Clinical trial NCT01973998
Conditions: COPD
Keywords: COPD Emphysema Roflumilast readmission
Sponsor: Temple University
Start date: 2013-11-01; Completion date: 2017-11-30
Enrollment: 68 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background: COPD exacerbations add considerably to patients' burden because they: (1) cause frequent hospital admissions and relapses or readmissions, (2) contribute directly to the death of many patients, either during hospitalization or shortly thereafter, (3) cause patients significant stress, prolonged physical discomfort, disability and dramatically reduced quality of life, (4) consume the majority of the resources available to manage this chronic condition, (5) frequently progress to a severe stage warranting hospitalization before any abortive treatment is instituted, and (6) may hasten the progressive loss of lung function, a steady decline that is a cardinal feature of COPD itself. Hence, investigations of new therapies to treat COPD patients who are hospitalized with a severe exacerbation are desperately needed.

Objective: To test the feasibility of roflumilast to decrease all cause readmission and mortality 180 days after hospitalization for acute COPD exacerbation.

Methods: Parallel-group, prospective, randomized, double blind, placebo-controlled trial of roflumilast 500 ug daily vs. placebo in approximately 100 hospitalized AECOPD patients. Inclusion Criteria. Primary diagnosis of AECOPD; admission to the hospital \<12 hours; patient age \>40, \< 80 years old; cigarette smoking \> 10 pack-years. Exclusion Criteria. Prior diagnosis or high suspicion for asthma; pulmonary edema, pneumonia, interstitial lung disease or significant bronchiectasis; intubated and mechanically ventilated at the time of evaluation; active liver disease, or transaminase elevations (\> 3xULN); history of heavy ethanol use; history of suicidal behavior ≤ 2 years or suicidal ideation ≤ 6 months prior to enrollment; pregnant or lactating females. Those on the following excluded medications: P450 inducers and CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously

Detailed description:
Background :Chronic obstructive pulmonary disease (COPD) afflicts 24 million US residents and is the 3th leading cause of death in the United States. Each year, 150,000 patients die from COPD in the U.S. or about one patient every 4 minutes. Health care costs for COPD patients in the US is approximately $6.5 billion/ year, but its indirect costs probably double the costs of care when taking into account lost productivity and caretaker expenses. COPD exacerbations add considerably to that burden because they: (1) cause frequent hospital admissions and relapses or readmissions, (2) contribute directly to the death of many patients, either during hospitalization or shortly thereafter, (3) cause patients significant stress, prolonged physical discomfort, disability and dramatically reduced quality of life, (4) consume the majority of the resources available to manage this chronic condition, (5) frequently progress to a severe stage warranting hospitalization before any abortive treatment is instituted, and (6) may hasten the progressive loss of lung function, a steady decline that is a cardinal feature of COPD itself.

Hospitalized exacerbations result in a profound impact on patient survival, function, symptoms and health status as well as costs. Re-hospitalization in COPD is frequent and associated with a particularly negative impact. Patients discharged from the hospital after a COPD exacerbation have a high mortality and are frequently readmitted with recurrent exacerbations. Although a number of pharmacologic and behavioral interventions have been used to decrease exacerbations in COPD, it is not clear that these same interventions are successful in reducing hospital admission rates or re-admission rates. Except for the use of noninvasive ventilation in patients that present in acute respiratory failure during COPD hospitalization, no new therapies have been discovered in the last 3 decades.

A. Specific Aims: In this pilot proposal, we will test the feasibility of roflumilast to decrease all cause readmission and mortality 180 days after hospitalization for acute COPD exacerbation. We propose to conduct this study in 100 patients at three centers to assess the tolerance and treatment effect of roflumilast in order to power an appropriate definitive phase III multicenter trial.

B. Study Design and Synopsis: Parallel-group, prospective, randomized, double blind, placebo-controlled trial of roflumilast 500 ug daily vs. placebo in approximately 100 hospitalized AECOPD patients. Both groups will receive GOLD guideline-recommended care.

Patients hospitalized with AECOPD will be eligible for enrollment ≤ 12 hours after admission. Demographics, blood tests, health related quality of life, comorbidity (Deyo-Charlson index), post bronchodilator spirometry, vital signs, dyspnea measured by MMRC, SaO2 and amount of inspired O2 to maintain SaO2\> 90% at rest, serum fibrinogen levels, HBA1c, Biomarkers and Genetics will be obtained after enrollment and then patients will be randomized to standard AECOPD care plus roflumilast 500 ug daily vs. placebo. Patients will begin roflumilast or placebo \< 12 hours of hospitalization for a total period of 180 days post enrollment. On discharge day (approximately day 3-4 after admission based on the recent COPD CRN zileuton study of hospitalized AECOPD), the measurements will be repeated as indicated (baseline measurements), with follow-up phone assessments at days 7, 30, 60, 90, 120 and 194 days post enrollment. An in-person clinical visit will be conducted at days 14 and 180 post randomization.

Study will begin within 12 hours of patient's admission and last for 194 days. Baseline: Will occur within 12 hours of patient's admission to the hospital. Patients will have a medical history taken as well as smoking history. Patients will also be given a physical exam including vital signs. A spirometry test will also be performed. Women with the potential to become pregnant will be given a pregnancy test. Data will also be collected in regards to dyspnea scales, Deyo-Charlson index, and GOLD classification. Patients will complete a Columbia Suicide Severity Rating Scale to exclude patients with a history of suicidal behavior ≤ 2 years or suicidal ideation ≤ 6 months prior to enrollment Randomization: Patients will be randomized to one of two treatment groups. Randomization will be done using a randomized block design stratified by treatment center. One group will receive roflumilast 500 mcg (Daliresp®) and the other will receive a placebo tablet. Patients will begin one of these treatment arms within 12 hours of hospitalization for a total period of 180 days post enrollment.

Day of hospital discharge: A spirometry test will be performed and an adverse event assessment will be completed.

Day 7: Phone Visit. Data collected includes: interim history, adverse events, vital status, and exacerbation history. During this telephone visit the study doctor or nurse coordinator will ask how the patient is feeling and if they have needed to visit the doctor or go to the emergency room or hospital since the last time they were contacted. They will be asked how well they are tolerating the study drug.

Day 14: Clinic Visit. At this visit vital signs, C-SSRS test, interim history, adverse event assessment, vital status, and exacerbation history will be recorded. The following questionnaires will given: EQ-5D, the St. George's Respiratory Questionnaire (SGRQ), and the Modified Medical Research Council dyspnea score (MMRC).

Days 30, 60, 90, \& 120: Phone Visit. Data to be collected includes: interim history, adverse events assessments, vital status, and exacerbation history. During each of these telephone visits the study doctor or nurse coordinator will ask how the patient is feeling and if they have needed to visit the doctor or go to the emergency room or hospital since the last time they were contacted. They will be asked how well they are tolerating the study drug.

Day 180: Clinic Visit. At this visit vital signs, C-SSRS test, interim history, adverse event assessment, vital status, and exacerbation history will be recorded. A spirometry test will be performed as well during this visit. The following questionnaires will given: EQ-5D, the St. George's Respiratory Questionnaire (SGRQ), and the Modified Medical Research Council dyspnea score (MMRC).

Day 194: Phone Visit. This phone call covers the wash out period for the study treatments. Data to be collected includes: interim history, adverse events assessments, vital status, and exacerbation history. During this telephone visits the study doctor or nurse coordinator will ask how the patient is feeling and if they have needed to visit the doctor or go to the emergency room or hospital since the last time they were contacted.

All patients will receive standardized, optimized care for AECOPD. Nebulized albuterol (2.5 mg in 0.5 ml, dilute to 3 ml NSS administered every 4-6 hours) and ipratropium bromide (0.5 mg in 0.5 ml, diluted with 2.5 ml of saline administered every 6 hours) will be given. A 14-day course of systemic steroids consisting of intravenous methylprednisolone 125 mg every 6 hours for up to 72 hours, followed by once daily oral prednisone 60mg/day for days 4-7, 40 mg prednisone days 8-11 and 20 mg prednisone days 12-14 will be provided. A 7-day course of antibiotics will be selected based on patient's medical allergy history and relevant culture data if available. Supplemental oxygen will be provided by route and dose to achieve maximum patient comfort and compliance to maintain a SaO2 \> 92%. Noninvasive positive pressure ventilation will be utilized at the discretion of the treating physicians.

Following oral administration, roflumilast is rapidly absorbed with a tmax of about 1 hour and an 80% bioavailability. Roflumilast is metabolized by CYP3A4 and CYP1A2 enzymes with N-oxide being the principal major metabolite. N-oxide has selectivity for the PDE4 isoenzyme and mainly accounts for roflumilast's in vivo bioactivity. No major interactions have been reported between roflumilast and other COPD medications.

The present proposal is a pilot study designed to test the feasibility of a future project to be conducted in a multicenter trial in hospitalized patients. Determine the treatment effect of roflumilast as add-on therapy to decrease all cause readmission and mortality as a composite endpoint 180 days after randomization to roflumilast or matching placebo ≤ 12 hours after hospitalization for acute COPD exacerbation.

The primary analysis for all study outcomes will be performed on an intention to treat basis. In the intention to treat approach, all subjects are analyzed in the group to which they were randomized, regardless of whether the assigned treatment was adhered to and regardless of whether there were any eligibility violations.

