A Study in Patients With Chronic Obstructive Pulmonary Disease

Chiesi Farmaceutici S.p.A.419 enrolled

Overview

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Inhaler CFC-free 20 μg), 1 inhalation four times daily (daily dose of 80 μg) and had any nonpermitted medication withdrawn prior to entry into test treatment period; * A randomisation visit (V2, week 0) during which patients were randomly allocated to one of the two treatment arms,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.

Study Type

INTERVENTIONAL

Eligibility

Sex: ALLMin age: 40 Years

Medical Language ↔ Plain English

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

Locations (68)

Aarhus University Hospital

Aarhus, Denmark

Bispebjerg Hospital

Copenhagen, Denmark

Dept. of Cardiology and Respiratory Medicine

Copenhagen, Denmark

Gentofte Hospital

Gentofte Municipality, Denmark

Odense University Hospital

Odense, Denmark

Centre Hospitalier

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

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

Time frame: on Day 1 (V2)

Transition Dyspnoea Index (TDI) Score at Day 84

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.

Time frame: Day 84 (V5)

Secondary Outcomes

AUC 0-30min Standardized by Time of Change From Pre-dose in FEV1 in the Morning of Day 84

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. Assessments were implemented pre-dose, 5, 15 and 30 minutes post inhalation.

Time frame: 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

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. Assessments were implemented at baseline and 5,15 and 30 minutes post inhalation.

Time frame: on Day 84 (V5)

Change From Baseline (CFB) in Pre-dose Morning FEV1

Time frame: Weeks 4, 8 and 12

Change From Baseline in Pre-dose Morning Forced Vital Capacity (FVC)

FVC is is a measure of lung function and is defined as the amount of air that can be forcefully exhaled from lungs after taking the deepest breath possible, FVC was measured using spirometry at baseline and all clinical visits. Higher values indicate improved lung capacity and reduced airway obstruction. Adjusted means were reported.

Time frame: Weeks 4, 8 and 12

Change From Pre-dose in Morning FEV1 at 5, 15 and 30 Min After Drug Intake

Time frame: 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

Time frame: 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

Time frame: 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

COPD symptom scores consists of following 6 items recorded by the participants in diary. * the ability to perform the usual daily activities; * breathlessness over the previous 24h; * waking at night due to respiratory symptoms; * breathlessness on rising; * cough over the previous 24h; * sputum production over the previous 24h. Each symptom score is recorded on a scale from 0 (no symptoms) to 3 (worst), the total score ranges from 0 (no symptoms) to 18 (worst). Baseline COPD symptom score has been calculated as the mean of the COPD symptom scores recorded in the run-in period. Each item or total scores were averaged over each 2 week period. Average COPD symptom score in each two-week period has been calculated as the mean of the item or total score recorded in each two-week period. Adjusted means were reported.

Time frame: 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

COPD symptom scores consists of following 6 items recorded by the participants in diary. * ability to perform the usual daily activities; * breathlessness over the previous 24h; * waking at night due to respiratory symptoms; * breathlessness on rising; * cough over the previous 24h; * sputum production over the previous 24h. Each symptom score is recorded on a scale from 0 (no symptoms) to 3 (worst), the total score ranges from 0 (no symptoms) to 18 (worst). A COPD symptom-free day is a day with total COPD symptom scores = 0. Baseline % of COPD symptom-free days is calculated as the % ratio between the number of COPD symptom-free days and the number of days with data recorded in the run-in period)\*100. Reported values (in form of adjusted means) reflect a percentage (%). % of COPD symptom-free days in each two-week period is calculated as % (ratio between the number of COPD symptom-free days and the number of days with data recorded in the two-week period)\*100.

Time frame: 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

COPD symptom scores consists of following 6 items recorded by the participants in diary. * ability to perform the usual daily activities; * breathlessness over the previous 24h; * waking at night due to respiratory symptoms; * breathlessness on rising; * cough over the previous 24h; * sputum production over the previous 24h. Each symptom score is recorded on a scale from 0 (no symptoms) to 3 (worst), the total score ranges from 0 (no symptoms) to 18 (worst). A COPD symptom-free day is a day with total COPD symptom scores = 0. Reported values (in form of adjusted means) reflect a percentage (%). Baseline % of COPD symptom-free days is calculated as (% ratio between the number of COPD symptom-free days and the number of days with data recorded in the run-in period)\*100. % of COPD symptom-free days in each two-week period is calculated as (% ratio between the number of COPD symptom-free days and the number of days with data recorded in the two-week period)\*100.

