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
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Chiesi Farmaceutici S.p.A.
- Enrollment
- 419
- Locations
- 68
- Primary Endpoint
- Area Under the Curve (AUC) 0-30min Standardized by Time of Change From Pre-dose in Forced Expiratory Volume in One Second (FEV1) in the Morning of Day 1
Study Overview
Brief Summary
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.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 40 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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.
- •Outpatients with a diagnosis of COPD and including:
- •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.
- •Use of bronchodilators in the previous 2 months to visit
- •Post-bronchodilator FEV1 < 60% of the predicted normal value.
- •Post-bronchodilator FEV1/FVC < 0.
- •A ≥ 5% response to a reversibility test.
- •A Baseline Dyspnoea Index (BDI) focal score less or equal than 10 (to be met also at visit 2).
- •History of no more than one COPD exacerbation in the previous 12 months (without considering the last 2 months) to visit
- •A cooperative attitude and ability to be trained to the proper use of pMDI and DPI (Accuhaler®, circular moulded plastic inhaler) inhalers.
Exclusion Criteria
- •Diagnosis of asthma or respiratory disorders (other than COPD) which could interfere with data interpretation according to the investigator's opinion.
- •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:
- •Surgical sterilization (e.g., bilateral tubal ligation, hysterectomy);
- •Hormonal contraception (implantable, patch, oral, injectable);
- •Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/cream/suppository.
- •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.
- •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.
- •Patient with narrow-angle glaucoma.
- •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.
- •Patients with COPD exacerbation (see previous at inclusion criteria no. 3) in the 2 months prior to screening and during the study period.
- •Patients requiring long term (> 12 hours daily) oxygen therapy for chronic hypoxemia.
- •Patients treated with depot corticosteroids in the 2 months preceding the visit 1 and during the run-in period.
- •Patients with known allergy, sensitivity or intolerance to sympathomimetic drugs or inhaled corticosteroids or to any of the excipients contained in the study drugs.
- •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.
- •Major surgery in the previous 3 months and during the trial which could affect patient's compliance in the study procedures (e.g. spirometry).
- •Participation in another clinical trial with an investigational drug in the 2 months preceding visit
- •Patients requiring chronic mechanical ventilation for COPD
Arms & Interventions
Foster®
Participants received 2 puffs of Foster® (beclomethasone dipropionate 100 µg plus formoterol 6 µg/unit dose) administered via a pMDI twice daily (BID), resulting in a total daily dose of beclomethasone dipropionate 400 μg plus formoterol 24 μg, for a duration of 12 weeks. To ensure blinding, participants received one inhalation of placebo matching Seretide® Accuhaler® via a inhaler BID, for a duration of 12 weeks.
Intervention: Beclomethasone Dipropionate - Formoterol (Drug)
Seretide® Accuhaler®
Participants received one inhalation of Seretide® Accuhaler® (fluticasone 500 μg plus salmeterol 50 μg/actuation) administered via inhaler, BID resulting in a total daily dose of fluticasone 1000 μg plus salmeterol 100 μg, for a duration of 12 weeks. To ensure blinding, participants receieved two puffs of placebo matching Foster® via pMDI, BID for a duration of 12 weeks.
Intervention: Fluticasone - Salmeterol (Drug)
Outcomes
Primary Outcomes
Area Under the Curve (AUC) 0-30min Standardized by Time of Change From Pre-dose in Forced Expiratory Volume in One Second (FEV1) in the Morning of Day 1
Time Frame: on Day 1 (V2)
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured using spirometry, conducted at baseline and all clinical visits. An increase in FEV1 reflects improved airway patency, while a decrease suggests worsening obstruction. Higher FEV1 values indicate better lung function. Adjusted means were reported. Assessment were implemented at pre-dose, and 5, 15 and 30 minutes post inhalation
Transition Dyspnoea Index (TDI) Score at Day 84
Time Frame: Day 84 (V5)
TDI has three domains as follows: 1. Functional impairment, which determines the impact of breathlessness on the ability to carry out activities; 2. Magnitude of task, which determines the type of task that causes breathlessness; 3. Magnitude of effort, which establishes the level of effort that results in breathlessness The TDI score ranges from -3 (major deterioration) to +3 (major improvement) for each domain. The sum of all domains yields the TDI focal score of -9 (major deterioration) to +9 (major improvement). Adjusted means were reported.
Secondary Outcomes
- AUC 0-30min Standardized by Time of Change From Pre-dose in FEV1 in the Morning of Day 84(on Day 84 (V5))
- AUC 0-30min Standardized by Time of Change From Baseline in FEV1 After Drug Inhalation in the Morning of Day 84(on Day 84 (V5))
- Change From Baseline (CFB) in Pre-dose Morning FEV1(Weeks 4, 8 and 12)
- Change From Baseline in Pre-dose Morning Forced Vital Capacity (FVC)(Weeks 4, 8 and 12)
- Change From Pre-dose in Morning FEV1 at 5, 15 and 30 Min After Drug Intake(5, 15, 30 Min post inhalation at Weeks 0 (V2) and 12 (Day 84, V5))
- Change From Baseline in Morning FEV1 at 5, 15 and 30 Min After Drug Intake(at 5, 15 and 30 mins post inhalation at Week 12 (Day 84, V5))
- Change From Pre-dose in Morning FVC at 5, 15 and 30 Min After Drug Intake(at 5, 15 and 30 min post inhalation Week 0 (V2) & Week 12 Day 84, (V5))
- Change From Baseline to Each Two-Week Period in COPD Symptom Scores(Weeks 1-2, 3-4, 5-6, 7-8, 9-10, 11-12)
- Change From Baseline to Each Two-Week Period in Percentage of COPD Symptom-Free Days(Weeks 1-2, 3-4, 5-6, 7-8, 9-10, 11-12)
- Change From Baseline to Entire Treatment Period in Percentage of COPD Symptom-Free Days(Baseline, Weeks 1 through 12)
- Change From Baseline to Each Two-Week Period in Average Use of Rescue Salbutamol Consumption(Weeks 1-2, 3-4, 5-6, 7-8, 9-10, 11-12)
- Change From Baseline to Each Two-Week Period in Percentage of Rescue Salbutamol-Free Days(Weeks 1-2, 3-4, 5-6, 7-8, 9-10, 11-12)
- Change From Baseline to Entire Treatment Period in Percentage of Rescue Salbutamol-Free Days(at week 12 (V5))
- Change From Baseline in the St George's Respiratory Questionnaire (SGRQ) Component and Total Scores(at Week 12 (V5))
- Change From Baseline in Pre-dose and in Post-dose Distance Walked (6 Minute Walking Test - 6MWT)(Week 12 (V5), pre-dose and post-dose)
- Change From Pre-dose in Post-dose Distance Walked (6MWT)(on Week 0 (Day 1, V2) and Week 12 (V5, Day 84))
- Number of Participants With COPD Exacerbations From Week 0 Through Week 12(Week 12)
- Number of Participants With Treatment Emergent Adverse Events (TEAEs)(From first dose of study drug until end of the treatment (up to 84 days))