Clinical trial NCT02813447
Conditions: COPD Anxiety Depression Stress Interstitial Lung Disease
Sponsor: Duke University
Start date: 2016-08-01; Completion date: 2019-02-20
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Objective: Determine whether treatment of perceived stress, anxiety, and depression with anti-depressant therapy improves dyspnea scores, 6-minute walk (6MW) distance and quality of life (QoL) in patients with Chronic Obstructive Pulmonary Disease (COPD) and ILD (Interstitial Lung Disease) undergoing pulmonary rehab.

The study is a prospective, randomized, double-blinded, placebo-controlled study to assess the effect of an SSRI on 6MW, dyspnea scores, and QoL in COPD and ILD patients undergoing pulmonary rehab. Thirty subjects that carry an ICD-9 code diagnosis of COPD and/or ILD and CES-D (Center for Epidemiologic Studies Depression) score of \> 16 will be recruited from Duke Pulmonary Rehab.

Multivariable regression models will be constructed to evaluate the relationship between perceived stress, anxiety, and depression with adjustments by race, gender, age, BMI and GOLD score. A multivariable regression model will be constructed to assess whether treatment of perceived stress, depression, and anxiety with antidepressant therapy (sertraline) is an effect modifier on 6MW distance and dyspnea scores in patients with COPD or ILD who are enrolled in pulmonary rehab.

Descriptive statistics will be used to examine the socio-demographic characteristic data. Student t-tests will be performed to assess group differences in continuous data. Categorical variables will be examined using the Pearson's Chi-Squared test.

Detailed description:

Arms: arm 1: Subjects randomized into this arm will be given active study drug (sertraline). Subjects will take 25mg tablets by mouth daily starting at visit 1 along with participating in the intensive pulmonary rehab program. Subjects will be assessed at one week intervals +/- 7 days for tolerability and side effects, and if tolerating study drug, the dose will be increased weekly by 25mg over the course of the first four weeks with maximum effective dose of 100mg daily by the end of week four. Subjects will continue this dose over the course of the remaining 8 weeks of the study, while participating in the graduate program of pulmonary rehab. arm 2: Subjects randomized to the placebo arm will have the same procedures as described above in the study drug arm with the exception that they will be receiving matched placebo drug.
Interventions: intervention 1: Sertraline intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
NCT02813447 
Pro00071349 
Safety of Anti-Depressant in Chronic Obstructive Pulmonary Disease (SAD-COPD) 
Approval Date: 07/26/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCT02813447 
Purpose of the Study 
Purpose of the Study: In COPD and ILD (Interstitial Lung Disease) patients with perceived stress, anxiety and depression, 
does the addition of anti-depressant therapy improve lung function and dyspnea better than pulmonary rehab alone?  
  
Primary Outcome: The addition of anti-depressant therapy will improve lung function and dyspnea in patients with 
COPD and/or ILD with perceived stress, anxiety, and depression better than pulmonary rehab alone. 
  
Secondary Outcomes:  
The addition of anti-depressant therapy will improve QOL scores in COPD and ILD patients with perceived stress, anxiety, 
and depression better than pulmonary rehab alone. 
The addition of anti-depressant therapy will improve measures of perceived stress, anxiety, and depression in COPD and 
ILD patients with stress, anxiety, and depression better than pulmonary rehab alone. 
  
Specific Aim 1:  
Determine whether treatment of perceived stress, anxiety, and depression with anti-depressant therapy improves 
dyspnea scores, 6MW distance and QOL in patients with COPD undergoing pulmonary rehab.  We will: 
Patients with COPD and/or ILD undergoing pulmonary will be randomized to treatment arm (anti-depressant therapy) 
vs. placebo arm prior to initiating pulmonary rehab. 
We will administer comprehensive surveys, including measures of anxiety and depression (HADS, AIR), perceived stress 
(GHQ-12), dyspnea (UCSD), and quality of life (QOL) along with performing 6-minute walk, physical exam, and 
pulmonary function testing at visits 1, 4, and 6. 
We will also assess tolerability of treatment with SSRI (sertraline) and appropriateness of further dose increase, or need 
for dose decrease, in the study drug at visits 2-4, which are at 1 week intervals (+ 7 days).  
We will re-administer measures of anxiety and depression (HADS, AIR) as well as dyspnea scores (UCSD) and QOL at visit 
5. 
  