Univariate descriptive statistics will be calculated for baseline parameters overall and by treatment group. For categorical outcomes, these will include the number percentage of subjects in each category. For continuous variables, these will include the mean and standard deviation for variables with approximately normal distributions and the median and 25th and 75% percentiles for variables with skewed distributions.

The primary outcome is time from randomization to a composite outcome of all cause re-hospitalization and all-cause mortality, whichever comes first. The primary analysis will be a log-ranked test and associated Kaplan-Meier plot, unadjusted for any covariates. Censoring will occur at the earliest date of any of the following occurrences, unless the subject has already experienced the primary outcome event:

* Lost to follow-up despite intensive efforts
* Subject or healthcare proxy withdrawal of consent
* 180 days after randomization. 3. Analysis of secondary outcomes. Primary analysis of other time to event outcomes will be performed using unadjusted log rank tests that have associated Kaplan-Meier plots, similar to the primary analysis of the primary study outcome. Secondary analysis of these outcomes will use Cox regression to adjust for baseline subject factors (covariates) that are known to be associated with the outcome.

The primary analyses of changes in continuous measures such as absolute and percent changes in spirometry and dyspnea scores, for example, will be analyzed using an analysis of covariance where change from baseline to a particular time period is the dependent variable.

In this pilot proposal, the treatment effect of roflumilast vs. placebo to prolong the time to event of a combined endpoint of death or re-hospitalization will be assessed in an intention to treat manner. In a similar manner, the treatment effect of roflumilast vs. placebo to effect all of the secondary endpoints proposed to be measured in the pivotal phase III trial will also be measured (time to respiratory death or respiratory re-hospitalization during the 180 days post-randomization; rate of death or readmission at 30 days post-discharge; treatment failure; change in health status, change in FEV1, and dyspnea during the 180 days post-randomization; length of hospital stay during the index hospitalization; and the tolerance of roflumilast vs. placebo in hospitalized AECOPD).

Because this is a pilot study the intent is to see if there is a signal that would justify a larger clinical trial. Therefore the significance level has been set to 0.1 and the power has been set at 0.7. A total of 100 patients will enter this two treatment parallel-design study. The probability is 70 percent that the study will detect a treatment difference at a two sided 10.0 percent significance level, if the true hazard ratio is 1.654. This is based on the assumption that the accrual period will be 36 months and the follow up period will be 6 months and the median time to event is 8 months. The total number of events will be 73.

Arms: arm 1: 500 ug tablet daily for 180 days arm 2: Placebo 1 tablet daily x 180 days
Interventions: intervention 1: Roflumilast intervention 2: Placebo
Intervention descriptions: intervention 1: PDE4 inhibitor intervention 2: Inactive substance.

Protocol documents:
Prot_SAP_000.pdf: 
Version 04.13.2015 
 
Effects of Roflumilast in Hospitalized COPD on Mortality and Re-hospitalization 
 
 
 
Submitted by 
Gerard J. Criner, M.D. 
Professor and Chairman, Department of Medicine 
Florence P. Bernheimer Distinguished Service Chair 
Temple University School of Medicine 
745 Parkinson Pavilion 
3401 North Broad Street 
Philadelphia Pa 19140 
Phone: 215 707-8113 
Fax: 215 707-6867 
Email: gerard.criner@tuhs.temple.edu 
 
 
 
 
 April 13, 2015 
 
 
 
 
 
1. Research plan. 
1.A. Background Chronic obstructive pulmonary disease (COPD) currently afflicts 24 
million US residents and is the 3th leading cause of death in the United States {{164 
Anonymous 2001; 368 Mannino,D.M. 1997}}. Each year, 150,000 patients die from 


Version 04.13.2015 
 
COPD in the U.S. or about one patient every 4 minutes. Health care costs for COPD 
patients in the US is approximately $6.5 billion/ year, but its indirect costs probably 
double the costs of care when taking into account lost productivity and caretaker 
expenses {{465 Sin,D.D. 2002; 378 Miravitlles,M. 2002; 473 Sullivan,S.D. 2000}}. COPD 
exacerbations add considerably to that burden because they: (1) cause frequent hospital 
admissions and relapses or readmissions, (2) contribute directly to the death of many 
patients, either during hospitalization or shortly thereafter, (3) cause patients significant 
stress, prolonged physical discomfort, disability and dramatically reduced quality of life, 
(4) consume the majority of the resources available to manage this chronic condition, (5) 
frequently progress to a severe stage warranting hospitalization before any abortive 
treatment is instituted, and (6) may hasten the progressive loss of lung function, a steady 
decline that is a cardinal feature of COPD itself {{280 Garcia-Aymerich,J. 2003; 452 
Seemungal,T.A. 1998}}. Two studies have estimated that acute exacerbations of COPD 
(AECOPD) account for 31 to 68% of the total costs of COPD care in the US {{378 
Miravitlles,M. 2002; 294 Halpern,M.T. 2003}}. Hence treatment that could prevent or 
ameliorate frequent or severe AECOPD could significantly lessen COPD morbidity and 
mortality as well as costs. 
Hospitalized exacerbations are particularly relevant in COPD patients. Hospitalized 
exacerbations result in a profound impact on patient survival, function, symptoms and 
health status as well as costs Hospitalizations accounted for a significant component of 
COPD related costs. Re-hospitalization in COPD is frequent and associated with a 
particularly negative impact.  Patients discharged from the hospital after a COPD 
exacerbation have a high mortality and are frequently readmitted with recurrent 
exacerbations. The cause of these high rates of readmission is not well understood.  
Although a number of pharmacologic and behavioral interventions have been used to 
decrease exacerbations in COPD, it is not clear that these same interventions are 
successful in reducing hospital admission rates or re-admission rates. Except for the use 
of noninvasive ventilation in patients that present in acute respiratory failure during 
COPD hospitalization, no new therapies have been discovered in the last 3 decades. 
Hence, investigations of new therapies to treat COPD patients who are hospitalized with 
a severe exacerbation are desperately needed. 
1. B. Why survival and readmission rates are desirable outcomes for studying 
interventions in hospitalized acute COPD exacerbations. The Pennsylvania Cost 
Containment Council (PHC4) reported in 2012 using a statewide database of several 
million Pennsylvania residents hospitalized in FY 2009 that COPD was the third most 
common cause of readmission within the year post discharge (25.7%) and that 9.5% of 
patients were readmitted more than once in the year following hospitalization. In fact, 4.2 
% of the COPD patients were readmitted 3+ times in the year post hospitalization. 
(Figure 1). 
 
 


Version 04.13.2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
Others have reported similarly high readmission rates following COPD hospitalization as 
enumerated in the Table 1: 
Table1. Readmission rates following COPD Hospitalization 
Citation 
Study Structure 
30 day readmission 
60 day 
readmission 
90 day 
readmission 
Lau et al 2001 
Retrospective 
~15% 
~25% 
~30% 
Almagro et al 2002 
Prospective 
~5% 
~10% 
~13% 
Roberts et al 2002 
Retrospective 
34% 
14% respiratory 
NA 
NA 
Westert et al 2002 
Retrospective 
USA 4.1-1.3% 
Europe 8.5-13.4% 
NA 
NA 
Almagro et al 2005 
Prospective 
16% 
~25% 
35% 
Schiotz et al 2011 
Retrospective 
21.4 in 2007 
 
NA 
NA 
Nansupawat et al 2012 
Retrospective 
13.6% 
NA 
NA 
Moullec et al 2012 
Prospective 
~20% 
~30% 
~40% 
1.


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Dinesen et al 2012 
Prospective 
~5% 
~6% 
~10% 
 
The rate of 30 day readmissions in these reports varies from 5-34% with the majority of 
studies suggesting that approximately 15% suffer such an event in that time frame.  This 
readmission rate increases further by 60 days (6-30%) and 90 days (10-40%).Data from 
the AHRQ using the HCUP database found that 20.5% of U.S. COPD patients were 
readmitted within 30 days and that 85% of these included COPD as the primary or 
secondary diagnosis).{{1159 Elixhauser,A. 2011}} A summary of published literature 
suggests that readmissions are frequently seen in this population. 
  Survival is another extremely 
relevant endpoint to study the 
effect of an intervention during 
COPD 
hospitalization. 
The 
Study 
to 
Understand 
Prognosis and Preferences for 
Outcomes 
and 
Rates 
of 
Treatment (SUPPORT enrolled 
patients admitted with COPD 
exacerbations and reported an 
in-hospital mortality of 11% in 
patients presenting with acute 
hypercapneic 
respiratory 
failure.{{1152 Connors,A.F.,Jr 
1996}} The 180 day mortality 
was 33% and the 2-year 
mortality was 49%. Several 
other studies have reported in-hospital mortality rates of 11-24% and 22-35% after one 
and two year’s follow-up respectively (Figure 2). The 2010 PHC4 dataset reports the 
average inpatient mortality rate for COPD readmissions to be 3.9%, but ranges from 
non-complicated readmission mortality rates of 1.45 % to 5.0% if pneumonia is the 
cause of readmission in a patient initially admitted with COPD or even higher at 11.6% 
mortality if respiratory failure is the cause for readmission.  
 
