Long-term Observational Study of the Safety of Roflumilast
Long-term Observational Study of the Safety of Roflumilast
This is a retrospective cohort study comparing COPD patients aged 40 years and older with new
 exposure to roflumilast with up to 5 unexposed (ie, not roflumilast-exposed) COPD controls
 matched by propensity score (PS), age, sex, and year of cohort entry. The study is using
 electronic healthcare databases in the US (Military Health System database), Germany (GER)
 (German Pharmacoepidemiological Research Database), and Sweden (SWE) (national databases
 including healthcare, death, and demographics data). The main objective of this study is to
 evaluate the long-term safety of roflumilast in the treatment of COPD with main focus on the
 primary outcome of all-cause mortality and evaluation of potential safety issues identified
 during the clinical trials of roflumilast. Crude mortality and incidence rates will be
 compared between roflumilast exposed and unexposed COPD patients and adjusted hazard ratios
 (HRs) of the primary and secondary outcomes will be calculated.
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.