Primary Hypothesis: 
We hypothesize that because depression, anxiety and perceived stress are associated with decreased exercise tolerance 
and lower QOL, then treatment of depression, anxiety and stress with an anti-depressant will modify the clinical efficacy 
of pulmonary rehab in patients with COPD and/or ILD who have depression, anxiety and stress. 
Background & Significance 
Chronic Obstructive Pulmonary Disease (COPD) is a highly prevalent disease and a major cause of morbidity and 
disability in those age 40 years and older (1-3).  Like other chronic diseases, COPD and ILD have a significant impact on 
the psychological well being of those affected.  It has been well documented that mental health problems, particularly 
depression and anxiety, are well-recognized major comorbidities in chronic lung disease (2-4) and contribute to 
increased mortality in these patients as well (2, 5).   The prevalence of anxiety and depression is higher in patients with 
COPD compared to the general population (2, 6), and may even be more prevalent in COPD compared with other 


NCT02813447 
chronic illnesses (7).  The reported prevalence of both anxiety and depression in patients with chronic lung disease is 
varied, depending on the population surveyed and the tools used to assess depression and anxiety.  However, it has 
been established that the prevalence of depression increases with severity of COPD (3, 8).  Furthermore, since a high co-
morbidity (up to > 50%) exits between depression and anxiety (9), it is assumed that anxiety is more prevalent as well.   
There is a higher likelihood of exacerbations, frequent readmissions, greater disability, and overall worse survival 
reported in COPD patients with depressive symptoms (2, 5,10-13).  Additionally, others have shown anxiety has been 
linked to frequent exacerbations and readmissions as well as greater disability (14-16).  Furthermore, patients with 
COPD who have anxiety often hyperventilate, which is associated with dynamic hyperinflation, resulting in worsening 
dyspnea and exercise intolerance (3, 17-18).  
  
The impact of depression, anxiety, and even perceived stress on morbidity and mortality in patients with COPD and ILD 
is significant, specifically in terms of medication adherence, frequent exacerbations, overall quality of life, perceived 
dyspnea, and exercise intolerance.  Consequently, there has been a growing interest in reducing the negative impact of 
these comorbidities in patients with chronic lung disease, particularly in COPD (3).  Pulmonary rehab has been shown by 
many to be an essential therapeutic intervention for people who are symptomatic from chronic lung diseases, such as 
COPD and ILD (19, 20).  Specifically, documented benefits from pulmonary rehab include improvement in quality of life 
and exercise tolerance, and a reduction in symptoms of dyspnea and fatigue (3, 21).  Over the last decade, pulmonary 
rehab has also demonstrated reduction in symptoms of depression and anxiety in patients with moderate to severe 
COPD (22-24).  However, there are varying results regarding whether the burden of depression and anxiety or even 
patients illness perceptions impact outcomes with pulmonary rehab and its effectiveness in patients with COPD (25-27).  
Additionally, there has been limited data looking at treating specific symptoms of perceived stress, anxiety, and 
depression concurrently with pulmonary rehab.  Coventry et al conducted a systematic review with meta-analysis 
examining the comparative effects of a range of psychological and/or lifestyle interventions on depression and anxiety in 
COPD (28).  This meta-analysis observed that the only intervention associated with significant improvements in 
depression and anxiety was a multicomponent pulmonary rehab, with an exercise component, relaxation techniques, 
and self-management education (4, 28, 29).  This suggests that complex interventions that contain a combination of 
psychological techniques and exercise training have the greatest impact on depression and anxiety.  
  