These data demonstrate that readmission and survival following COPD hospitalization 
are clinical relevant and meaningful endpoints that occur with increased frequency 
following the index hospitalization. 
2. Research plan. 
2.A. What drives the increased morbidity and mortality associated with 
hospitalized acute COPD exacerbations? The inflammation associated with COPD, 
especially the heightened inflammation that occurs during hospitalized AECOPD, may 
contribute to the higher rates of morbidity and mortality. Data that demonstrates that 
inflammation is heightened in stable COPD and especially during an exacerbation is 
robust and identifies multiple potential responsible inflammatory cell lines, chemokines 
and cytokines. Elevations in serum systemic inflammatory mediators correlate with the 
Figure 2. One-Year Survival for 1,016 COPD Patients 
Following Index Hospitalization (Connors)


Version 04.13.2015 
 
presence or worsening of COPD.  A meta-analysis of 14 studies with data on systemic 
inflammation markers (e.g., CRP, fibrinogen, IL-6) and COPD confirmed the association 
between reduced lung function and systemic inflammation {{278 Gan,W.Q. 2004}}. 
COPD exacerbations are linked to increased signals of systemic oxidative stress (e.g., 
higher serum lipid peroxidation byproducts; up-regulated CD11/CD18 neutrophil 
adhesion molecules; increased cytochrome oxidase activity in lymphocytes and skeletal 
muscle {{420 Rahman,I. 1996; 395 Noguera,A. 1998; 442 Sauleda,J. 1998}}. CRP can 
induce pro-inflammatory cytokine and chemokine expression and the up-regulation of 
adhesion molecules that may promote lung inflammation {{411 Pepys,M.B. 2003}}.  CRP 
levels appear to correlate with the future risk of morbidity and mortality in COPD {{364 
Man,S.F. 2006; 239 Dahl,M. 2007}}. One group has reported that CRP is the biomarker 
that correlates best with the presence of a symptomatic exacerbation {{311 Hurst,J.R. 
2006}}. Acute exacerbations that are slow to resolve are associated with higher CRP 
levels.  A large population based study confirmed a significantly increased risk of 
hospitalization in COPD patients with CRP levels above 3 mg/L {{412 Perera,W.R. 2007; 
239 Dahl,M. 2007}}. 
IL-6 is also considered part of the acute phase response and appears to be a potent 
inducer of CRP expression in the liver. IL-6 levels are increased in sputum, 
bronchoalveolar lavage fluid and blood in COPD and are even further increased during 
periods of exacerbation {{364 Man,S.F. 2006; 198 Bhowmik,A. 2000; 207 Bucchioni,E. 
2003; 518 Wedzicha,J.A. 2000}}. As with CRP, elevated IL-6 levels are associated with 
decreases in pulmonary function and a higher number of exacerbations per year {{260 
Donaldson,G.C. 2005; 517 Wedzicha,J.A. 2002}}.  
Additional pro-inflammatory mediators may be implicated based on published evidence 
of a correlation in the elevations in these biomarkers with disease severity {{208 
Calikoglu,M. 2004;311 Hurst,J.R. 2006; 518 Wedzicha,J.A. 2000; 205 Bozinovski,S. 
2008 }}. Activated bronchial epithelial cells, macrophages and neutrophils produce IL-8 
{{471 Spruit,M.A. 2003;518 Wedzicha,J.A. 2000; 205 Bozinovski,S. 2008; }}, which is a 
potent chemoattractant for neutrophils and monocytes and likely contributes to the 
mobilization of these cells into the lung. IL-8 levels are increased in the sputum of COPD 
patients and correlate with the intensity of the neutrophilic response. TNF-α is a critical 
pro-inflammatory molecule that is believed to primarily work by inducing a broad 
spectrum of pro-inflammatory cytokines, chemokines, proteases and adhesion 
molecules by activating transcriptional activating factor p38 mitogen-activated protein 
kinases and nuclear factor (NF)-κB in macrophages and epithelial cells {{205 
Bozinovski,S. 2008;471 Spruit,M.A. 2003; 518 Wedzicha,J.A. 2000; 529 Yamamoto,C. 
1997; 235 Crooks,S.W. 2000; 288 Gompertz,S. 2001 }}.. IL-15 is important for the 
function of CD8 positive cells {{346 Ku,C.C. 2000; }}, an important inflammatory cell 
population in the lung in COPD.  IL-17 is now understood to be a very critical pro-
inflammatory cytokine, produced by highly inflammatory CD4 and CD8 T cells, which 
promotes the recruitment of numerous inflammatory leukocyte populations, and induces 
the expression of mucin by lung epithelial cells{{538 Oda,N. 2005;539 Chen,Y. 2003; 
540 Hashimoto,K. 2004;  }}.  IL-18 is produced by inflammatory macrophages, and 
induces the production of chemoattractant factors including IL-8 (which attracts 
neutrophils and monocytes/macrophages to the site of inflammation){{541 Imaoka,H. 
2008;542 Petersen,A.M. 2007; 543 Hoshino,T. 2007;  }}, and the expression of 
additional pro-inflammatory mediators such as GM-CSF and IL-6.  Pulmonary and 
activation-regulated chemokine (PARC/CCL18) is produced at high levels in the lung, 


Version 04.13.2015 
 
and is up-regulated with activation of alveolar macrophages, and strongly recruits both 
CD4 and CD8 T cells to sites of inflammation. MPIF-1 (CCL23) is produced by activated 
macrophages, and acts to attract both monocytes and T cells to inflamed tissue, 
including the lung.  Eotaxin-2 (CCL24) is produced in part by alveolar epithelial cells in 
response to pro-inflammatory cytokines such as TNFα, and may reflect the degree of 
both the local inflammatory status, and the state of epithelial cell activation in the 
diseased lung.  Surfactant protein D (SP-D) is a large hydrophilic protein that is a 
member of the collagen containing C-type lectins or collectins and plays a role in 
protecting against viral infection, in clearing bacteria, fungi and apoptotic cells, and in 
resolving inflammation{{337 Kierstein,S. 2006;342 Kishore,U. 2006;  }}.  Serum SP-D is 
elevated in COPD compared to current and former smokers with airflow limitation and 
that serum SP-D levels greater than the 95th percentile of non-smokers are at increased 
risk for exacerbation in the subsequent 12 months {{357 Lomas,D.A. 2009; }}.    
Inflammation associated with COPD exacerbation may be responsible for some of the 
non-pulmonary manifestations of an acute exacerbation and may explain some of the 
morbidity and mortality associated with these events. Cardiac events (e.g., arrhythmias, 
acute myocardial infarction, and unstable angina) are a major cause of morbidity and 
mortality in COPD and vascular dysfunction is commonly observed in even stable COPD 
{{374 McAllister,D.A. 2007; 532 Zureik,M. 2001; 483 Tillie-Leblond,I. 2006; 319 
Janssens,J.P. 2001; 237 Curkendall,S.M. 2006; 297 Hansell,A.L. 2003; 262 
Engstrom,G. 2002; 263 Engstrom,G. 2001; 372 Marcus,E.B. 1989; 413 Persson,C. 
1986; 274 Friedman,G.D. 1976}}.  Donaldson et al has recently reported that acute 
myocardial infarctions and cerebrovascular accidents more likely to occur 1-2 months 
following an acute exacerbation and correlate with increases in IL-6 and 
fibrinogen.{{1163 Donaldson,G.C. 2010}} Brekke and colleagues have shown that 
elevations of cardiac specific troponin are frequently present in acute COPD 
exacerbations and levels inversely correlate with long-term survival. {{1162 Brekke,P.H. 
2009}}Flow mediated dilation (e.g., measure of vascular function) is impaired in stable 
COPD outpatients and is more impaired with worsened airflow obstruction or increased 
systemic inflammation {{536 Eickhoff,P. 2008; 187 Barr,R.Graham 2007; 537 Moro,L. 
2008}}. We have recently reported that during an acute hospitalized exacerbation, 
COPD patients have markedly impaired flow mediated dilation that is worse than that 
reported in other disorders associated with severe systemic inflammation such as 
rheumatoid arthritis. {{1153 Marchetti,N. 2011}} 
Increased thrombotic events are also found in COPD and those experiencing an acute 
hospitalized exacerbation.{{1144 Rizkallah,J. 2009}} An autopsy study in 46 patients 
who died within 24 hours of AECOPD hospitalization suggested cause of death as CHF 
in 37% and VTE in 21% {{534 Zvezdin,B. 2009}}. VTE occurs 5 times more commonly in 
COPD and can be an unexpected cause of AECOPD in up to 25% of hospitalized 
patients {{483 Tillie-Leblond,I. 2006}}. We have shown that COPD patients have 
increased levels of procoagulant factor VII levels and thrombin anti-thrombin products 
that indicate a heightened state of thrombosis.{{361 Vaidyula,V.R. 2009}} Others have 
reported denser fibrin complexes in COPD compared to age-matched controls. {{1161 
Undas,A. 2009}} COPD, cardiac disease and VTE are closely coupled by shared risk 
factors (older age and smoking) as well as common pathophysiological features 
(presence of acute inflammation). Inflammation is present in all COPD stages and a 
variety of systemic inflammatory markers elevated in cardiovascular disease and VTE 
(IL-6, IL1 -β, TNF-α, MMP-9, MCP-1 and CRP) are also elevated in COPD{{278 


