Evaluation of Tolerability and Pharmacokinetics of Roflumilast, 250μg and 500μg, as add-on to Standard COPD Treatment to Treat Severe COPD
Condition: Chronic Obstructive Pulmonary Disease (COPD)
MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: Roflumilast; Roflumilast Placebo; Standard of Care COPD Treatment
Intervention description: Roflumilast tablets; Roflumilast placebo-matching tablets; The participant is on standard of care COPD maintenance treatment including LABAs, long-acting anticholinergics, or any combination thereof taken on a constant daily dose within 12 weeks prior to Screening (Visit V0) Examples of LABA containing products are: Formoterol, Salmeterol, Indacaterol, Formoterol/Budesonide, Salmeterol/Fluticasone, Treatment including lon-acting anticholinergics: Tiotropium, Aclidinium.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1323.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: Drug therapy

Summary:

      The purpose of this study is to evaluate discontinuation rates of roflumilast using an
      up-titration regimen for the first 4 weeks of treatment compared with continuous treatment of
      500 μg one daily (OD) during the entire 12-week main period, and to evaluate if participants
      who do not tolerate roflumilast 500 μg OD have a drug exposure with 250 μg roflumilast OD
      similar to that observed in other participants with the 500 μg OD dose.
    

Eligibility criteria:

        Inclusion Criteria:

          1. In the opinion of the investigator, the participant is capable of understanding and
             complying with protocol requirements.

          2. The participant or, when applicable, the participant's legally acceptable
             representative signs and dates a written, informed consent form and any required
             privacy authorization prior to the initiation of any study procedures.

          3. Has a history of chronic obstructive pulmonary disease (COPD) (according to Global
             Initiative for Chronic Obstructive Lung Disease (GOLD) 2013) for at least 12 months
             prior to Screening (Visit V0) associated with chronic productive cough for 3 months in
             each of the 2 years prior to Screening (Visit V0, with other causes of productive
             cough excluded).

          4. Shows a post-bronchodilator forced expiratory volume in 1 second (FEV1) of ≤50% of
             predicted.

          5. Shows an FEV1/forced vital capacity (FVC) ratio (post-bronchodilator) <70%.

          6. Has at least one documented COPD exacerbation within one year prior to Screening
             (Visit V0).

          7. Is on standard of care COPD maintenance treatment including Long Acting β2-Agonist
             (LABAs), long-acting anticholinergics, or any combination thereof taken on a constant
             daily dose within 12 weeks prior to Screening (Visit V0).

          8. Must be a former smoker (defined as smoking cessation at least one year ago) or
             current smoker both with a smoking history of at least 10 pack years.11

          9. Is male or female and aged 40 or older.

         10. A female participant of childbearing potential who is sexually active with a
             nonsterilized male partner agrees to use routinely adequate contraception from signing
             of informed consent throughout the duration of the study.

        Exclusion Criteria:

        Criteria affecting the read-out parameters of the study

          1. Has a COPD exacerbation ongoing at the Screening (Visit V0), or has a COPD
             exacerbation between V0 and V1.

          2. Has a lower respiratory tract infection not resolved 4 weeks prior to Screening (Visit
             V0).

          3. Has a diagnosis of asthma and/or other relevant lung disease (eg, history of primary
             bronchiectases, cystic fibrosis, bronchiolitis, lung resection, lung cancer,
             interstitial lung disease [eg, fibrosis, silicosis, sarcoidosis], or active
             tuberculosis).

          4. Has a known α1-antitrypsin deficiency.

          5. Has taken roflumilast within 6 months of Screening (Visit V0).

             Criteria within ethical considerations in terms of general health

          6. Has clinically relevant abnormal laboratory values suggesting an undiagnosed disease
             requiring further clinical evaluation (as assessed by the investigator).

          7. Has a history of severe psychiatric or neurological disorders.

          8. Has a history of depression associated with suicidal ideation or behavior.

          9. Has congestive heart failure severity grade IV according to New York Heart Association
             (NYHA) Functional Classification.

         10. Has hemodynamically significant cardiac arrhythmias or heart valve deformations.

         11. Has computed tomography (CT) or chest x-ray findings indicating an acute pulmonary
             disease other than COPD (eg, tuberculosis, severe bronchiectasis, tumors).

         12. Has severe immunological diseases (eg, known human immune deficiency virus (HIV)
             infection, multiple sclerosis, lupus erythematosus, progressive multifocal
             leukoencephalopathy).

         13. Has liver impairment Child-Pugh B or C and/or active viral hepatitis.

         14. Has severe acute infectious diseases (eg, tuberculosis, or acute hepatitis).

         15. Has a history of malignant disease (except basal cell carcinoma) within 5 years before
             Screening (Visit V0).

         16. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol
             abuse within one year before Screening (Visit V0).

         17. Has a history of hypersensitivity or allergies to roflumilast or rescue medication or
             ingredients thereof, or any other contraindication for the use thereof.

         18. If female, the participant is pregnant or lactating or intending to become pregnant
             before, during, or within 12 weeks after participating in this study; or intending to
             donate ova during such time period.

         19. Intends to donate blood, organs, or bone marrow during the course of the study.

         20. Has received any investigational compound within 30 days prior to Screening (Visit
             V0), is currently participating in another interventional clinical study, or has been
             previously enrolled in this study.

         21. Is suspected to be unable or unwilling to comply with study procedures (eg, language
             problems, psychological disorders, number and timing of visits at the center).

         22. Suffers from any concomitant disease that might interfere with study procedures or
             evaluations.

         23. Is required to take excluded medications.

         24. Is an immediate family member, study center employee, or is in a dependent
             relationship with a study site employee who is involved in conduct of this study (eg,
             spouse, parent, child, sibling), or may consent under duress.