There is a paucity of research looking at the effects of pharmacological and non-pharmacological therapies used to treat 
depression and anxiety in COPD or ILD.  Aside from pulmonary rehab, there are no guidelines regarding other treatment 
options in patients with chronic lung disease and mental health issues.   There is some data looking at non-
pharmacologic interventions, including relaxation therapy, cognitive behavioral therapy (CBT), interpersonal therapy 
(IPT), and self-management programs for treatment of anxiety and depression (30).  However, the quantity and 
methodological difficulties have hindered the integration of their use in formal treatment guidelines for either COPD or 
ILD (3). 
  
Pharmacotherapy is used in standard clinical practice for treatment of anxiety and depression, and appears to be 
commonly used in patients with COPD and ILD as well as in other chronic diseases. In cardiac disease, Jiang, has looked 
at the effect of treating depression with an SSRI on outcomes in patients with CHF.  Patients whose depression remitted 
had a smaller number of nonfatal cardiovascular events per patient as well as less fatal and nonfatal events combined 
(31, 32).  Evidence for the role of anti-depressant therapy to treat mood disorders in chronic lung disease is limited.  Of 
the available studies, most are small with large dropout rates and short follow-up period, and most have looked at the 
role of anti-depressants in COPD alone.  SSRIs are generally considered as preferred first-line agents for treatment of 
depression and anxiety in patients with chronic lung disease (3).  Some evidence has shown better depression scores as 


NCT02813447 
well as quality of life (33, 34).  Eiser et al showed significant reductions in depression scores, improved walking distance 
and health-related quality of life at 3-month follow-up with paroxetine.  Furthermore, a systematic review by Usmani et 
al showed a non-significant but clinically relevant benefit with the use of SSRI for treatment of anxiety symptoms in 
COPD patients (35).  Case reports have also shown improvement in symptoms of anxiety in COPD when treated with 
sertraline (36).  
  
To date no one has looked at the role of pharmacologic treatment of perceived stress, anxiety and depression in 
improving outcomes with pulmonary rehab in patients with COPD and/or ILD.  We suspect that perceived stress, anxiety, 
and depression are effect modifiers on outcomes in pulmonary rehab in COPD and ILD patients.  Furthermore, we 
believe that pharmacologic treatment of anxiety and depression with an SSRI while participating in pulmonary rehab will 
improve outcomes, including improvement in walking distance, exercise tolerance, and lung function.   Treatment with 
SSRI will also reduce perceived dyspnea scores as well.  Thus, this will lead to overall improvement in quality of life. 
Design & Procedures 
The study is a prospective, randomized, double-blinded, placebo-controlled study to assess the effect of an SSRI on 6MW, 
dyspnea scores, and QOL in COPD and ILD patients undergoing pulmonary rehab.  Thirty subjects that carry an ICD-9 code 
diagnosis of COPD and/or ILD and have evidence of depressive symptoms according to a CES-D (Center for Epidemiologic 
Studies Depression) score of > 16 will be recruited from Duke Pulmonary Rehab.  Once subjects have been determined to be 
eligible for enrollment based on inclusion criteria and consent has been signed, they will be randomly assigned to 12 weeks of 
double-blind treatment with SSRI or matched placebo while concurrently participating in pulmonary rehab. 
  
Subjects will also have a physical exam, 6-minute walk test, and spirometry at Visits 1, 4, and 6.  Both spirometry and the 6-
minute walk test are performed clinically in both the COPD and ILD diseased patients to evaluate functional status and assess 
progress in pulmonary rehab, so this is not unusual for the population. 
  
Questionnaires will be performed specifically for research evaluation of perceived stress, anxiety, and depression in this 
population. 
  
Screening (Visit 0):  
 
Explain the study, and informed consent will be obtained. 
 
Perform a comprehensive medical history.   
 
Urine pregnancy testing for women of childbearing potential (WOCBP)** 
 
A comprehensive physical exam will be performed, including vital signs. 
 
A formal psychiatric assessment, including psychiatric or mental health history, will be performed using the Mini 
International Neuropsychiatric Interview (MINI). 
 
If there is concern for cognitive impairment, the MMSE will be used to assess whether there is clinically significant 
cognitive impairment due to dementia or delirium. 
 
