Asthma
Conditions
Keywords
Maintenance and Reliever Treatment, MART, Foster
Brief summary
Primary objective: The primary objective of the study was to compare the efficacy of Maintenance and Reliever Therapy (MART) with Foster® 100/6 μg (one inhalation bid) plus additional inhalations as needed, with the standard treatment of Foster® 100/6 μg (one inhalation bid) plus salbutamol 100 μg (Ventolin ®) additional inhalations as needed in not fully controlled asthmatic patients. Secondary objectives: The secondary objectives of the study were: * to evaluate the effect of treatments on lung function parameters and on other clinical outcome measures, and * to assess the safety and the tolerability of Foster® as MART.
Detailed description
This was a 48-week phase III, double-blind, randomized, 2-arm parallel group study in asthmatic patients (adults of both sexes) not fully controlled under ICS treatment. The study plan included: * A pre-screening visit (V0, 3-10 days before V1) to explain the aim of the study, to sign the informed consent form and to prepare patients for V1; * A screening visit (V1, week -2) to assess inclusion/exclusion criteria followed by a 2-week run-in period when the patients received Foster® 100/6μg, one inhalation twice a day plus salbutamol for reliever medication; * A randomization visit (V2, week 0) when patients were allocated to one of the two treatment arms: A) Foster® 100/6 μg one inhalation bid for maintenance plus additional inhalations as needed; B) Foster® 100/6 μg one inhalation bid for maintenance plus salbutamol as needed. * And subsequent visits taking place at clinics after 4 (V3), after 12 (V4), after 24 (V5), after 36 (V6) and after 48 weeks (V7) of treatment. The total study duration per participant was 50 weeks, including the 2-week run-in period, 48-week treatment phase. Salbutamol was used as a rescue medication.
Interventions
DRUGSalbutamol
Administered via a pressurized metered-dose inhaler
DRUGBeclomethasone dipropionate + Formoterol
Administered via a pressurized metered-dose inhaler
Sponsors
Chiesi Farmaceutici S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written signed and dated informed consent obtained from patient; 2. Male or female patients aged ≥ 18 years; 3. Clinical diagnosis of asthma for ≥ 6 months; 4. A positive reversibility test, defined as an increase of at least 12% and at least 200 mL from pre-dose in FEV1 30 minutes following 4 puffs (4 × 100 μg) of inhaled salbutamol pMDI. If this could not be achieved, a documented reversibility test to salbutamol within the last 6 months was acceptable for eligibility; 5. Patients who experienced at least one severe exacerbation in the 12 months before entry (but not in the last month), defined as deterioration in asthma resulting in hospitalization or emergency room treatment due to asthma worsening, or the need for systemic steroids for at least 3 days because of asthma; 6. Using inhaled corticosteroids (ICS) in monotherapy or using ICS in a fixed or free combination with long acting β2 agonists (LABA) at a constant dose (changes in doses for less than seven days were accepted) for two months before V1. * If patients were under ICS only, the daily dose had to be ≥ non-extrafine 1000 μg BDP or equivalent. * If patients were under ICS + LABA, the ICS daily dose had to be ≥ non-extrafine 500 μg BDP or equivalent. LABA were to be stopped at least 24 hours before V1. 7. Not fully controlled asthmatics (which means partly controlled or/and uncontrolled patients according to GINA guidelines 2007) (apart from asthma exacerbation criteria) in the last month before V1. Asthma control was assessed in terms of: * Daytime symptoms (more than twice a week); * Limitation of activities (any); * Nocturnal symptoms/awakening (any); * Need for rescue (more than twice a week); * Forced expiratory volume in the first second (FEV1) \< 80% predicted (or personal best, if known) on any day. Partly controlled patients were those with at least one of the above mentioned symptoms/signs in any week of the last month before V1. Uncontrolled patients were those with 3 or more features of partly controlled asthma present in any week of the last month before V1. 8. FEV1 ≥ 60% of predicted for the patient normal value; 9. Non smokers or ex-smokers (defined as those who have stopped smoking for more than one year and with a smoking history of less than 10 pack/years); Pack/year: number of cigarettes smoked per day multiplied by the number of years of smoking/20. 10. A co-operative attitude and ability to be trained to correctly use the pMDI; 11. Subjects who were willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Not fully controlled asthma (defined according to criterion No. 7) in the last week of the run-in was to be confirmed at Visit 2.
