjects who must 
travel 20 miles or more (each way) will be compensated for their mileage at the current University of 
Vermont rate. 
 
• You may be required to provide your social security number to be paid for taking part in this study. 
Federal tax law requires that you report your research payments when you file your taxes. If your 
total payments from Johns Hopkins University exceed $600 per year, Johns Hopkins will report 
these payments to the Internal Revenue Service and you will receive a 1099-MISC form from us.  
 
10. Can you leave the study early?    
 
• Your participation in this research study is voluntary.  You may decline to participate or you may 
withdraw at any time without prejudice, penalty or loss of benefits to which you are entitled. 
 
• If you do cancel your permission to use and disclose your information, your part in this study will 
end and no further information about you will be collected. Any information collected up to the 
point you wish to stop your participation will be used for research purposes. 
 


Protocol: Trial of Roflumilast in Asthma Management 
CHRMS 17-0047 
 
 
Site Version: 10 Jul 2020 
 
 
Page 8 of 13 
 
 
11. Why might we take you out of the study early? 
 
• The investigator may end your participation in this study without your consent for any of the 
following reasons:  
 
o it is not in your best medical interests to continue 
 
o you need treatment not allowed in this study 
 
o you cancel permission to disclose your health information 
 
o you fail to follow instructions 
 
o the study is canceled 
 
o there may be other reason s to take you out of the study that we do not know about at this 
time 
• If you are taken out of the study early, Johns Hopkins may use or give out your health information 
that it has already collected if the information is needed for this study or any follow-up activities.  
 
12. How will your privacy be protected? 
 
• We have rules to protect information about you.  Federal and state laws and the federal medical 
Privacy Rule also protect your privacy.  By signing this form you provide your permission, called 
your “authorization,” for the use and disclosure of information protected by the Privacy Rule. 
 
• The research team working on the study will collect information about you.  This includes things 
learned from the procedures described in this consent form.  They may also collect other information 
including your name, address, date of birth, and information from your medical records (which may 
include information about HIV status, drug, alcohol or STD treatment, genetic test results, or mental 
health treatment). 
 
• The research team will know your identity and that you are in the research study.  Other people at 
Johns Hopkins, particularly your doctors, may also see or give out your information. We make this 
information available to your doctors for your safety.    
 
• People outside of Johns Hopkins may need to see or receive your information for this study.  
Examples include government agencies (such as the Food and Drug Administration), safety 
monitors, other sites in the study and companies that sponsor the study.  
 
• We cannot do this study without your authorization to use and give out your information.  You do 
not have to give us this authorization.  If you do not, then you may not join this study. 
 
• We will use and disclose your information only as described in this form and in our Notice of 
Privacy Practices; however, people outside Johns Hopkins who receive your information may not be 
covered by this promise or by the federal Privacy Rule.  We try to make sure that everyone who 
needs to see your information keeps it confidential – but we cannot guarantee that your information 
will not be re-disclosed. 


Protocol: Trial of Roflumilast in Asthma Management 
CHRMS 17-0047 
 
 
Site Version: 10 Jul 2020 
 
 
Page 9 of 13 
 
 
• The use and disclosure of your information has no time limit. You may revoke (cancel) your 
permission to use and disclose your information at any time by notifying the Principal Investigator 
of this study by phone or in writing.  If you contact the Principal Investigator by phone, you must 
follow-up with a written request that includes the study number and your contact information.  The 
Principal Investigator’s name, address, phone and fax information are on page one of this consent 
form.  
 
• If you do cancel your authorization to use and disclose your information, your part in this study will 
end and no further information about you will be collected. Your revocation (cancellation) would not 
affect information already collected in the study, or information we disclosed before you wrote to the 
Principal Investigator to cancel your authorization. 
• The health information we plan to collect for this study is listed below. 
 
o Medical history and past pulmonary function tests  
 
o Information that identifies you, such as your name, address, age, and sex 
 
o Reports from hospital and clinic visits 
 
o Laboratory and other test results 
 
o X-ray and other images and reports 
 
o Lists of medications you are taking 
 
o Responses to health surveys and questionnaires 
 
Who is disclosing your health information for this research study? 
 
• The University of Vermont Medical Center  
 
• Other doctors’ offices and hospitals where you may receive medical care while this study is active. 
 