Version 04.13.2015 
 
Gan,W.Q. 2004; 260 Donaldson,G.C. 2005; 455 Shapiro,S.D. 2001; 426 Retamales,I. 
2001; 434 Rutter,M.K. 2004; 340 Kinlay,S. 2003; 247 de Torres,J.P. 2008; 219 Churg,A. 
2004; 528 Yamada,S. 2001}} 
As described below, therapies such as PDE-4 inhibitors like roflumilast that can 
decrease lung and systemic inflammation may be useful in decreasing the acute 
pulmonary as well as non-pulmonary morbidity and mortality that is associated with 
severe COPD exacerbations that require hospitalization. 
2.B. PDE-4 Inhibitors and specifically Roflumilast may have beneficial anti-
inflammatory effects in the lung that may be relevant for COPD patients during an 
acute severe hospitalized exacerbation.   
PDE-4 inhibition has consistently demonstrated a reduction in activity of several pro-
inflammatory cells that are involved in the pathophysiology of COPD. There is some 
evidence that PDE-4 inhibition can suppress pro-inflammatory cell recruitment and 
chemokine and cytokine production. 
Clinical data has supported the notion that roflumilast via its PDE-4 inhibition pathway 
may have important effects on decreasing exacerbation in COPD. Calverley has shown  
in COPD patients with moderate to severe disease that roflumilast for one year results in 
a small but significant improvement in FEV1 and moderate reduction in exacerbation rate 
{{ Calverley, AJRCCM, 2007}} Fabbri et al has reported the effects of roflumilast vs. 
placebo in addition to salmeterol or tiotropium and found that roflumilast use was 
associated with sustained improvements in FEV1 and reductions in exacerbations 
rates.{{ Fabbri, 2009, Lancet}} Calverley again reported in two additional studies that 
roflumilast use compared to placebo was associated with significant but modest increase 
in FEV1, but more impressively, substantial reduction in both moderate and severe 
exacerbations. {{Calverley, Lancet, 2009}}. These data highlight the potential importance 
that roflumilast may have on decreasing the intensity of symptoms around the time of an 
acute severe exacerbation that requires hospitalization and its potential benefit on 
reducing mortality and the need for readmission. 
3. Study design 
3. A. Specific Aims:  In this pilot proposal, we will test the feasibility of roflumilast to 
decrease all cause readmission and mortality 180 days after hospitalization for acute 
COPD exacerbation. We propose to conduct this study in 100 patients at three centers 
to assess the tolerance and treatment effect of roflumilast in order to power an 
appropriate definitive phase III multicenter trial.  
Our ultimate specific aims in the phase III trial will be to assess: 1) Primary aim: 
Evaluate the effects of roflumilast 500 ug daily in hospitalized AECOPD patients on time 
to all-cause mortality or re-hospitalization during the 180 days following randomization 
and; 2) Secondary aims: Evaluate the effects roflumilast 500 ug daily in this population 
on the following outcomes: respiratory-related death or re-hospitalization during the 180 
days following randomization; rate of death or readmission during the 30 days post-
discharge; treatment failure (see definition below); change in health status, FEV1, and 
dyspnea during the 180 days following randomization; post-randomization ICU 
admission, need for non-invasive or invasive mechanical ventilation, and length of 


Version 04.13.2015 
 
hospital stay during the index hospitalization and; 3) Other: Assess tolerance of 
roflumilast vs. placebo in hospitalized AECOPD  
3.B. Study Design and Synopsis: Parallel-group, prospective, randomized, double 
blind, placebo-controlled trial of roflumilast 500 ug daily vs. placebo in approximately 100 
hospitalized AECOPD patients (Figure 3). Both groups will receive GOLD guideline-
recommended care. 
 
 
 
 
 
Outcomes: 
In this pilot proposal, 100 patients at three centers will be evaluated to test the feasibility 
of conducting this study and to assess the treatment effect of roflumilast to be able to 
power an appropriate definitive phase III multicenter trial. Our ultimate aims of the phase 
III trial will be: 
1) Primary: time to all-cause mortality or re-hospitalization during the 180 days post-
randomization. 2) Secondary: respiratory death or respiratory re-hospitalization during 
the 180 days post-randomization; rate of death or readmission during the 30 days post-
discharge; treatment failure (see definition below); change in health status, FEV1, and 
dyspnea during the 180 days post-randomization; length of hospital stay during the index 
hospitalization. 3) Other: assess tolerance of roflumilast vs. placebo in hospitalized 
AECOPD.  
Figure 3. Roflumilast in Hospitalized AECOPD: Pilot Study of Effects on 180 
day post Hospitalization All Cause Readmission & Mortality 
100 COPD Hospitalizations 
Meets entry 
criteria 
Enrolled 
Baseline testing 
Randomized 
Standard of care                     
& Placebo 
Standard of care             
& Roflumilast 
All Cause Readmission or Mortality 
180 Days 


Version 04.13.2015 
 
Hospitalized for 
acute COPD 
exacerbation 
(AECOPD)
Standard of care plus Placebo                                                             
vs.                                                       
Standard of care plus Roflumilast 500ug 
daily
1Baseline measurements: history and physical examination, demographics, smoking history, spirometry (FEV1 
FVC,FEV1/FVC, FEV6), dyspnea (MMRC), Deyo- Charlson index, SGRQ, EQ-5D, GOLD classification, C-SSRS, HBA1c, 
Biomarkers, Genetics
3 Day 7 phone visit: interim history-vital status, exacerbation history
Enroll, 1
Phone 
visit 
day 73
4 Day 14 clinic visit: interim history, vital signs, dyspnea (MMRC), SGRQ, EQ-5D, C-SSRS
Figure 4. Roflumilast in Hospitalized AECOPD: Pilot Study of Effects on 180 day 
post Hospitalization All Cause Readmission & Mortality
6 Day 180 clinic visit: interim history, vital signs, dyspnea (MMRC), spirometry (FEV1 FVC,FEV1/FVC, FEV6), SGRQ, EQ-
5D, HBA1c, Biomarkers, Genetics
Phone 
visits 
days 30-
1205
2Study drug begins prior to hospital discharge to day 180
5 Phone visits days 30, 60, 90, 120: interim history-vital status, exacerbation history
Clinic 
visit 
at day 
14 4
Phone 
washout 
day 
1947
Clinic 
visit at 
180 day 6
7 Phone washout visit day 194: interim history-vital status, exacerbation history
 
Figure 4 shows the overall study design, proposed study measurements, and time points 
for assessment. Patients hospitalized with AECOPD will be eligible for enrollment during 
their hospitalization with treatment being started before discharge from the hospital.. 
Demographics, blood tests, health related quality of life, comorbidity (Deyo-Charlson 
index), post bronchodilator spirometry, vital signs, dyspnea measured by MMRC, SaO2 
and amount of inspired O2 to maintain SaO2> 90% at rest, serum fibrinogen levels, 
HBA1c, Biomarkers and Genetics will be obtained after enrollment and then patients will 
be randomized to standard AECOPD care plus roflumilast 500 ug daily vs. placebo.  
Patients will begin roflumilast or placebo < 12 hours of hospitalization for a total period of 
180 days post enrollment. On discharge day (approximately day 3-4 after admission 
based on the recent COPD CRN zileuton study of hospitalized AECOPD), the 
measurements will be repeated as indicated (baseline measurements), with follow-up 
phone assessments at days 7, 30, 60, 90, 120 and 194 days post enrollment. An in-
person clinical visit will be conducted at days 14 and 180 post randomization. 
4. Methods:  
4. A. Study Population.  100 AECOPD patients hospitalized at Temple University 
Hospital, Temple University Episcopal Hospital Campus, Jeanes Hospital and St Mary’s 
Hospital. 
Inclusion Criteria. Primary diagnosis of AECOPD defined as acute increase in 
dyspnea, sputum volume, and/or sputum purulence without other identified cause; 
consent obtained and treatment started before discharge from the  hospital ; patient age 
>40, < 80 years old; cigarette smoking > 10 pack-years; informed written consent.  
Exclusion Criteria. Prior diagnosis or high suspicion for asthma based on investigator 
judgment; pulmonary edema, pneumonia, interstitial lung disease or significant 


Version 04.13.2015 
 
bronchiectasis based on admission chest x-ray; intubated and mechanically ventilated at 
the time of evaluation; active liver disease, or transaminase elevations (> 3xULN); 
history of alcoholism or heavy ethanol use; history of suicidal behavior ≤ 2 years or 
suicidal ideation ≤ 6 months prior to enrollment; pregnant or lactating females. Those on 
the following excluded medications: P450 inducers (e.g., rifampicin, phenobarbital, 
carbamazepine, and phenytoin) and CYP3A4 inhibitors or dual inhibitors that inhibit both 
CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, 
enoxacin, cimetidine. 
4.  B. Study Procedure 
Study will begin before patient’s discharge from the hospital and last for 194 days.  
Baseline: Will occur during the duration of admission stay in the hospital. Patients will 
have a medical history taken as well as smoking history. Patients will also be given a 
physical exam including vital signs. A spirometry test will also be performed. Women 
with the potential to become pregnant will be given a pregnancy test. Data will also be 
collected in regards to dyspnea scales, Deyo-Charlson index, and GOLD classification.  
Patients will complete a Columbia Suicide Severity Rating Scale to exclude patients with 
a history of suicidal behavior ≤ 2 years or suicidal ideation ≤ 6 months prior to enrollment  
Randomization: Patients who are eligible to enroll in this study will be randomized to one 
of two treatment groups. Randomization will be done using a randomized block design 
stratified by treatment center.  One group will receive roflumilast 500 mcg (Daliresp®) 
and the other will receive a placebo tablet. Patients will begin one of these treatment 
arms prior to hospital discharge for a total period of 180 days post enrollment.  
Day of hospital discharge: A spirometry test will be performed and an adverse event 
assessment will be completed.  
Day 7: Phone Visit. Data to be collected includes: interim history, adverse events 
assessments, vital status, and exacerbation history. During this telephone visit the study 
doctor or nurse coordinator will ask how the patient is feeling and if they have needed to 
visit the doctor or go to the emergency room or hospital since the last time they were 
contacted.  They will be asked how well they are tolerating the study drug.  
Day 14: Clinic Visit. At this visit vital signs, C-SSRS test, interim history, adverse event 
assessment, vital status, and exacerbation history will be recorded. The following 
questionnaires will given: EQ-5D, the St. George’s Respiratory Questionnaire (SGRQ), 
and the Modified Medical Research Council dyspnea score (MMRC).  
Days 30, 60, 90, & 120: Phone Visit. Data to be collected includes: interim history, 
adverse events assessments, vital status, and exacerbation history. During each of 
these telephone visits the study doctor or nurse coordinator will ask how the patient is 
feeling and if they have needed to visit the doctor or go to the emergency room or 
hospital since the last time they were contacted.  They will be asked how well they are 
tolerating the study drug. 
Day 180: Clinic Visit. At this visit vital signs, C-SSRS test, interim history, adverse event 
assessment, vital status, and exacerbation history will be recorded. A spirometry test will 
be performed as well during this visit. The following questionnaires will given: EQ-5D, 
the St. George’s Respiratory Questionnaire (SGRQ), and the Modified Medical Research 
Council dyspnea score (MMRC).  


