Main adverse events of Roflumilast are weight loss, loss of appetite, insomnia, headache, diarrhea, vomiting, and nausea. Although the majority of these adverse reactions were mild or moderate. They occurred mainly at the beginning of therapy and mostly resolved with continued treatment around for two weeks according to experiences of clinicians. These adverse events occur more often in Roflumilast 500 μg than 250 μg, having negative impact on compliance of patients at the early stage of treatments.

Thus, investigators aim to compare the drop-out rates between the usual dosage (Roflumilast 500 μg once daily) and the dose escalation (Roflumilast 250 μg once daily for 4 weeks and then escalating dose of 500 μg once daily).

Inclusion Criteria:

1. Male or female older than 40 years
2. Clinical diagnosis of COPD (confirmed with a post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity [FVC] ratio ≤70%) at least 4 weeks prior to the study and post-bronchodilator FEV1 is 50% or less than the predicted value
3. Former smokers or current smokers with at least a 10 pack-year history
4. A history of exacerbation (scheduled/unscheduled visits to primary care physicians, specialists or allied healthcare professionals, or emergency room, or hospitalization due to purulent sputum or increased sputum, or increased dyspnea) in the previous year (at least one)
5. Chronic bronchitis (cough and sputum production for at least three months within two years)
6. Able to have the signed written informed consent prior to any study-related procedures.

Exclusion Criteria:

1. COPD exacerbation or respiratory infection 4 weeks prior to the baseline visit
2. Known a1-antitrypsin deficiency
3. Need for long-term oxygen therapy
4. Moderate to severe liver impairment (Child-Pugh B or C)
5. Severe immunological diseases (e.g. HIV infection, multiple sclerosis, lupus erythematosus, etc)
6. Severe acute infectious diseases
7. Cancers
8. Subjects being treated with immunosuppressive medicinal products (i.e.: methotrexate, azathioprine, infliximab, etanercept, or oral corticosteroids to be taken long-term) except short-term systemic corticosteroids)
9. Latent infections such as tuberculosis, viral hepatitis, herpes viral infection and herpes zoster
10. Subjects with congestive heart failure (NYHA grades 3 and 4)
11. Subjects with a history of depression associated with suicidal ideation or behavior
12. Clinically meaningful bronchiectasis
13. Pregnancy or breast feeding, or Female subjects of childbearing potential unwilling to use effective contraception
14. Patients with known hypersensitivity to Roflumilast or rescue medication and their ingredients
15. Patients with previous Roflumilast therapy within past 3 months