Long-term Observational Study of the Safety of Roflumilast

Rationale and background Roflumilast is licensed (i) for maintenance treatment of severe
chronic obstructive pulmonary disease (COPD) (FEV1 post-bronchodilator less than 50%
predicted) associated with chronic bronchitis (CB) in adult patients with a history of
frequent exacerbations as add on to bronchodilator treatment (EU) and (ii) as a treatment to
reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic
bronchitis and a history of exacerbations (US). As a condition of approval for marketing in
the EU, the European Medicines Agency requested the Marketing Authorisation Holder to conduct
a long-term comparative observational safety study. Research question and objectives The main
objective of this study is to evaluate the long-term safety of roflumilast in the treatment
of COPD with main focus on 5-year all-cause mortality and evaluation of potential safety
issues identified during the development programme of roflumilast. Study design Retrospective
cohort study comparing COPD patients aged 40 years and older with new exposure to roflumilast
with up to 5 unexposed (i.e. not roflumilast exposed) COPD controls matched by propensity
score (PS), age, sex, and year of cohort entry. PS matching was used as an established method
to control for confounding. Crude mortality and incidence rates were compared between
roflumilast exposed and unexposed COPD patients and adjusted hazard ratios (HRs) of the
primary and secondary outcomes were calculated in GER and SWE, while in the US adjusted HRs
were only calculated for the primary outcome and are not yet available for secondary
outcomes. Reported adjusted HRs for secondary outcomes therefore only refer to GER and SWE.
Setting Electronic healthcare databases in the United States (US), Germany (GER), and Sweden
(SWE) holding demographic data, data on health, and dispensing of medication. The initial
assessment of the number of cohorts in each database including the years 2011, 2012, and 2013
resulted in a total of 54985 (9573 exposed), 50493 (8775 exposed), and 18602 (3207 exposed)
COPD patients in the US, GER, and SWE, respectively. Variables and data sources Exposure
variable: Use of roflumilast (ATC code R03DX07) Outcomes: The primary outcome in the study is
5-year all-cause mortality. Secondary outcomes are death by suicide or hospitalisation for
suicide attempt, hospitalisation for any cause, major cardiovascular events, respiratory
disease related hospitalisation, new diagnosis of depression, new diagnosis of malignant
neoplasm, hospitalisation due to serious diarrhoea of non-infectious origin, abnormal and
unexplained weight loss, and new diagnosis of tuberculosis or hepatitis B or C or other
severe viral hepatitis infection (except hepatitis A). Other covariates: Characterisation of
baseline therapy, baseline medical history and other socio-demographic covariates. Data
sources: Military Health System database (US), German Pharmacoepidemiological Research
Database (GER), national databases including healthcare, death, and demographics data (SWE).

Exposed Cohort selection

Inclusion Criteria:

- Have one or more prescription(s) of roflumilast with the date of first
prescription/dispensation defined as the Cohort Entry Date

- Have active data in the respective database(s) for at least 1 year prior to the Cohort
Entry Date

- Be at least 40 years old at Cohort Entry Date

- Have a diagnosis of COPD or chronic bronchitis prior to the Cohort Entry Date
(databases with outpatient diagnoses) or (databases without outpatient diagnoses)
either a hospital diagnosis of COPD or chronic bronchitis prior to the Cohort Entry
Date or a proxy for such indication based on prescription data.

Non-Exposed Cohort selection Patients meeting the following inclusion criteria belong in
the Non-Exposed Cohort and are eligible as Matched Non-Exposed controls. Each patient in
the Non-exposed Cohort selected as matched exposed patient is assigned as a Cohort Entry
Date the date of the first roflumilast prescription of the matched exposed patient.