If subject is determined to be eligible for enrollment, subjects will then be randomly assigned to one of the two 
treatment arms (either matched placebo or anti-depressant therapy/sertraline), and the study drug will be dispensed 
at the end of Visit 1.    
 
Subjects will be asked to bring the medication bottle containing the study drug with them to all scheduled visits to 
assess medication use and compliance by pill counting. 
  
Visit 1 (day of enrollment into pulmonary rehab/may be same day as visit 0):  
 
If visit 1 does not occur on the same day as visit 0, a comprehensive physical exam will be performed (similar to Visit 
0) and urine pregnancy testing for WOCBP. 
 
Perform Spirometry (does not need to be repeated if performed during enrollment into pulmonary rehab). 
 
Perform 6-Minute Walk test (does not need to be repeated if performed during enrollment into pulmonary rehab). 
 
Administer questionnaires, including the General Health Questionnaire (GHQ-12), Hospital Anxiety and Depression 
Scale (HADS), Anxiety Inventory for Respiratory Disease (AIR), UCSD dyspnea scale, and Quality of Life (QOL) scale 
(UCSD dyspnea scale and QOL does not need to be repeated if performed during enrollment into pulmonary rehab). 
 
Administer study drug.   


NCT02813447 
  
Visits 2-3 (scheduled at 1 week intervals + 7 days):  
 
Urine pregnancy test for WOCBP 
 
Assessment of medication compliance by pill counting. 
 
Assessment of tolerability for further dose titration for study drug, and if deemed appropriate, will increase dose of 
study drug.    
  
Visit 4 will also include the following (scheduled at 1 week intervals + 7 days): :  
 
Administer questionnaires, including the HADS, and AIR, to assess symptoms of perceived stress, anxiety, and 
depression.  
 
Administer UCSD dyspnea scale and QOL scale. 
 
Perform Spirometry. 
 
Perform 6-Minute Walk test (does not need to be repeated if performed during pulmonary rehab). 
 
Urine pregnancy test for WOCBP 
 
Administer General Health Questionnaire (GHQ-12). 
 
Assessment of medication compliance by pill counting. 
 
Assessment of tolerability for further dose titration for study drug, and if deemed appropriate, will increase dose of 
study drug. 
  
Of note, during the first 4 weeks of the trial, subjects will be participating in an intensive program of pulmonary 
rehab as per standard of care.  However, during the last 8 weeks, subjects will participate in a modified-graduate 
program of pulmonary rehab per standard of care.  
  
Visit 5 (scheduled at 1 month interval from visit 4 + 7 days): 
 
Urine pregnancy test for WOCPB 
 
Administer questionnaires, including the HADS, AIR, UCSD dyspnea scale, and QOL scale. 
 
Assessment of medication compliance by pill counting. 
  
Visit 6 (scheduled at 1 month interval from visit 5 + 7 days): 
 
A comprehensive physical exam will be performed (similar to Visit 0). 
 
Urine pregnancy test for WOCPB 
 
Perform Spirometry. 
 
Perform 6-Minute Walk test. 
 
Assessment of medication compliance by pill counting. 
 
Administer questionnaires, including the General Health Questionnaire (GHQ-12), Hospital Anxiety and Depression 
Scale (HADS), Anxiety Inventory for Respiratory Disease (AIR), UCSD dyspnea scale, and Quality of Life (QOL) scale. 
  
Scheduled and Missed Visits:  
All visits will be scheduled based on the date of randomization (Visit 0).  Visits 1-4 will be scheduled at 1 week intervals + 7 
days, and visits 5 and 6 will be scheduled at 1 month intervals + 7 days over the 12-week treatment period.  A missed 
appointment or visit should be followed by a telephone call to the subject. 
 
**According to the HRPP pregnancy testing policy: urine pregnancy test will be acceptable in this study. WOCPB who have 
active menses or who are on a medically acceptable contraceptive for 3 months, urine pregnancy test will be performed. If 
not, a serum pregnancy test will be done.** 


NCT02813447 
 
End of Treatment Recommendations: 
At the last treatment visit, subjects that continue to show anxiety or depressive symptoms will be further evaluated and the 
study physicians will make patient care recommendations.  All subjects with depressive symptoms or significant anxiety will 
be referred for treatment to an outside psychiatrist or follow-up with his or her primary care physician.  Treatment 
assignment will be disclosed at the end of the study unless a clinical emergency resulting in the subject’s withdrawal from the 
study or that necessitates this to be disclosed earlier in the study. 
  