Version 04.13.2015 
 
Day 194: Phone Visit. This phone call covers the wash out period for the study 
treatments. Data to be collected includes: interim history, adverse events assessments, 
vital status, and exacerbation history. During this telephone visits the study doctor or 
nurse coordinator will ask how the patient is feeling and if they have needed to visit the 
doctor or go to the emergency room or hospital since the last time they were contacted. 
4. C. Demographics and Medical History.  Age, gender, body mass index (BMI), 
smoking history (debut, amount, duration), presence of comorbidities, current medical 
therapy (bronchodilators, steroids, oxygen), history of pulmonary rehabilitation, influenza 
and pneumococcal vaccination, emergency room visits and hospitalizations during last 
year, number of prior exacerbations in prior year, history of coronary artery disease, 
stroke, transient ischemic attacks, and peripheral vascular disease. The Deyo-Charlson 
index, a standard and validated measure of co-morbidity {{252 Deyo,R.A. 1992; }}, will 
be used to assess the impact of other chronic illnesses on outcome. 
4. D. Spirometry. Spirometry will be performed (post bronchodilator administration) at 
enrollment (baseline) or as soon as the subject is able to perform it after hospitalization, 
at the day of discharge and then 180 days post randomization according to ATS 
guidelines. {{174 Anonymous American Thoracic Society. 1995}} We realize that all 
subjects may not be able to perform spirometry initially upon presentation, but 
Niewoehner has reported that spirometry was able to be performed in a multicenter trial 
in acute hospitalized COPD patients 96% of the time at some point during the initial 
hospitalization.{{1143 Niewoehner,D.E. 2000}}Data will be presented in absolute 
numbers and as percent of reference predicted values, using prediction equations from 
Crapo {{233 Crapo,R.O. 1981}} for whites and by multiplying Crapo’s predicted values 
by 0.88 to correct for blacks’ smaller lung volumes. Airflow obstruction will be defined by 
postbronchodilator measured FEV1/FVC < 70% and FEV1 < 70% predicted at time of 
inclusion and will be used to define GOLD Grades.{{154 Global Initiative for Chronic 
Obstructive Lung Disease (GOLD) Guidelines.}} 
4. E.  Measurement of Hospitalization Duration. 
Hospitalization duration will be measured both as the actual days of hospitalization, and 
as the number of days from admission to the day when patients meet criteria for 
discharge as outlined by others {{1028 Stevenson,N.J. 2005;415 Pinto-Plata,V.M. 2007; 
90 Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2008;}}. These criteria 
include: 1) stable vital signs (respiratory rate < 25 breath/minute, heart rate below 100 
beats/minute, oral body temperature between 97 to 100°F) 2) ability to walk 50 feet 
without disabling dyspnea; 3) SpO2> 90% with ≤ 4 LPM oxygen at rest; 4) use of β-
agonist therapy > every 4 hours; 5) no escalation of care within the previous 12 to 24 
hours.  We plan to use these criteria to define when patients can be discharged to 
calculate hospital duration rather than the number of hospitalization days to avoid the 
social and non-clinical obstacles that are inadvertently wrapped into length of stay (e.g., 
getting a ride home, too late in the day, need other support services, etc.). 
4. F. Measurement of Treatment Failure During Initial Hospitalization. 
We have modified the definition of Niewoehner {{387 Niewoehner,D.E. 1999}}as follows:  
treatment failure during the initial hospitalization will include all-cause death, need for 
intubation and mechanical ventilation, post-randomization use of noninvasive ventilation, 
or intensification of pharmacologic treatment. Intensification of pharmacologic treatment 


Version 04.13.2015 
 
will be defined as an increased dose of systemic steroids (higher dose or longer 
duration), increased use of antibiotics (change in antibiotic or longer course), addition of 
theophylline, increased liter flow of supplemental oxygen > 2 at rest, and increase in 
frequency or dose of inhaled bronchodilators.  
4. G. Quality of Life and Functional Status.  Patients will complete a general and 
disease-specific self-administered quality of life and functional questionnaires.  We will 
use EQ-5D and the St. George’s Respiratory Questionnaire (SGRQ). Both are validated 
tools extensively used in COPD.{{1167 Meguro,M. 2007}}{{1166 Pickard,A.S. 2008}} 
4. H. Columbia–Suicide Severity Rating Scale (C-SSRS). The Columbia–Suicide Severity 
Rating Scale (C-SSRS) is a 2-page questionnaire that 
prospectively assesses suicidal ideation and behavior using a structured interview face 
to face for patient responses. The C-SSRS will be performed during each evaluation visit 
according to the assessment schedule on Figure 4.   Suicidal ideation is classified on a 
5-item scale: 1 (wish to be  dead), 2 (nonspecific active suicidal thoughts), 3 (active 
suicidal ideation with any methods [not plan] without intent to act), 4 (active suicidal 
ideation with some intent to act, without specific plan), and 5 (active suicidal ideation 
with specific plan and intent). The C-SSRS also captures information about the intensity 
of ideation, specifically the frequency, duration, controllability, deterrents, and reasons 
for the most severe types of ideation. Suicidal behavior is classified on a 5-item scale: 0 
(no suicidal behavior), 1 (preparatory acts or behavior), 2 (aborted attempt), 3 
(interrupted attempt), and 4 (actual attempt). The C-SSRS will be performed during each 
evaluation visit according to the assessment schedule (see Figure 4). During visit, patients will 
complete the assessment with the health professional. Patients who do not have suicidal behavior 
or ideation will answer a limited number of questions and will usually complete the assessment in 
approximately 3 minutes. Patients with significant suicidal ideation and/or behavior may require 
up to 10 minutes to answer all relevant questions.  
The patient should not be released from the evaluation site until it is confirmed 
that the patient is not considered to be at any suicidal risk and all responses negative to the C-
SSRS. 
Positive reports are generated for any of the following findings: 
• Suicidal ideation with intention to act (score of “4”) 
• Suicidal ideation with specific plan and intent (score of “5”) 
• Made suicide attempt 
• Interrupted suicide attempt 
• Aborted suicide attempt 
• Preparatory behaviors for making a suicide attempt 
At Screening (Visit 1), the C-SSRS will be completed for the patient’s lifetime history 
of suicidal ideation and behavior. At all other visits, the C-SSRS will be completed for 