• Our research team will use your health information.  We may also share it with those who assist with 
the conduct of the research or oversight of the activities for this study.  The representatives from the 
institutions, organizations, and agencies are listed below. 
 
o The University of Vermont and its Committees on Human Research 
 
o The University of Vermont Medical Center  
 
o Other researchers and centers that are a part of this study, including individuals who 
oversee research at those sites 
 
o Officials from agencies and organizations that provide accreditation and oversight of 
research 
 


Protocol: Trial of Roflumilast in Asthma Management 
CHRMS 17-0047 
 
 
Site Version: 10 Jul 2020 
 
 
Page 10 of 13  
 
o The sponsor of this study, American Lung Association – Airways Clinical Research 
Center (ALA-ACRC), or others who fund the research, including the government 
 
o Federal and state agencies that oversee or review research information, such as the U.S. 
Food and Drug Administration (FDA), the Department of Health and Human Services, 
the National Institutes of Health, and public health and safety authorities 
 
o Your health insurer, for portions of the research and related care that are considered 
billable 
 
• Your health information is protected by a federal law called the Health Information Portability and 
Accountability Act (HIPAA).  Once your health information is shared outside of the University of 
Vermont Medical Center, we cannot guarantee that these laws will continue to apply.  As a result, 
your health information could be further disclosed for other purposes.  In the absence of a Certificate 
of Confidentiality, it is also possible for a court or other government official to order the release of 
study data. The confidentiality of your health information cannot be guaranteed if you agree it may 
be used in this study. 
 
• Your permission to use your health information will not end until the study is completed.  During 
this study, you will not have access to study data.  You may ask for your data once study activities 
are complete.  You have a right to receive a copy of the information in your medical record at any 
time. 
 
• If you decide not to allow the use and disclosure of your health information, you may not take part in 
this study.  Your decision will have no effect on your current or future medical care. 
 
• If you choose to stop taking part in this study in the future, you may cancel permission for the use of 
your health information. You should let the research team know that you are cancelling your 
permission. A member of the research team will assist you in making your decision effective. The 
study will continue to use your health information already collected for the study before you 
canceled your permission, and you cannot get back information that was already shared with others.  
 
• If you have questions or concerns about the use and disclosure of your health information, you 
should ask a member of the study team at (802) 847-2193 or the Privacy Officer at The University of 
Vermont Medical Center, Inc, at (802) 847-2667. 
 
Safeguarding Your Health Information 
 
• A record of your progress will be kept in a confidential form at the Vermont Lung Center.  
The security of your record will be maintained by study staff in a locked office. The results 
of this study may eventually be published and information may be exchanged between 
medical investigators, but patient confidentiality will be maintained.   
 
• If your record is used or disseminated for government purposes, it will be done under 
conditions that will protect your privacy to the fullest extent possible consistent with laws 
relating to public disclosure of information and the law-enforcement responsibilities of the 
agency.   
 


Protocol: Trial of Roflumilast in Asthma Management 
CHRMS 17-0047 
 
 
Site Version: 10 Jul 2020 
 
 
Page 11 of 13  
 
• You may be requested to provide your name, social security number, and address.  This 
information will be disclosed one time to either the University of Vermont’s Procurement 
Services Department or UVM Medical Center Accounts Payable Department for purposes of 
reimbursing you for participation in this study.  If you are not a US Citizen or Permanent 
Resident Alien you will be required to complete additional paperwork for payment.   
 
 
13. What treatment costs will be paid if you are injured in this study?  
 
The UVM Medical Center Policy 
 
• If you are injured or become ill as a result of being in this research, the UVM Medical Center, the 
hospital partner of the University of Vermont, will provide reasonable and usual medical care for 
that injury or illness. There will be no cost to you if the conditions listed below apply to your injury 
or illness. These conditions are: 
 
1. The investigator, in consultation with the study sponsor, determines that your injury or 
illness results from the research and not from your underlying condition or its usual 
treatment. 
 
2. You let the investigator know about the injury or illness when you first notice it; and  
 
3. You follow medical advice about proper treatment options for the injury or illness. 
 
• The UVM Medical Center may claim payments for your medical treatment directly from the study 
sponsor or your insurance company when these payments are allowed. 
 