At the end of the study, the outside treating physician will receive a formal letter indicating that the subject has participated 
in the SAD-COPD protocol and recently ended a double-blind treatment for depression and/or anxiety and the treatment 
assignment will be disclosed.  
  
The principal investigator or co-investigator, will prescribe sertraline for the subsequent 30 days depending on the response to 
treatment as assessed on the last treatment visit completed.  If the subject shows no response to the study medication (non-
responder), specific instructions about tapering off the study medication will be given at the last visit completed and forwarded 
to the subject’s physician. 
  
For the purpose of end of treatment recommendations, treatment responders will be defined as a subject with score of < 8 
on either the anxiety or depression component of the HADS, and a non-responder will be defined as a subject with a score 
of > 8 on either the anxiety or depression component of the HADS. 
 


NCT02813447 
 
Selection of Subjects 
Potentially eligible subjects include individuals with clinically stable COPD as defined by the following criteria: 
  
Inclusion Criteria 
 
Male or female with an ICD-9 code diagnosis of COPD and/or ILD and enrolling in the Duke Pulmonary Rehabilitation 
Center 
 
Age 40 years or older 
 
Mild, moderate, or severe major depression symptoms based on Center of Epidemiologic Studies Depression (CES-D) 
score > 16. 
 
Able to give inform consent† 
 
Read and write in English 
  
Exclusion criteria: 
 
Current treatment with antidepressants 
 
Current treatment with anti-psychotics 
 
Severe physical disability that would interfere with lung assessment 
 
History of major psychiatric illness, including bipolar disorder, psychoses, and/or severe personality disorder. 
 
Active suicidal ideations 
 
Serious cognitive problems (dementia syndrome) or cognitive impairment defined as MMSE < 22 
 
Recent loss of spouse within 6 weeks of study enrollment. 
 
History of alcohol or drug dependence in the last 6 months. 
 
Pregnant women or nursing mothers 
 
Poorly controlled concomitant conditions that pose additional procedure risk as determined by the investigator. 
Study Interventions 
Subjects will be randomized to receive either anti-depressant therapy (sertraline) or matched placebo to take daily along with 
participating in pulmonary rehab program.  
  
Study Drug Procedures:            
Storage, Dispensing, and Disposition 
Duke Investigational Drug Services (IDS) will be used.  The drugs will be prepared in bottles according to randomization and 
dispensed to the study team to provide to subjects at Duke Pulmonary Rehab facility on the day of dispensing according to the 
Maestro Care Order built by DOCR. 


NCT02813447 
  
The IDS will perform the randomization of study drug versus placebo and will provide a blinded drug accountability form to the 
study team.  All capsules of the active study drug will be 25mg each.  IDS will dispense bottles of study drug or placebo each 
week for the first 4 weeks (visits 1-4) with each bottle containing one week worth +/- 7 days of pills.  At visit 4 and 5, subjects 
will be provided one month supply of study drug or placebo (depending on their randomization and final determined dose) +/- 
7 days.  All unused drug will be returned to IDS. 
  
Special emphasis will be placed on designing packaging and labeling that meets all of the required regulations, supports the 
interaction between the health care provider and the patient, and assists in meeting the clinical objectives set forth in the 
protocol. IDS will over-encapsulate for blinding purposes as per their SOP. 
 
Storage of Study Drug 
The clinical supplies should be stored at room temperature in a restricted area, free of environmental extremes. This should 
be a locked storage area with access limited to the co-investigators and other authorized staff only. 
 
Study Drug Accountability and Disposition 
PI, Co-Investigator, or study coordinator will be in charge of counting pills at each scheduled visit.  The co-investigator must 
maintain adequate records of the disposition of all study drugs at each scheduled evaluation. This includes the date, quantity, 
and use by patient for each dose of drug dispensed. The number of bottles dispensed is dependent upon the patient’s dose and 
next visit. 
 