Version 04.13.2015 
 
ideation and behavior since the previous visit. The patient’s responses should remain negative 
throughout the entire trial.  If a possible exclusion alert is triggered 
by a positive response at Screening (Visit 1), 2 additional questions at the bottom of the 
report will need to be asked to determine whether exclusion criteria 9a and/or 9b have 
been met. A response of “Yes” to either one or both of the follow-up questions will exclude the 
patient from the trial and necessitate immediate psychiatric referral of the patient on the same 
date as the screening visit. For all subsequent visits after Screening (Visit 1), if the patient’s 
response generates a change in the findings report from negative to positive, the patient should be 
referred for immediate psychiatric evaluation on the same date as the site visit and the PI will 
should be contacted. Positive suicidality indication findings reports after the Screening Visit 
(Visit 1), if confirmed by the Investigator, should be considered to be an AE. SAEs must be 
reported as outlined in Section 6. Ultimately, the determination of suicidality and risk is up to the 
Investigator’s clinical judgment. 
4. I. Measurements of Dyspnea. Dyspnea will be measured by use of the modified 
Medical Research Council Dyspnea score. This is a well-known, validated and easy to 
use scale that is a reliable and sensitive tool specific to COPD patients that will allow 
detection of a response to therapy as well as comparison to other studies reporting 
dyspnea as an outcome in other COPD trials.  
4.  J. Description of Optimized Standard Care for COPD Exacerbations.  All patients 
will receive standardized, optimized care for AECOPD {{387 Niewoehner,D.E. 1999}}. 
Nebulized albuterol (2.5 mg in 0.5 ml, dilute to 3 ml NSS administered every 4-6 hours) 
and ipratropium bromide (0.5 mg in 0.5 ml, diluted with 2.5 ml of saline administered 
every 6 hours) will be given. A 14-day course of systemic steroids consisting of 
intravenous methylprednisolone 125 mg every 6 hours for up to 72 hours, followed by 
once daily oral prednisone 60mg/day for days 4-7, 40 mg prednisone days 8-11 and 20 
mg prednisone days 12-14 will be provided. A 7-day course of antibiotics will be selected 
based on patient’s medical allergy history and relevant culture data if available. 
Supplemental oxygen will be provided by route and dose to achieve maximum patient 
comfort and compliance to maintain a SaO2 > 92%. Noninvasive positive pressure 
ventilation will be utilized at the discretion of the treating physicians but will follow 
accepted guidelines {{133 Keenan,S.P. 2003; 136 Lightowler,J.V. 2003}}. 
4. K. Intervention with Roflumilast. An IND for using roflumilast will not be required 
because this is an FDA approved medication for oral use and we are not seeking a 
change in label indications.  
4. L. Drug/Placebo supply. Roflumilast and matching placebo will be provided by 
Forest Laboratories and stored by the Investigational Pharmacy Unit at Temple 
University Hospital. 
4. M. Pharmacokinetics of Roflumilast. Following oral administration, roflumilast is 
rapidly absorbed with a tmax of about 1 hour and an 80% bioavailability. Roflumilast 
shows linear dose-proportional pharmacokinetics over a dose range of 250-1000 ug and 
plasma disposition half-life is about 10-20 hours making once daily dosing a feasible 
option. roflumilast is metabolized by CYP3A4 and CYP1A2 enzymes with N-oxide being 
the principal major metabolite. N-oxide has selectivity for the PDE4 isoenzyme and 


Version 04.13.2015 
 
mainly accounts for roflumilast’s in vivo bioactivity. No major interactions have been 
reported between roflumilast and other COPD medications.  
4.  N. Contraindications and side effects to the use of Roflumilast. 
1. Contraindications: Roflumilast in contraindicated in patients with moderate or severe 
liver impairment (Child-Pugh class B and C) 
2. Side effects: Adverse events experienced by > 3% of patients in clinical trials of 
roflumilast included diarrhea (9.5%), weight loss (7.5%), nausea (4.7%), headache 
(4.4%) and back pain (3.2%). Patients discontinued therapy due to adverse effects more 
frequently with roflumilast (14.8%) compared to placebo (9.9%). Diarrhea and nausea 
were the most common adverse reactions leading to drug discontinuation in prior trials. 
Serious adverse events that occurred more frequently with roflumilast compared to 
placebo included diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute 
pancreatitis acute renal failure. Less common adverse events, (1-2%) of patients that 
were more frequently reported with roflumilast use as compared to placebo included 
abdominal pain, anxiety, heartburn, depression, gastritis, rhinitis, sinusitis, muscle 
spasms, tremor, urinary tract infection, and vomiting. Roflumilast carries a warning for 
increased psychiatric adverse events and suicidality. Patient should be monitored for 
changes in mood including worsening insomnia, anxiety or depression or suicidal 
ideations. Roflumilast also carries a warning for weight loss. 20% of patients may 
experience moderate weight loss between 5 to 10% of ideal body weight compared to 
7% with placebo. 
Roflumilast side effects reported in ≥ 2% of recipients from 8 clinical trials as listed in the 
manufacturer’s package insert are listed in the table below. 
Treated with Roflumilast 500 mcg daily and Greater Than Placebo Treatment  
Adverse Reactions  
Roflumilast  
Placebo  
(Preferred Term)  
(N=4438)  
(N=4192)  
 
n (%) 
n (%)  
Diarrhea  
420 (9.5)  
113 (2.7)  
Weight decreased  
331 (7.5)  
89 (2.1)  
Nausea  
209 (4.7)  
60 (1.4)  
Headache  
195 (4.4)  
87 (2.1)  
Back pain  
142 (3.2)  
92 (2.2)  
Influenza  
124 (2.8)  
112 (2.7)  
Insomnia  
105 (2.4)  
41 (1.0)  
Dizziness  
92 (2.1)  
45 (1.1)  


Version 04.13.2015 
 
Decreased appetite  
91 (2.1)  
15 (0.4)  
 
Other side effects reported in 1- 2% of recipients include: Gastrointestinal disorders (abdominal 
pain, dyspepsia, gastritis, vomiting); Infections and infestations (rhinitis, sinusitis, urinary tract 
infection); Musculoskeletal and connective tissue disorders (muscle spasms); Nervous system 
disorders (tremor); and Psychiatric disorders (anxiety, depression). 
 
4.  O. Drug Interactions with Roflumilast. 
1. Drugs That Induce Cytochrome P450 (CYP) Enzymes  
Strong cytochrome P450 enzyme inducers decrease systemic exposure to 
roflumilast and may reduce the therapeutic effectiveness of roflumilast. Therefore 
the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, 
carbamazepine, and phenytoin) with roflumilast is not recommended and these 
medications will be excluded from use in the trial.   
2. Drugs That Inhibit Cytochrome P450 (CYP) Enzymes 
  
The co-administration of roflumilast (500 mcg) with CYP3A4 inhibitors or dual 
inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, 
ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic 
exposure and may result in increased adverse reactions.  
Prior studies have shown that the overall pattern of adverse events in patients with or 
without roflumilast and long acting beta agonists use is similar. There's no indication 
from prior studies that roflumilast increases long acting beta agonist related adverse 
events such as tachycardia or cardiovascular events, and that concomitant long acting 
beta agonist use does not increase the frequency of events associated with roflumilast 
treatment alone.  
4.  P. Assessment of Safety  
1. Definition of adverse event.  
An adverse event is any untoward medical experience occurring in a subject doing the 
trial whether or not is related to study drug. An adverse event includes a concurrent 
illness, injury, or any other aspect of the subject's health, as well as abnormal laboratory 
findings found to be of clinical significance. An adverse event includes worsening of an 
existing symptom or condition or post treatment events that occur as a result of protocol 
– mandated procedures.  
An adverse event may be a disease, a set of related symptoms or signs, or single 
symptom or sign including an abnormal laboratory value.  
For the purposes of this trial, all adverse events will be collected including adverse 
events that occurred subjects were permanently off of study drug but who continue to be 
followed for outcomes.  
A serious adverse event is an adverse event occurring any does that results in any of 
the following, whether or not it is related to study drug: death, immediately life-


Version 04.13.2015 
 
threatening circumstance, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability.  
Life-threatening means that the subject in the view of the investigator was thought to be 
at immediate risk of death from the event as it occurred.  
Serious events will be collected, including serious adverse events occurring when 
subjects were permanently off study drug but who continue to be follow-up for outcomes.  
2. Unanticipated problems.  
An unanticipated problem is any incident, experience, or outcome involving risk to 
subjects that meets all of the following criteria: unexpected in nature, severity or 
frequency; related or possibly related to participation in the research; and suggests that 
the research places subjects or others at a greater risk of harm.  
3. Relatedness or causality.  
Causality is defined as definitely, probably, possibly or not related to the investigational 
product:  
– Not related, event clearly related to other factors  
– Possibly related, sequence of events is compatible with study procedure but could 
have been produced by other factors  
– Probably related, sequences of events that is compatible with study procedure that 
cannot be explained by other factors without much doubt  
– Definitely related, sequence of events that is compatible with study related procedure 
and cannot be explained by other factors beyond a reasonable doubt.  
4.Severity or intensity definition.  
Severity describes the intensity of a specific event and is not related to whether or not it 
is a serious adverse event. Severity is defined as:  
– Mild: symptoms barely noticeable or does not make the subject uncomfortable.  
– Moderate: symptom of sufficient severity to make the subject very uncomfortable.  
– Life-threatening: symptom of a sufficient severity to cause the subject to be in 
immediate risk of death. Treatment for the symptom may be given.  
5. Documentation of adverse events.  
Any adverse event, serious adverse event, or unanticipated problem occurring during 
the study must be documented in the subject source documents on the appropriate case 
report form page. Information relating to the adverse event such as onset, cessation 
date and times, intensity, seriousness, relationship to study drug and outcome is also 
documented in the case report form.  
All adverse events will be followed until resolution, stabilization or until they are judged 
by the investigator to be no longer be clinically significant. All serious adverse events will 
be followed until resolution, stabilization, death, or subject withdrawal. Case report forms 
will be updated with any new or additional information as appropriate.  
6. Reporting responsibilities of the investigator.  
All serious adverse events, regardless of expectedness or causality will be reported by 
the site immediately (no later than 24 hours after occurrence to the sponsor, Temple IRB 
in accordance with IRB regulations and guidelines of the Temple IRB. 