Time frame: Baseline, Weeks 1 through 12

Change From Baseline to Each Two-Week Period in Average Use of Rescue Salbutamol Consumption

Number of rescue salbutamol puffs per day were recorded in the diary. Baseline use of rescue medication has been calculated as the mean number of puffs per day in the run-in period. Average use of rescue medication in each two-week period has been calculated as the mean number of puffs per day in each two week period. Adjusted means were reported.

Time frame: 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

A rescue medication-free day is a day with number of puffs of rescue medication = 0. Reported values (in form of adjusted means) reflect a percentage (%). Baseline percentage (%) of rescue medication-free days is calculated as (% ratio between the number of rescue medication-free days and the number of days with data recorded in the run-in period)\*100. % of rescue medication-free days in each two-week period is calculated as (% ratio between the number of rescue medication-free days and the number of days with data recorded in the two-week period)\*100.

Time frame: 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

A rescue medication-free day is a day with number of puffs of rescue medication = 0. Reported values (in form of adjusted means) reflect a percentage (%). Baseline % of rescue medication-free days is calculated as (% ratio between the number of rescue medication-free days and the number of days with data recorded in the run-in period)\*100. % of rescue medication-free days in the entire treatment period is calculated as (% ratio between the number of rescue medication-free days and the number of days with data recorded in the entire treatment period)\*100.

Time frame: at week 12 (V5)

Change From Baseline in the St George's Respiratory Questionnaire (SGRQ) Component and Total Scores

SGRQ is a 76-item questionnaire developed to measure health in chronic airflow limitation and designed to be self-completed by the participant. It consists of 76-items across three domains: * Symptoms, which evaluates the frequency and severity of respiratory issues like coughing, sputum production, and breathlessness; * Activity, which measures limitations in physical activities due to breathlessness; * Impacts, which examines psychological and social effects, including feelings of stigma, loss of control, and daily life disruption. Each domain score ranges from 0 to 100 with higher scores indicating the worst health status. Total score was obtained by combining the weighted scores from each domain and ranging from 0 (better health) to 100 (Worst health).

Time frame: at Week 12 (V5)

Change From Baseline in Pre-dose and in Post-dose Distance Walked (6 Minute Walking Test - 6MWT)

The 6MWT was carried out following standardized procedures, according to ATS guidelines. The test was performed indoors, along a long, flat, straight, 30m-long corridor, and one well-trained researcher supervised the test. Prior to start walking, patients were explained that the aim of the test was to walk from end to end along the corridor and to cover as much distance as possible in the period of 6 minutes. The patients sit at rest for at least 10 minutes before the test start. The longer distance covered, the better the outcome.

Time frame: Week 12 (V5), pre-dose and post-dose

Change From Pre-dose in Post-dose Distance Walked (6MWT)

Time frame: on Week 0 (Day 1, V2) and Week 12 (V5, Day 84)

Number of Participants With COPD Exacerbations From Week 0 Through Week 12

A COPD exacerbation is defined as "a sustained worsening of the participants condition (dyspnoea, cough and/or sputum production/purulence), from the stable state and beyond normal day-to-day variations, that is acute in onset and requires unscheduled medical intervention \[leading to prescriptions of systemic corticosteroids (at least 3 days)\] and/or antibiotics (at least 5 days), or need for a visit to an emergency department or hospitalization) in a participant with underlying COPD".

Time frame: Week 12

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

AE=An untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine. Serious AE= An adverse event that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect. ADR=A response to a medicinal product which is harmful and unintended. Response in this context means that a causal relationship between the medicinal product and an adverse event is at least a reasonable possibility Serious ADR=An adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect. Severe AE= "Severe" refers to the intensity of an AE; the event itself may be of relatively minor medical significance but intense.

Time frame: From first dose of study drug until end of the treatment (up to 84 days)

A Study in Patients With Chronic Obstructive Pulmonary Disease

Overview

Conditions

Interventions

Eligibility

Locations (68)

Outcomes

Primary Outcomes

Secondary Outcomes