Unused Study Drug  
After completion of the study, all unopened and unused study drug will be destroyed on-site by IDS or per hospital policy.  
  
Study Drug Packaging 
Each enrolled subject will be assigned study drug according to their randomization.  Subjects will be dose-escalated by 25 mg 
(or placebo capsule) during the first 4 weeks, unless the increased dose is not tolerated.  All study drug capsules will contain 
sertraline 25mg or dextrose for placebo.  Week one study drug bottles will contain 14 capsules for the subject to take 1 capsule 
per day for 7 days, with a +/- 7 day supply.  Week 2 bottles will contain 28 capsules to account for the dose increase where 
subjects will take 2 capsules per day with a +/- 7 day supply.  Week 3 bottles will contain 42 capsules to account for the dose 
increase with a +/- 7 days supply.  Week 4 bottles will contain 56 capsules to account for the dose increase and a +/- 7 days 
supply.  The remainder of study drug dispensing will be dependent on the Maestro Care order based on the subjects’ 
tolerability.   Bottles will be labeled according to IDS policy to meet the needs of the protocol and to meet North Carolina Board 
of Pharmacy requirements. 
  
Study Drug Administration 
The study drug should be taken by mouth once daily, preferably with the morning meal. The first dose should be taken the 
morning following randomization (Day 2). If necessary, the timing of the dosing may be adjusted by the co-investigator. 
  
Stage 1 begins with randomization so significant delays in dispensing or taking of the study medication will not result in the 
subject receiving less than 12 weeks of treatment. Care must be taken to ensure that the subject has sufficient study drug to 
cover any delay in a scheduled visit. Telephone contacts should be made as clinically indicated during the trial. In particular, a 
missed appointment should be followed by a telephone call. 
  
The study drug dose will be increased in 25mg increments during the first 4 weeks.  However, the study drug may be decreased 
in 25mg increments due to intolerability at any time during the study per the PI’s judgment.  The target maximum dosage will 
be 100 mg/day.  Subjects who stop treatment before the end of the study treatment should be evaluated for safety and efficacy 
at the final visit. Subjects who are withdrawn from the study for any reason should be followed as clinically appropriate. 
  
The initial dose will be 25mg per day. The PI based on clinical response, will adjust study medication dosage by 25mg at visits 
2-4. In the absence of dose-limiting adverse events, the dose will be further increased to 2 capsules (50mg/placebo) at the 
end of Week 2, to 3 capsules (75mg/placebo) at the end of Week 3, and to 4 capsules  (100mg/placebo) at the end of Week 
4.  
  
Decision to decrease the dosage of the study medication will be based upon clinical opinion of the PI as she is a trained 
psychiatrist.  Specifically, if the subject demonstrates evidence of significant side effects from or is unable to tolerate current 
dose, the dose will be decreased by 1 capsule (or 25mg).  Significant side effects or intolerability will be defined as evidence 
of serotonin syndrome, significant agitation or tremor, worsening in anxiety or depression such that the subject is having 
suicidal ideation or intent.  
  
End of treatment recommendations for treatment responders and non- responders are detailed above. 


NCT02813447 
  
Study Drug Compliance 
Study drug must be returned and counted at each scheduled visit (visits 2-6). 
 
If pill counts on the returned drug indicate that the subject has not taken the entire supply of prescribed study drug, 
the subject will be counseled on the importance of compliance and the proper way to take the study drug. 
 
Study medication non-compliance on the part of the subject, defined as 3 or more days of missing medications 
determined by admission or pill count, will result in discontinuation of the subject. 
 
Study medication not taken due to any reason for 14 days will result in discontinuation of the subject. 
  
Study Drug Overdose 
Treatment of possible overdose of sertraline will be dealt with by contacting the subject’s primary care provider, and a treatment 
plan will be developed.  
  