Exclusion criteria
1. Pregnant or nursing (lactating) women, where pregnancy was defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum human chorionic gonadotrophin laboratory test (\> 5 mIU/mL). Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precluded intercourse with a male partner and women whose partners had been sterilized by vasectomy or other means, unless they met the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels \> 40 mIU/mL 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); 3. Double-barrier methods (any double combination of: IUD, male or female condom, diaphragm, sponge, cervical cap). Acceptable methods of contraception could include total abstinence at the discretion of the investigator in cases where the age, career, lifestyle, or sexual orientation of the patient ensured compliance. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal were not acceptable methods of contraception. Reliable contraception should be maintained throughout the study and for 30 days after study drug discontinuation; 2. Body Mass Index (BMI) \> 34 kg/m2; 3. Patients with lower respiratory tract infections affecting the patient's asthma within 30 days of the screening visit; 4. Use of systemic steroids in the last month; 5. Patients with other lung diseases such as (but not limited to) COPD, cystic fibrosis, interstitial lung diseases or any other clinically or functionally significant lung disorder; 6. Patients who had an uncontrolled respiratory, haematological, immunologic, renal, neurologic, hepatic, endocrinal or other disease, or any condition that could, in the judgment of the investigator, represent for the patients an undue risk or that could compromise the results or interpretation of the study; 7. History or current evidence of uncontrolled heart failure, clinically relevant coronary artery disease, recent myocardial infarction, severe hypertension, uncontrolled cardiac arrhythmias; 8. Cancer or any other chronic disease with poor prognosis (less than 2 years) and /or affecting patient status; 9. Clinically relevant laboratory abnormalities such as (but not limited to) hypokaliemia (\<3.5 mEq/L), that could compromise patient's safety or compliance, interfere with evaluation, or preclude completion of the study, in the judgment of the investigator. Patients with uncontrolled diabetes, including patients with a history of serum glucose levels consistently out of the normal range (\> 140 mg/dl) or HbA1c \> 8.0%, were to be excluded from the study; 10. Patients who had an abnormal QTcF interval value in the screening visit ECG test (i.e., \> 450 msec in males or \> 470 msec in females); 11. Intolerance or contra-indication to treatment with β2-agonists and/or ICS or allergy to any component of the study treatments; 12. Patients treated with slow-release corticosteroids in the 3 months prior to screening visit; 13. Patients unlikely to comply with the study protocol or unable to understand the nature and scope of the study or the possible benefits or unwanted effects of the study treatments; 14. Patients being treated with anti-IgE antibodies; 15. Patients treated with LABA or ICS/LABA fixed combination in the 24 hours before visit 1; 16. Patients having received an investigational drug within 2 months before the screening visit; 17. Inability to comply to study procedures or to study treatment intake; 18. Inability to carry out a valid spirometry; 19. Severe asthma exacerbation in the last month before screening visit; 20. Severe asthma exacerbation during the run-in period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Number of Patients With Severe Asthma Exacerbation by Inter-visit (Measured in Weeks) | From First dose to end of each interval: 0-4, 4-12, 12-24, 24-36, 36-48 weeks | A severe asthma exacerbation was defined as asthma worsening resulting in hospitalization or emergency room treatment due to asthma worsening, or the need for systemic steroids for ≥ 3 days because of asthma. First severe asthma exacerbation occurred after the first dose of randomised study drug and within end of study was considered for the analysis. Patients without a severe asthma exacerbation or withdrawn before having it, are considered as 'censored' at the last day in the study or at the time of the withdrawal. As already anticipated in the primary endpoint, since the median time (50th percentile) and the other key percentiles (25th and 75th) were not reached, and the median time of first exacerbation is not available (N.A.), to provide meaningful information, the cumulative number of patients who experienced a severe exacerbation at the end of each time period is here reported. |
