Study to investigate the effects of symptom-driven maintenance and reliever therapy in COPD.

Rationale: Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide and its morbidity and mortality are still rising. A symptom-driven maintenance and reliever therapy (SMART) with budesonide/formoterol is a frequently used treatment strategy in asthma. Several studies have shown that the SMART approach effectively reduces the number of asthma exacerbations when compared to a fixed maintenance dose of, e.g. fluticasone/salmeterol. In addition, larger improvements in lung function and symptoms have been observed in asthma patients with the SMART approach. Thus far, no studies have investigated the efficacy of the SMART approach in patients with COPD. The investigators hypothesize that SMART treatment with budesonide/formoterol will be more effective than fluticasone/salmeterol fixed dose treatment in COPD.

Objective: This research proposal aims to investigate the efficacy of the SMART approach with budesonide/fomoterol versus fixed dose treatment with fluticasone/salmeterol in patients with COPD.

Study design: This will be a randomized, parallel 2-arm, open-label, multi-centre study.

Study population: A total of 260 COPD patients will be included with a smoking history of >10 pack years, an FEV1 <80% predicted either or not using inhaled corticosteroids and having had at least one COPD exacerbation during the 2 years prior to inclusion.

Intervention: COPD patients will be randomized to one of the following two treatment groups:

A: One year Spiromax® budesonide/formoterol 160/4.5 μg two inhalations twice daily + Spiromax® budesonide/formoterol 160/4.5 μg as needed with a maximum of 8 inhalations daily.

B: One year Diskus® fluticasone/salmeterol 500/50 μg one inhalation twice daily + salbutamol 100 μg as needed with a maximum of 8 inhalations daily.

Main study endpoints/objectives: The primary endpoint is the reduction in number of COPD exacerbations requiring treatment with oral prednisolone).

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: This study has no specific benefits for the participating patients. The study also has no major risks. Minor risks for participants in this study are:

• Nasal epithelium collection may cause a temporary nose bleed.
• Blood collection may cause bruising.
• All drugs may cause side effects. The combination treatments with an inhaled corticosteroid and long-acting β2-agonist: budesonide/formoterol and fluticasone/salmeterol are medicinal products that have been on the market for many years in many countries and they are often prescribed both in asthma and COPD.

Inclusion Criteria:

• Age between 40 and 80 years
• Smoking history of > 10 pack years
• COPD patients with an FEV1 < 80% predicted either or not using inhaled corticosteroids.
• At least one COPD exacerbation for which oral prednisolone had to be prescribed during 2 years prior to inclusion in the study

Exclusion Criteria:

• History of asthma.

• Exacerbation or respiratory tract infection during the last 4 weeks prior to randomization.

• Females of childbearing potential without an efficient contraception unless they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH >40 mIU/mL or the use of one or more of the following acceptable methods of contraception:

  1. Surgical sterilization (e.g. bilateral tubal ligation, hysterectomy).
  2. Hormonal contraception (implantable, patch, oral, injectable).
  3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/cream/suppository.
  4. Continuous abstinence.

• Periodic abstinence (e.g. calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Reliable contraception should be maintained throughout the study and for 30 days after study drug discontinuation.