A Study in Patients With Chronic Obstructive Pulmonary Disease

A 12-week, Multicentre, Multinational, Randomized, Double-blind, Double-dummy, 2-arm Parallel Group Study Comparing the Efficacy and Safety of Foster® 100/6 (Beclomethasone Dipropionate 100 µg Plus Formoterol 6 µg/Actuation), 2 Puffs b.i.d., Versus Seretide® 500/50 (Fluticasone 500 µg Plus Salmeterol 50 µg/Actuation), 1 Inhalation b.i.d., in Patients With Chronic Obstructive Pulmonary Disease

The primary objective of the study was to demonstrate the superiority of Foster® 100/6 (two puffs b.i.d.) versus Seretide® 500/50 (one inhalation b.i.d.), in terms of pulmonary function (AUC0-30min standardized by time of change from pre-dose in FEV1) after drug inhalation in the morning of day 1, and the equivalence between Foster® 100/6 (two puffs b.i.d.) and Seretide® 500/50 (one inhalation b.i.d.) in terms of Transition Dyspnoea Index (TDI) score at day 84 in patients with COPD.

The secondary objectives of the study were:

• To evaluate the efficacy of the test treatments in terms of additional spirometric parameters and of clinical outcome measures;
• To assess the safety and tolerability;
• To perform an exploratory analysis evaluating the consumption of resources deriving from COPD management in the perspective of the Healthcare System.

This was a phase IIIb, multicentre, multinational, randomized, double-blind, double-dummy, 2-arm parallel group design preceded by a 2-week run-in period in patients with COPD. The study compared the efficacy and safety of Foster® 100/6 (two puffs b.i.d.) versus Seretide® 500/50 (one inhalation b.i.d.), over a 12-week treatment period.

The study plan included:

• A pre-screening visit (V0, at week -3 days before the randomization visit) during which clinical instructions to determine patients' adaptability to the study procedures were given. This could be done only after the participants agreed to participate and signed the Informed Consent form;
• A screening visit (V1, week -2) in which patients with COPD were selected;
• A run-in period, lasting from a minimum of 12 to a maximum of 16 days, where patients received a standardised treatment with inhaled aerosol ipratropium bromide (Atrovent® Inhaler CFC-free 20 μg), 1 inhalation four times daily (daily dose of 80 μg) and had any nonpermitted medication withdrawn prior to entry into test treatment period;
• A randomisation visit (V2, week 0) during which patients were randomly allocated to one of the two treatment arms, and subsequent visits taking place at clinics after 4 (V3), after 8 (V4) and after 12 weeks (V5) of treatment. The end of the trial was defined as the last visit of the last subject on the trial. After 7-10 days of last study medication intake, a follow-up phone contact to document and treat adverse events that might possibly occur was performed.

The total study duration per participant was 16 weeks, including the 2-week run-in period, 12-week treatment phase, and 7-10 days of follow-up.

Salbutamol was used as a rescue medication.

Inclusion Criteria:

1. Male or female patients aged ≥ 40 years, who have signed an Informed Consent form prior to initiation of any study-related procedure or once applicable written informed consent obtained by legal representative.

2. Outpatients with a diagnosis of COPD and including:

   1. Smoking history of at least 10 pack years defined as [(number of cigarettes smoked per day) x (number of years of smoking) / 20], both current and ex-smokers are eligible.
   2. Use of bronchodilators in the previous 2 months to visit 1.
   3. Post-bronchodilator FEV1 < 60% of the predicted normal value.
   4. Post-bronchodilator FEV1/FVC < 0.7.
   5. A ≥ 5% response to a reversibility test.
   6. A Baseline Dyspnoea Index (BDI) focal score less or equal than 10 (to be met also at visit 2).

3. History of no more than one COPD exacerbation in the previous 12 months (without considering the last 2 months) to visit 1.

4. A cooperative attitude and ability to be trained to the proper use of pMDI and DPI (Accuhaler®, circular moulded plastic inhaler) inhalers.

Main Exclusion Criteria:

1. Diagnosis of asthma or respiratory disorders (other than COPD) which could interfere with data interpretation according to the investigator's opinion.

2. Pregnant or lactating women. Females of childbearing potential without an efficient contraception UNLESS they met the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or were using 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 (e.g. nuns). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal were not acceptable methods of contraception. Reliable contraception should have been maintained throughout the study and for 30 days after study drug discontinuation.

3. Clinical or functional unstable concurrent disease: e.g. hyperthyroidism, diabetes mellitus or other endocrine disease; significant hepatic impairment; significant renal impairment; cardiovascular disease (e.g. uncontrolled coronary artery disease, hypertension, heart failure); gastrointestinal disease (e.g. active peptic ulcer); neurological disease; haematological disease; autoimmune disorders, or other which could impact the evaluation of the results of the study according to investigator's judgement.

4. Patient with narrow-angle glaucoma.

5. Clinically significant laboratory and ECG abnormalities indicating a significant or unstable concomitant disease which could impact the evaluation of the results of the study and the safety of the patient according to investigator's judgement.

6. Patients with COPD exacerbation (see previous at inclusion criteria no. 3) in the 2 months prior to screening and during the study period.

7. Patients requiring long term (> 12 hours daily) oxygen therapy for chronic hypoxemia.

8. Patients treated with depot corticosteroids in the 2 months preceding the visit 1 and during the run-in period.

9. Patients with known allergy, sensitivity or intolerance to sympathomimetic drugs or inhaled corticosteroids or to any of the excipients contained in the study drugs.

10. Patients who had evidence of alcohol or drug abuse, who were not compliant with the study protocol or not compliant with the study treatments according to investigator's judgement.

11. Major surgery in the previous 3 months and during the trial which could affect patient's compliance in the study procedures (e.g. spirometry).

12. Participation in another clinical trial with an investigational drug in the 2 months preceding visit 1.

13. Patients requiring chronic mechanical ventilation for COPD