| Time to First Severe Asthma Exacerbation | From First IMP dose to week 48 (EOT) | A severe asthma exacerbation was defined as asthma worsening resulting in hospitalization or emergency room treatment due to asthma worsening, or the need for systemic steroids for ≥ 3 days because of asthma. First severe asthma exacerbation occurred after the first dose of randomised study drug and within end of study was considered for the analysis. Patients without a severe asthma exacerbation or withdrawn before having it, are considered as 'censored' at the last day in the study or at the time of the withdrawal. Since the median time (50th percentile) and the other key percentiles (25th and 75th) were not reached, the median time of first exacerbation is not available (N.A.). So, to provide meaningful information, the cumulative number of patients who experienced a severe exacerbation at the end of each time period was reported separately. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pre-Dose Forced Expiratory Volume in the First Second (FEV1) at Each Visit | Baseline, Weeks 4 (V3), 12 (V4), 24 (V5), 36 (V6), 48 (V7) | 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. |
| Change From Baseline in Pre-Dose Forced Expiratory Flow Between 25% and 75% of Vital Capacity (FEF25-75%) at Each Visit | Baseline, Weeks 4 (V3), 12 (V4), 24 (V5), 36 (V6), 48 (V7) | FEF is a lung function test and is measured using the spirometery. The FEF25%-75% is the forced expiratory flow from 25% to 75% of FVC. FEF25%-75% measurement is conducted at baseline and all clinical visits. An increase in FEF25%-75% reflects improved airway patency, while a decrease suggests worsening obstruction. Higher FEF25%-75% values indicate better lung function. Adjusted means were reported. |
| Number of Severe Asthma Exacerbations Per 100 Patients Per Year | First dose to end of the study (Up to 48 Weeks) | A severe asthma exacerbation was defined as asthma worsening, resulting in hospitalization or emergency room treatment due to asthma worsening, or the need for systemic steroids for ≥ 3 days. As per the outcome measure title, the total number of severe exacerbations (this outcome), of hospitalisations/emergency room treatment, of systemic corticosteroids use (other outcomes) is expressed as rate (events per 100 patients per year) and compared between arms. Please note that in case of two close severe asthma exacerbations (start date of a severe asthma exacerbation is less than 10 days from the stop date of the previous severe asthma exacerbation), only the first was counted for the analysis. |
| Number of Systemic Corticosteroids Courses to Treat Asthma Per 100 Patients Per Year | First dose to end of the study (Up to 48 Weeks) | Systemic corticosteroids courses to treat asthma started at or after the first dose of randomised study drug and with at least one day from the stop date of a systemic corticosteroids course and the start date of the following one have been considered for analysis. As per the outcome measure title, the total number of severe exacerbations (other outcome), of hospitalisations/emergency room treatment (other outcome), of systemic corticosteroids use (this outcome) is expressed as rate (events per 100 patients per year) and compared between arms. |
| Number of Hospitalisation/Emergency Room Treatments Due to Asthma Per 100 Patients Per Year | From first dose to end of the study (Up to Week 48) | Hospitalization or emergency room treatment due to asthma started at or after the first dose of randomised study drug was be considered for the analysis. As per the outcome measure title, the total number of severe exacerbations (another outcome), of hospitalisations/emergency room treatment (this outcome), of systemic corticosteroids use (other outcomes) is expressed as rate (events per 100 patients per year) and compared between arms. |
| Change From Baseline in Asthma Control Questionnaire (ACQ) Score to Each Visit | Week 4 (V3), Week 12 (V4), Week 24 (V5), Week 36 (V6), Week 48 (V7) | The Asthma Control Questionnaire is a tool used to asses how well a participant asthma is controlled and consists of seven questions scored. On average/in general, during the past week 0 (no impairment), 6 (maximum impairment for symptoms). 1. how often were you woken by your asthma during the night? 2. how bad were your asthma symptoms when you woke up in the morning? 3. how limited were you in your activities because of your asthma? 4. how much shortness of breath did you experience because of your asthma? 5. how much of the time did you wheeze? 6. how many puffs/inhalations of short-acting bronchodilator have you used each day? 7. FEV1 pre-bronchodilator, FEV1 predicted FEV1 % predicted (by clinical staff) The ACQ total score has been calculated as the mean of the seven question scores ranging from 0 (totally controlled) and 6 (severely uncontrolled). Higher scores indicate the worse outcomes. Adjusted means were reported. |