Study Drug Unblinding 
Treatment assignments will be revealed at the end of study. The following describes exceptional circumstances that may lead 
to the disclosure of the double-blind treatment assignment during the study. 
 
Clinical Emergency during Acute Treatment Stage: 
If a clinical emergency arises at any time during the study, IDS will be contacted for the subject’s randomization 
assignment.  The PI and the co-investigators will not be unblinded until either has approved unblinding in the form of a 
documented written request that is submitted to IDS. Then the patient’s primary care provider will be contacted, and a 
treatment plan will be developed.  In the event that the PI or the co-investigators are not available, there will be a back-up 
physician (Dr. Neil MacIntyre) assigned for emergency un-blinding of treatment. 
  
Safety Measures:  
Vital signs, heart, lung, and other physical exam findings will be collected at the initial visit (visit 1) and again at the final 
treatment visit (visit 6).  COPD exacerbations or respiratory complications and suicidality will be gathered during the 12-week 
acute treatment phase. The event page will be used to record COPD GOLD stage and to monitor for significant events, such 
as: 
 
Deaths and cause of death 
 
All in-patient admissions and reasons for the admission, emergency room visits, urgent care or outpatient visit for acute 
respiratory reason 
 
Successful and unsuccessful suicide attempts 
  
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29. Wiles L, Cararella P, Williams MT. Exercise training combined with psychological interventions for people with chronic 
obstructive pulmonary disease. Respirology 2015; 20: 46-55. 
30. Smith SMS, Sonego S, et al. A review of the effectiveness of psychological interventions used for anxiety and depression 
in chronic obstructive pulmonary disease. BMJ Open Resp Res 2014; 1: e000042. 
31. Jiang W, Krishnan R, et al. Characteristics of depression remission and its relationship with cardiovascular outcome 
among patients with chronic hear failure. Am J Cardiology 2011; 107: 545-551. 
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COPD. COPD 2005; 2: 233-241. 
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Dis 2004; 61: 140-7. 
35. Usmani ZA, Carson KV, et al. Pharmacological interventions for the treatment of anxiety disorders in chronic obstructive 
pulmonary disease. Cochrane Database Systematic Review 2011; (11). 
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disease. Psychosomatics 1998; 39: 24-9. 
Risk/Benefit Assessment 
Study Drug: Subjects will be randomized either to receive anti-depressant therapy with a selective serotonin reuptake 
inhibitor (sertraline) or a matched placebo.  Subjects are informed of the mechanism of action of SSRIs as well as the 
potential benefits, which include improvement in their mood and reduction in symptoms of depression or anxiety. 
  
Additionally, subjects are informed of potential side effects of SSRIs, including common potential side effects like the 
following: feeling agitated, shaky, or anxious, feeling or being sick, indigestion or gastritis, diarrhea or constipation, loss of 
appetite or weight loss, dizziness, blurred vision, dry mouth, excessive sweating, insomnia or drowsiness, headaches, low 
sex drive, difficulty achieving orgasm during sex or masturbation, and in men, difficulty obtaining or maintaining an erection 
(erectile dysfunction).  Much less common side effects discussed during consent, include bruising or bleeding easily (including 
vomiting blood or blood in your stools), confusion, problems with movement (stiffness or shaking), seeing or hearing things 
that are not real, being unable to pass urine.  
  
Serotonin Syndrome:  Serotonin syndrome is an uncommon but potentially serious side effect linked to SSRIs.  Serotonin 
syndrome occurs when the levels of serotonin in your brain become too high.  It is usually triggered when you take an SSRI 


NCT02813447 
in combination with another medication or substance that also raises serotonins levels, such as another antidepressant or St 
John’s Wort.  Symptoms include: confusion, agitation, muscle twitching, flushing, sweating, shivering, diarrhea, fever, 
seizures, arrhythmias, and loss of consciousness.  
  
Hyponatremia:  Elderly people who take SSRIs may experience a severe fall in serum sodium known as hyponatremia. This 
may lead to a build-up of fluid inside the cells of the body, which can be potentially dangerous. This side effect can occur as 
SSRIs can block the effects of a hormone that helps regulate levels of sodium and fluid in the body. Elderly people are 
vulnerable because fluid levels become more difficult for the body to regulate. 
  