Version 04.13.2015 
 
Reporting of Serious Adverse Events to Forest Research Institute (FRI) 
Serious Adverse Event (SAE) 
A serious adverse event is one that: 
 
Results in death 
 
Is an immediate threat to life 
 
Requires inpatient hospitalization, or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly or birth defect. 
Causality Assessment 
For all AEs, the Investigator must provide an assessment of causal relationship to the IP. 
Causal relationship must be assessed by answering the following question: 
Is there a reasonable possibility the IP caused the event? 
Yes:           There is evidence to suggest a causal relationship between the drug and the 
adverse event (ie, there is a reasonable temporal relationship, and/or the 
events are unlikely to be attributable to underlying disease, other drugs, or 
other factors). Dechallenge and/or rechallenge (if available) is positive 
No:             The relationship is unlikely or nonexistent (ie, there is no reasonable 
temporal relationship and/or the events are likely to be manifestations of 
underlying diseases, or commonly occur in the study population 
independent of drug exposure or other drugs/factors provide plausible 
explanations for the events), or the patient did not take the investigational 
product. 
The Sponsor (Principal Investigator) is required to inform Forest Global Drug Safety of 
all SAEs. Forest Global Drug Safety must be notified immediately regarding any SAE 
that occurs after informed consent is obtained. 
The Principal Investigator must report the event within 24 hours of first knowledge of any 
AE that meets one of the criteria for an SAE, to Forest Global Drug Safety on an SAE 
report form. If, during follow-up, any non-serious AE worsens and eventually meets the 
criteria for an SAE, that AE should be recorded as a new SAE. 
The study center must transmit the SAE report form to the SAE fax number (631) 858-
7906 within 24 hours of first awareness of the event at the study center. 
Supplemental information shall be submitted as soon as available and may include 
laboratory results, radiology reports, progress notes, hospital admission and emergency 
room notes, holding and observation notes, discharge summaries, autopsy reports, and 
death certificates. 


Version 04.13.2015 
 
Reporting of Pregnancy to Forest Research Institute 
Study center personnel must report every pregnancy on a pregnancy report form as 
soon as possible (within 24 hours of first awareness of the pregnancy to the pregnancy 
fax number, (631) 858-7906), even if no AE has occurred, and follow it to term. If, 
however, the pregnancy is associated with an SAE (eg, if the mother is hospitalized for 
dehydration), in addition to the pregnancy report form, a separate SAE report form must 
be filed.  
Fax all relevant SAE or pregnancy information to Forest Global Drug Safety. Contact 
information for Forest Global Drug Safety, personnel is as follows: 
FOREST GLOBAL DRUG SAFETY DEPARTMENT  
Fax: (631) 858-7906 
4. Q. Assessment of effectiveness.  
The present proposal is a pilot study designed to test the feasibility of a future project to 
be conducted in a multicenter trial in hospitalized patients, to determine the tolerance of 
roflumilast in hospitalized COPD patients, and to determine the treatment effect of 
roflumilast to decrease all-cause mortality and all cause readmission rate as add-on 
therapy. The specifics aims will be: 
1. Determine the tolerance of roflumilast in hospitalized COPD patients 
2. Determine the treatment effect of roflumilast as add-on therapy to decrease all 
cause readmission and mortality as a composite endpoint 180 days after 
randomization to roflumilast or matching placebo ≤ 12 hours after hospitalization 
for acute COPD exacerbation. 
4.  R. Statistical analysis plan. 
The primary analysis for all study outcomes will be performed on an intention to treat 
basis. In the intention to treat approach, all subjects are analyzed in the group to which 
they were randomized, regardless of whether the assigned treatment was adhered to 
and regardless of whether there were any eligibility violations. 
1. 
Analysis of baseline characteristics. 
Univariate descriptive statistics will be calculated for baseline parameters overall and by 
treatment group. For categorical outcomes, these will include the number percentage of 
subjects in each category. For continuous variables, these will include the mean and 
standard deviation for variables with approximately normal distributions and the median 
and 25th and 75% percentiles for variables with skewed distributions. 
2. Analysis of the primary endpoint. The primary outcome is time from randomization 
to a composite outcome of all cause re-hospitalization and all-cause mortality, whichever 
comes first. The primary analysis will be a log-ranked test and associated Kaplan-Meier 
plot, unadjusted for any covariates. Censoring will occur at the earliest date of any of the 
following occurrences, unless the subject has already experienced the primary outcome 
event: 
 
Lost to follow-up despite intensive efforts 


Version 04.13.2015 
 
 
Subject or healthcare proxy withdrawal of consent 
 
180 days after randomization. 
3. Analysis of secondary outcomes. 
Primary analysis of other time to event outcomes will be performed using unadjusted log 
rank tests that have associated Kaplan-Meier plots, similar to the primary analysis of the 
primary study outcome. Secondary analysis of these outcomes will use Cox regression 
to adjust for baseline subject factors (covariates) that are known to be associated with 
the outcome. 
The primary analyses of changes in continuous measures such as absolute and percent 
changes in spirometry and dyspnea scores, for example, will be analyzed using an 
analysis of covariance where change from baseline to a particular time period is the 
dependent variable. 
4. Assessment of treatment effect 
In this pilot proposal, the treatment effect of roflumilast vs. placebo to prolong the time to 
event of a combined endpoint of death or re-hospitalization will be assessed in an 
intention to treat manner. In a similar manner, the treatment effect of roflumilast vs. 
placebo to effect all of the secondary endpoints proposed to be measured in the pivotal 
phase III trial will also be measured (time to respiratory death or respiratory re-
hospitalization during the 180 days post-randomization; rate of death or readmission at 
30 days post-discharge; treatment failure [see definition below]; change in health status, 
change in FEV1, and dyspnea during the 180 days post-randomization; length of hospital 
stay during the index hospitalization; and the tolerance of roflumilast vs. placebo in 
hospitalized AECOPD).  
 
Because this is a pilot study the intent is to see if there is a signal that would justify a 
larger clinical trial.  Therefore the significance level has been set to 0.1 and the power 
has been set at 0.7.  A total of 100 patients will enter this two treatment parallel-design 
study.  The probability is 70 percent that the study will detect a treatment difference at a 
two sided 10.0 percent significance level, if the true hazard ratio is 1.654. This is based 
on the assumption that the accrual period will be 36 months and the follow up period will 
be 6 months and the median time to event is 8 months. The total number of events will 
be 73. 
 
5. Strategy for Efficient Recruitment Strategies in Effects of Roflumilast in 
Hospitalized COPD on Mortality and Re-hospitalization 
To ensure participation of a broad cross-section of patients and timely enrollment in this 
study, we will employ an aggressive and well-tested Temple recruitment strategy and we 
will collaborate with the other clinical centers. The Temple Lung Center has a strong 
record of clinical study recruitment and retention in the Philadelphia area, the greater 
Delaware Valley, throughout Pennsylvania, and from the entire mid-Atlantic region. 
Because we admit more AECOPD patients than any other hospital in Pennsylvania, we 
are especially well suited to serve as the recruitment anchor for the proposed study. We 


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currently maintain an IRB-approved clinical research registry with over 2500 COPD 
patients interested in clinical trials. Approximately one third of our COPD patients are 
black and over half are women. We have consistently succeeded in translating our high 
patient volumes and rich patient diversity into productive enrollment for national clinical 
trials. For COPD inpatient trials, potential research participants are identified during 
rounds on the pulmonary units, the emergency room, and on the pulmonary consult 
service. Internal medicine teams and case managers are contacted on a daily basis 
during the week. A listing of respiratory admissions is reviewed each day. Pulmonary 
section faculty members are regularly invited to local and regional meetings as well as 
hospital grand rounds where our research activities are showcased.  
Because the proposed study seeks to enroll hospitalized COPD patients, we believe 
recruitment for this project will be challenging but achievable. This is why we propose a 
consortium of hospitals to achieve the recruitment endpoints. Temple Lung Center 
already has built a highly productive consortium of hospitals to participate in COPD trials 
such as the NHLBI long-term oxygen treatment trial (LOTT), simvastatin to prevent 
COPD exacerbations (STATCOPE), and our recently submitted NIH application for NIH 
RFP NHLBI-ECB-HR-2013-20-SS Engine for Fast Execution of Clinical Trials (EFFECT - 
Engine for Fast Execution of Clinical Trials). In both LOTT and STATCOPE, Temple 
leads recruitment of COPD subjects across all centers. In EFFECT, the planned focus is 
on hospitalized patients. For this study, we propose to use three of our consortium 
members from LOTT, STATSCOPE, and EFFECT.  
St. Mary Medical Center in Langhorne, Pennsylvania, is licensed for 327 beds and is 
part of Catholic Health East, the second largest regional healthcare system in the 
Delaware Valley. Its staff of over 500 physicians provides care for more than 20,000 
inpatients, 42,000 emergency department patients, and 150,000 outpatients annually. 
Over the past decade, St. Mary has participated in more than 50 sophisticated studies in 
cancer (e.g., Phase III trials of new treatments, pain management studies, and early 
detection studies), cardiology (e.g., protocols in acute coronary syndrome, unstable 
angina, myocardial infarction, and drug-eluting stents), osteoporosis, and diabetes.  Drs. 
Lee and Serpico direct the largest pulmonology practices in the area and have associate 
full-time pulmonologists who staff St. Mary and maintain substantial in- and out-patient 
COPD practices. Drs. Lee and Serpico will serve as co-PIs at the St. Mary site.  
Jeanes Hospital is a 176-bed, full-service acute-care hospital located in Northeast 
Philadelphia. Jeanes offers a complete range of medical and surgical care to the 
surrounding community. In 1996 Jeanes became a member of Temple University Health 
System and through this relationship it offers high-acuity medical services found at 
academic medical centers within the comfort of a local neighborhood hospital. Dr. 
Panetta, a recent graduate of the Temple Lung Center pulmonary and critical care 
fellowship program will serve as the PI at the Jeanes site. A set of recruitment tools and 
strategies will be produced and distributed for investigator and coordinator use. Temple 
University Hospital - Episcopal Campus is a full-service Emergency Department that 
provides high-quality care for 45,000 patients each year in North Philadelphia and is 3.5 
geographic miles away from Temple University Main Campus. The Emergency 
department treats patients who have serious injuries as well as patients with more minor 
illnesses and injuries. The Emergency department is open 24 hours a day, 365 days a 
year and is staffed by board-certified Temple doctors and specially trained nurses. There 
is also a 21-bed inpatient medical/telemetry unit at Temple University Hospital -


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 Episcopal Campus for patients who require a short hospital stay. Full-time registered 
nurses and hospitalists staff this modern unit. If required, the Emergency Department or 
21-bed inpatient telemetry unit can provide patients with fast access to specialized 
doctors and services at Temple University Hospital. All COPD patients seen at the 
Episcopal Campus who need inpatient care will be transferred as inpatients to Temple 
University Hospital Main Campus for their COPD hospitalization. 
Appendix: 
 
Biomarker Blood 
Biomarker specimens will be collected at baseline, every 6 months a participant is in the 
study, and at the last pre-washout visit. 
  