| Number of Mild Asthma Exacerbations Per 100 Patients / Year | From first dose through end of the study (Up to Week 48) | A mild asthma exacerbation was defined as two consecutive mild asthma exacerbation days satisfying the same criterion. In case periods satisfying different criteria overlapping, only one mild asthma exacerbation was considered. In case of two close mild asthma exacerbations (start date of a mild asthma exacerbation is less than 7 days from the stop date of the previous mild asthma exacerbation), only the first was counted for the analysis. Mild asthma exacerbations occurred at or after the first dose of randomised study drug and within end of study is considered for the analysis. As per the outcome measure title, the total number of mild asthma exacerbations is expressed as rate (events per 100 patients per year) and compared between arms. |
| Number of Mild Asthma Exacerbations: Number of Total Events | From first dose through end of the study (Up to Week 48) | A mild asthma exacerbation was defined as two consecutive mild asthma exacerbation days satisfying the same criterion. In case periods satisfying different criteria overlapping, only one mild asthma exacerbation was considered. In case of two close mild asthma exacerbations (start date of a mild asthma exacerbation is less than 7 days from the stop date of the previous mild asthma exacerbation), only the first was counted for the analysis. Total number of mild asthma exacerbation events were reported. Mild asthma exacerbations occurred at or after the first dose of randomised study drug and within end of study is considered for the analysis. . |
| Time to First Mild Asthma Exacerbation | From first dose to end of the study (Up to Week 48) | A "mild asthma exacerbation" was defined as two consecutive mild asthma exacerbation days satisfying the same criterion. In case periods satisfying different criteria overlapping, only 1 mild exacerbation was considered. In case of two close mild exacerbations (start date of a mild exacerbation is less than 7 days from the stop date of the previous mild exacerbation), only the first was counted for the analysis. First mild exacerbation occurred after the first dose of randomised study drug and within end of study is considered for the analysis. In patient with at least one mild exacerbation, the time to first mild exacerbation was calculated as the time in days between the first dose of randomised study drug (derived) and the time at which the first mild exacerbation occurs (date of the first day of the first mild exacerbation). Time to first mild asthma exacerbation (days) = (date of first day of first mild exacerbation - date of first dose of randomised study drug (derived)) +1 |
| Change From Baseline in Morning and Evening Peak Expiratory Flow (PEF) to Each Visit | Baseline, Weeks 4 (V3), 12 (V4), 24 (V5), 36 (V6), 48 (V7) | PEF is measured twice a day (morning and evening) with Spirotel, a portable electronic peak flow meter. PEF measurement recorded in the morning of the day of each clinic visit was considered as data of the period before clinic visit. During each measurement session (morning or evening before the intake of the study medication) the participant performed 3 blows and only the best PEF parameter was saved into the Spirotel memory. |
| Change From Baseline in Total Asthma Symptom Scores Measured Daily by Each Visit | Baseline, Weeks 4 (V3), 12 (V4), 24 (V5), 36 (V6), 48 (V7) | The asthma symptoms are: cough, wheeze, chest tightness and breathlessness. Each morning and evening asthma symptoms are to be scored, as respectively occurred during the night and during the day, as follows: Night-time asthma symptom score: 0 = No symptom, 1 = Mild: symptoms not causing awakening, 2 = Moderate: discomfort enough to cause awakening, 3 = Severe: causing awakening for most of the night / do not allow to sleep at all Day-time asthma symptom score: 0 = No symptom, 1 = Mild: aware of symptoms which can be easily tolerated, 2 = Moderate: discomfort enough to cause interference with daily activity, 3 = Severe: incapacitating with inability to work / take part in usual activity Total asthma symptoms score was calculated as the sum of the day-time and the night-time asthma symptoms score recorded on the following day and score ranges from 0 to 6, higher score indicates worse symptoms. |
