A multicenter, randomized, double-blind phase 3 study to evaluate tolerability and

INTERVENTION: Product Name: Roflumilast 250 µg Pharmaceutical Form: Tablet INN or Proposed INN: ROFLUMILAST CAS Number: 162401‐32‐3 Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 250‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Trade Name: Daliresp™ Product Name: Roflumilast 500 µg Pharmaceutical Form: Tablet INN or Proposed INN: ROFLUMILAST CAS Number: 162401‐32‐3 Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 500‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use CONDITION: chronic obstructive pulmonary disease (COPD) Therapeutic area: Diseases [C] ‐ Respiratory Tract Diseases [C08] PRIMARY OUTCOME: Main Objective: To evaluate discontinuation rates of roflumilast 500µg OD using an up‐titration regimen with either 250µg OD or 500µg EOD for the first 4 weeks of treatment followed by 500µg OD for 8 weeks compared with continuous treatment of 500µg OD during the entire 12‐week main period.; ; To evaluate if subjects who do not tolerate roflumilast 500µg OD have a drug exposure with 250µg roflumilast OD similar to that observed in other subjects with the 500µg OD dose. Primary end point(s): Percentage of subjects prematurely discontinuing study treatment due to any reason (during main period ie, Visit V1 to Vend). Secondary Objective: To evaluate the gastro‐intestinal tolerability of roflumilast 500µg OD with an up‐titration regimen compared with continuous treatment of 500µg OD.; To evaluate the safety, discontinuations and tolerability especially the gastro‐intestinal tolerability of roflumilast 250µg OD in subjects not tolerating the 500µg OD dose.; To evaluate the safety of roflumilast 500µg OD with an up‐titration regimen compared with continuous treatment of 500µg OD.; To evaluate the efficacy of roflumilast 500µg OD with an up‐titration regimen on lung function compared with continuous treatment of 500µg OD.; Timepoint(s) of evaluation of this end point: up to week 12 SECONDARY OUTCOME: Secondary end point(s): • Percentage of subjects with adverse events of interest to evaluate tolerability ‐ diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain (main period, V1 to Vend) ; • Change in pre‐bronchodilator FEV1 during the down‐titration period, from V0DT to VendDT ; • Percentage of subjects prematurely discontinuing study treatment due to any reason (during down‐titration period, V0DT to VendDT) ; Other secondary endpoints for this study are: ; • Change in pre‐bronchodilator FVC and pre‐bronchodilator FEV1 from V1 to V2, V3, V4 and Vend (during main period of the study) ; • To characterize the efficacy of roflumilast 250µg OD on lung function during a down‐titration period, in subjects who do not tolerate roflumilast 500µg OD ; • Change in subject‐assessed treatment satisfaction scores from V1 to V2, V3, V4 and Vend (during main period of the study) ; • To characterize subject‐assessed treatment satisfaction of roflumilast 250µg OD during a down‐titration period, in subjects who do not tolerate roflumilast 500µg OD. Timepoint(s) of evaluation of this end point: as shown in the list above, up to week 12 INCLUSION CRITERIA: 1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements. 4. The subject shows a post‐bronchodilator FEV1 of =50% of predicted. 5. The subject shows an FEV1/forced vital capacity (FVC) ratio (post‐bronchodilator) <70%. 6. The subject has at least one documented COPD exacerbation within one year prior to Screening (Visit V0). 7. The subject is on standard of care COPD maintenance treatment in 2. The subject or, when applicable, the subject’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. The subject has a history of COPD (according to GOLD 2013[1]) 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).