Preparation 
  
1. Label all vacutainers and cryo-vials before the participant arrives.  Use white labels for 
vacutainer tubes and colored cryo-labels for vials. Your sheet of white labels includes 
labels for the routine lab tubes and genetics tubes which you should also label at this 
time.  It is recommended to assemble all the labeled tubes and vials in a large zip-lock 
bag with a white label on it to reduce errors. 
2. Confirm that the participant has read, understood, and signed a consent form. 
4. Determine whether the participant has ever had a bleeding disorder.  If yes, check 
with the local study investigator regarding safety of proceeding. 
  
Blood Collection and Processing 
  
1.      Blood samples will be collected in one 10 ml purple top K2EDTA tubes 
2.      Tubes should be promptly mixed after being drawn by gentle inversion 8-10 times 
(do not shake). 
3.      *Centrifuge tubes at 1,100 RCF for 10 minutes.  
*Note:  You need to put a small spacer at the bottom of the sleeve when centrifuging 
lavender top tubes.  Don't use something that will get stuck in the sleeve or stuck on the 
tube (a cap from another tube, solid side up, has been suggested).  The reason for the 
spacer is that the design of the lavender cap doesn't allow it to sit at the bottom of the 
sleeve and the force of the centrifuging will separate the tube from its top. Be sure that 
the centrifuge is balanced. Always have equivalent tubes opposite each other in order to 


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achieve the balance. If a tube does not have an equivalent tube use a similar type of 
tube filled with water to achieve the balance.   
  
4.      After centrifugation of the lavender top tube(s), carefully remove the hemogard. 
Using a plastic transfer pipette, and being careful not to disturb the red or white cell 
layers, transfer the clear plasma into lavender-labeled vials (1 ml in each vial).  Note that 
1 ml is about half the vial. It is imperative for analysis that the first tube of plasma be 
harvested from the very top of the plasma layer. You must aliquot sequentially. The last 
aliquot may be less than 1 ml (depending on what volume is remaining in the lavender 
top tube), but that aliquot should also be saved.  Thus, the initial vials will contain 1 ml of 
plasma, the last vial may contain less than 1 ml, and some vials may remain empty and 
can be discarded.  Never 'top off' the last vial as contents will expand and squeeze out 
the cap as they freeze. Always use a different pipette for every source tube. Remember 
that it’s more important to get a pure sample than to get every last drop of plasma . 
  
5.      When filling vials, do not try to spread the contents equally across all available 
vials.  Fill each vial to at least the 1 ml mark and put the remainder (< 1 ml) in the last 
vial.  In most cases you will fill fewer vials than you have labeled. 
  
6.      If the plasma or serum has a slight pinkish color, hemolysis has occurred. 
Hemolysis results from the escape of hemoglobin from inside the red cells into the 
serum or plasma. Try to avoid the following things which cause hemolysis: 
        •        Using too small a needle gauge 
        •        Shaking the tubes 
        •        Drawing blood from a hematoma 
        •        Centrifuging the blood before it is completely clotted 
  
7.      The plasma must be isolated and aliquoted within 60 minutes of the draw. 
  
8.      Dispose of remaining blood products into red biohazard bag. 
  
9. Seal cryo-vials firmly and place upright in tube rack or box. Place tube rack or box into 
-80°C freezer immediately.  After the vials are frozen, the vials can be transferred into 
the participant's zip-lock bag awaiting shipment to the DCC.  If it is more convenient for 
your lab, vials may remain in cell-divided freezer boxes for shipping to the DCC as long 
as vials remain in order by ID number and there is a separate packing list for each 


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ID.  Boxes should be numbered (Box 1, Box 2, etc.) and the starting corner should be 
marked. 
  
I. 
All vials should be in the -70°C freezer within 2 hours of phlebotomy. 
  
 
 Storage and Shipment of Vials  
  
1.      Vials should remain at -70°C until shipment. 
   
PAXGENE TUBES: 
  
Obtain specimen in Pax Gene Tube 
Specimen remains at room temperature for for 2-2.5 hrs 
Freeze at -20 for 24 hours 
After 24 hours freeze at  -70 until shipment 
 
 
 
Columbia Suicide Severity Rating Scale 
The Columbia–Suicide Severity Rating Scale (C-SSRS) is a 2-page questionnaire that 
prospectively assesses suicidal ideation and behavior using a structured interview face to face for 
patient responses. Suicidal ideation is classified on a 5-item scale: 1 (wish to be 
dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation with any 
methods [not plan] without intent to act), 4 (active suicidal ideation with some intent to 
act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). 
The C-SSRS also captures information about the intensity of ideation, specifically the 
frequency, duration, controllability, deterrents, and reasons for the most severe types of 
ideation. Suicidal behavior is classified on a 5-item scale: 0 (no suicidal behavior), 


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1 (preparatory acts or behavior), 2 (aborted attempt), 3 (interrupted attempt), and 
4 (actual attempt).  
The C-SSRS will be performed during each evaluation visit according to the assessment schedule 
(see Figure 4). During visit, patients will complete the assessment with the health professional. 
Patients who do not have suicidal behavior or ideation will answer a limited number of questions 
and will usually complete the assessment in approximately 3 minutes. Patients with significant 
suicidal ideation and/or behavior may require up to 10 minutes to answer all relevant questions.  
The patient should not be released from the evaluation site until it is confirmed 
that the patient is not considered to be at any suicidal risk and all responses negative to the C-
SSRS. 
Positive reports are generated for any of the following findings: 
• Suicidal ideation with intention to act (score of “4”) 
• Suicidal ideation with specific plan and intent (score of “5”) 
• Made suicide attempt 
• Interrupted suicide attempt 
• Aborted suicide attempt 
• Preparatory behaviors for making a suicide attempt 
At Screening (Visit 1), the C-SSRS will be completed for the patient’s lifetime history 
of suicidal ideation and behavior. At all other visits, the C-SSRS will be completed for 
ideation and behavior since the previous visit. The patient’s responses should remain negative 
throughout the entire trial.  If a possible exclusion alert is triggered 
by a positive response at Screening (Visit 1), 2 additional questions at the bottom of the 
report will need to be asked to determine whether exclusion criteria 9a and/or 9b have 
been met. A response of “Yes” to either one or both of the follow-up questions will exclude the 
patient from the trial and necessitate immediate psychiatric referral of the patient on the same 
date as the screening visit. For all subsequent visits after Screening (Visit 1), if the patient’s 
response generates a change in the findings report from negative to positive, the patient should be 
referred for immediate psychiatric evaluation on the same date as the site visit and the PI will 
should be contacted. Positive suicidality indication findings reports after the Screening Visit 
(Visit 1), if confirmed by the Investigator, should be considered to be an AE. Ultimately, the 
determination of suicidality and risk is up to the Investigator’s clinical judgment. 
 
Columbia –Suicide Severity Rating Scale Process 


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Forms: 
Baseline/Screening Version 
Since Last Visit Version 
 
 
1. Screening/Baseline Visit:  Patient must not have a history of suicidal behavior ≤ 2 
years or suicidal ideation ≤ 6 months prior to enrollment.  The 
Screening/Baseline Version will be used to screen patients.  During screening, if 
there is a positive response to questions 1 thru 5 do not enroll patient and notify 
the PI for possible psychiatric referral.   
 
2. Clinic Visit 14 or Clinic Visit 180 
 
o During study patient’s follow up clinic visit, the coordinator will assess for 
suicide risk utilizing the Since Last Visit version.  A positive answer to 
question 4 or 5 indicating presence of ideation with at least some intent to 
die suggests a clear need for further evaluation or clinical management.   
Discuss with PI while patient still at visit C-SSRS score.  Patient’s scoring 
a 4 or a 5 should be discontinued from study and sent to Temple ER or to 
Episcopal ER for immediate evaluation.      
                         
Suicide Ideation  
Level                                    MANAGEMENT PROTOCOL 
 
Level Severity 
 
0 
Low Risk 
ROUTINE  Behavioral Health Referral at physician discretion 
1 & 2 
Mild   
ROUTINE  Behavioral Health Referral at physician discretion 
3 
Moderate  Review by physician—Consider safety precautions and                   
telephone consult with Behavioral Health  
4 & 5 
Serious 
EMERGENT ACTION NECESSARY:  Behavioral Health             
Consultation and Patient Safety Monitor/Procedures   
 


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