• For an injury or illness that results from being in this study, the University of Vermont Medical 
Center will not offer you any other payments, such as lost wages or expenses, except for your 
medical care. Even though you may receive medical care at no cost to you under certain conditions if 
you are in this study, the UVM medical center and the University of Vermont do not admit to any 
responsibility for an injury or illness that results from being in the study.  If you agree to take part in 
this study and you sign this consent form, you are not giving up any of your legal rights.   
 
14. What other things should you know about this research study? 
 
a. What is the Institutional Review Board (IRB) and how does it protect you?  
 
• The Johns Hopkins Medicine IRB is made up of: 
 
o Doctors 
 
o Nurses 
 
o Ethicists 
 
o Non-scientists 
 
o and people from the local community.  


Protocol: Trial of Roflumilast in Asthma Management 
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Page 12 of 13  
 
• The IRB reviews human research studies. It protects the rights and welfare of the people taking part 
in those studies.  You may contact the IRB if you have questions about your rights as a participant or 
if you think you have not been treated fairly.  The IRB office number is 410-955-3008. You may 
also call this number for other questions, concerns or complaints about the research. 
 
• When the Johns Hopkins School of Medicine Institutional Review Board (IRB) reviews a study at 
another site, that site (institution) is solely responsible for the safe conduct of the study and for 
following the protocol approved by the Johns Hopkins IRB.   
 
b. What do you do if you have questions about the study? 
 
• You may contact Dr. Dixon, the Investigator in charge of this study, at (802) 847-1158 for 
more information about this study.  If you have any questions about your rights as a 
participant in a research project or for more information on how to proceed should you 
believe that you have been injured as a result of your participation in this study you should 
contact the Director of the Research Protections Office at the University of Vermont at 802-
656-5040. 
 
c. What should you do if you are injured or ill as a result of being in this study?  
 
• If you think you are injured or ill because of this study, call Dr. Dixon, at (802) 847-1158. 
 
d. What happens to Data and Biospecimens that are collected in the study?  
 
• Johns Hopkins and our research partners work to understand and cure diseases. The biospecimens 
and/or data you provide are important to this effort. 
 
• If you join this study, you should understand that you will not own your biospecimens or data, and 
should researchers use them to create a new product or idea, you will not benefit financially.  
 
• With appropriate protections for privacy, Johns Hopkins may share your biospecimens and 
information with our research sponsors and partners.  
 
15. What does your signature on this consent form mean?  
 
• Your signature on this form means that: You understand the information given to you in this form, you 
accept the provisions in the form and you agree to join the study. You will not give up any legal rights by 
signing this consent form.  
 
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM 
 
________________________________________________________________________________________________________________ 
Signature of Participant                                                                 (Print Name)                                                 
Date/Time  
 
________________________________________________________________________________________________________________ 
Signature of Person Obtaining Consent                                        (Print Name)                                             
Date/Time 
 
The rest of this page is intentionally left blank. 
 


Protocol: Trial of Roflumilast in Asthma Management 
CHRMS 17-0047 
 
 
Site Version: 10 Jul 2020 
 
 
Page 13 of 13  
 
Statement of Consent 
 
You have been given and have read or have had read to you a summary of this research study.  Should 
you have any further questions about the research, you may contact the person conducting the study at 
the address and telephone number given below.  Your participation is voluntary and you may refuse to 
participate or withdraw at any time without penalty or prejudice to your present and/or future care.  
 
You agree to participate in this study and you understand that you will receive a signed copy of this 
form. 
 
 
___________________________________________ 
____________________________         
 
Signature of Subject               
 
 
 
 
 
Date 
 
 
______________________________________________________________________ 
Name of Subject Printed 
 
 
 
 
 
 
 
 
 
 
This form is valid only if the Committees on Human Research’s current stamp of approval is shown 
below.   
 
 
_______________________________________________________________________                                           
Signature of Principal Investigator or Designee         
 
Date 
 
  
 
_____________________________________________________________________ 
Name of Principal Investigator or Designee Printed 
 
 
 
 
Principal Investigator: 
Anne Dixon 
Address:  
 
 
Given D209, 89 Beaumont Avenue, Burlington, VT 05405 
Telephone Number:   
802-847-1158