Effects of Roflumilast in Hospitalized Chronic Obstructive Pulmonary Disease( COPD) on Mortality and Re-hospitalization

Background :Chronic obstructive pulmonary disease (COPD) currently 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 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.

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 hospital stay during the index hospitalization
and; 3) Other: Assess tolerance of roflumilast vs. placebo in hospitalized AECOPD 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.

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.

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; admission to the hospital <12
hours; 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 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.

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 Procedure 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 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 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 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).

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.

Description of Optimized Standard Care for COPD Exacerbations. 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 but will follow accepted guidelines.

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 mainly accounts for roflumilast's in vivo
bioactivity. No major interactions have been reported between roflumilast and other COPD
medications.

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

- 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.

Inclusion Criteria:

Primary diagnosis of AECOPD defined as acute increase in dyspnea, sputum volume, and/or
sputum purulence without other identified cause; admission to the hospital <12 hours;
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 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.