Mild hyponatremia can cause symptoms similar to depression or side effects of SSRIs, such as feeling sick, headache, muscle 
pain, reduced appetite, and confusion.  
  
More severe hyponatremia can cause the following symptoms: feeling tired, confusion or disorientation, agitation, seeing or 
hearing things that are not real (hallucinations), psychosis (being unable to tell the difference between reality and your 
imagination, and seizures.  
  
The most serious cases of hyponatremia can cause you to stop breathing or enter a coma.  
  
Subjects will be instructed to stop the study drug, contact someone from the research team or their regular doctor, and go to 
the emergency room or nearest hospital if they begin to experience any of the above serious side effects, including serotonin 
syndrome, hyponatremia.  Subjects will be assessed for potential side effects related to the study drug at each scheduled 
visit. 
  
Suicidal thoughts: Some people experience suicidal thoughts and a desire to self-harm when they first take SSRIs.  At each 
scheduled visit, subjects will be assessed for thoughts of suicidality and/or self harm with the HADS questionnaire. Anyone 
exhibiting a serious suicidal intent will be immediately accompanied to an appropriate health facility such as an emergency 
room. 
  
Spirometry: Can sometimes cause coughing; you may also experience shortness of breath, chest tightness, or light 
headedness. 
  
Exercise tolerance: Subjects will undergo the 6-Minute Walk Distance test for exercise tolerance. The risks of this 
assessment are fatigue and falling. 
  
Questionnaires and assessments:  We will make every effort to protect privacy and keep data confidential.  There is a 
risk of breach of privacy and confidentiality.  To minimize risk, we will use only study codes to identify data and study 
records, and store study data and records in a secure place. All paper records will be kept secure within the research area at 
the Duke Asthma, Allergy, and Airway Center.  All electronic data collected in this study will be stored in Excel on the 
divisional shared drive and secured through the following methods: access rights granted and terminated for authorized 
users only, secure laptops and workstations, individual ID plus password protection, routine electronic back up, network 
restrictions. 
  
1. 
Some questionnaires inquire about anxiety and depression symptoms. If these conditions are severe enough, we will 
refer the subject to his or her primary care physician for evaluation and treatment. Anyone exhibiting a serious 
suicidal intent will be immediately accompanied to an appropriate health facility such as an emergency room. 
2. 
Cognitive functioning for eligibility will be assessed using the MMSE. If the subject scores less than 22 on this 
assessment, the clinic will provide the subject a letter referring him or her for further cognitive evaluation. In 
addition a secondary letter to explain the MMSE results suitable to be given to all subjects has been prepared. 
  
There is no guaranteed health benefit to subjects from involvement in this study. Subjects may have some emotional benefit 
to know that their participation may help other people with COPD in the future. 
 
Data Analysis & Statistical Considerations 
Multivariable regression models will be constructed to evaluate the relationship between perceived stress, anxiety, and 
depression with adjustments by race, gender, age, BMI and GOLD score.  A multivariable regression model will be 
constructed to assess whether treatment of perceived stress, depression, and anxiety with antidepressant therapy 
(sertraline) is an effect modifier on 6MW distance and dyspnea scores in patients with COPD and/or ILD who are enrolled in 
pulmonary rehab.  
  
Descriptive statistics will be used to examine the socio-demographic characteristic data. Student t-tests will be performed to 
assess group differences in continuous data. Categorical variables will be examined using the Pearson’s Chi-Squared test. 
Analysis for associations between known prognostic factors for COPD outcomes, measures of disease severity and patient 


NCT02813447 
reported outcomes measured in this study will rely on more complex multivariate models that include random effects terms 
for clinics and patients. 
 
Data & Safety Monitoring 
In accordance with federal regulations the PI will monitor for, review, and promptly report to the IRB, appropriate 
institutional officials, all unanticipated problems involving risks to subjects or others that occur in the course of a subject’s 
participation in a research, all AE reports will be reported per the DUHS IRB policies.