| Number of Inhalations of Reliever Medication Per Day by Each Two-Week Period | Weeks 1-2, 3-4, 5-6, 7-8, 9-10, 11-12, 13-14, 15-16, 17-18,19-20,21-22, 23-24, 25-26, 27-28, 29-30, 31-32, 33-34, 35-36, 37-38, 39-40, 41-42, 43-44, 45-46, 47-48 | The daily use of reliever medication was calculated as sum of the number of puffs taken during the day and the number of puffs taken during the night recorded on the following day. In case one session in a day is missing, only the available session (evening or morning) was considered for the daily use of reliever medication. A minimum of seven evaluable measurements are required in each two-week treatment period and during the two-weeks of the run-in period (baseline). |
| Percentage of Asthma Symptom-free Days by Each Two-Week Period | Week 3-4, 11-12, 23-24, 35-36 and 47-48 | Asthma symptom-free days are days with the total asthma symptom score equal to zero. Percentage of asthma symptom-free days will be calculated in each two-week period using the following formula: % of asthma symptoms- free days = Number o f asthma symptoms- free days in that two - week period/Number o f days with data recorded for asthma symptom scores in that two - week period X 100. |
| Percentage of Reliever-Medication-Free Days by Each Two-Week Period | Weeks 1-2, 3-4, 5-6, 7-8, 9-10, 11-12, 13-14, 15-16, 17-18,19-20,21-22, 23-24, 25-26, 27-28, 29-30, 31-32, 33-34, 35-36, 37-38, 39-40, 41-42, 43-44, 45-46, 47-48 | A day without reliever medication is a day in which the number of puffs of reliever medication taken in the 24 hours is zero. A day will be considered as missing if both measurements (evening and morning) are missing. A day will be considered as "not-free" if one session is recorded and the other is missing. Percentage of reliever medication-free days will be calculated in each two-week period using the following formula: % of reliever medication-free days = Number of reliever medication-free days in that two -week period/Number of days with data recorded for reliever medication in that two -week period X 100 |
| Percentage of Asthma Control Days by Each Two-week Period Before Clinic Visits | Week 3-4, 11-12, 23-24, 35-36 and 47-48 | Asthma control day is a day with total asthma symptom score equal to zero and without use of reliever medication. A day will be considered as missing if both measurements (evening and morning) are missing. A day will be considered as "not control" if one session is recorded and the other is missing. Percentage of asthma control days will be calculated in each two-week period using the following formula: % of asthma control days = Number of asthma control days in that two -week period/Number of days with data recorded for asthma symptom scores and reliever medication in that two-week period X100 |
| Number of Participants With Treatment Emergent Adverse Events | From first dose of study drug until end of the study (up to 48 weeks) | 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. |
| Number of Patients Who Required > 6 Rescue Inhalations Per Day for at Least Two Consecutive Days During During Treatment Period | From first dose of study drug until end of the study (up to 48 weeks) | Use of reliever medication was derived from the data of SpirotelTM. The event "more than six reliever medications per day for two consecutive days" is defined as at least two consecutive days with more than six puffs of reliever medication in the day. |
| Change From Baseline in Daily PEF Variability to Each Visit | Baseline, Weeks 4 (V3), 12 (V4), 24 (V5), 36 (V6), 48 (V7) | PEF is measured twice a day (morning and evening) with Spirotel. PEF measurement recorded in the morning of the day of each clinic visit was considered as data of the period before clinic visit. During each measurement session (morning or evening before the intake of the study medication) the participant will perform 3 blows and only the best PEF parameter will be saved into the Spirotel memory. The variability of PEF of a day will be calculated using the Best PEF morning and the Best PEF evening recorded in the same day. Variability of PEF is measured daily with Spirotel using the following formula: Best PEF evening - Best PEF morning/Best PEF evening + Best PEF morning/2 X 100 |
Countries
Bulgaria, Croatia, Czechia, France, Germany, Italy, Poland, Romania, Russia, Serbia, Spain, Turkey (Türkiye), Ukraine, United Kingdom
Contacts
PRINCIPAL_INVESTIGATORAlberto Papi, Professor
Universita degli Studi di Ferrara
Participant flow
Recruitment details
Participants were enrolled across 183 centers in 14 countries. A total of 2079 participants were screened for eligibility, 365 participants were screen failure and 1714 of them were enrolled and randomised in this study.
Pre-assignment details
Participants entered a 2-week run-in period receiving one inhalation of Foster (beclomethasone dipropionate 100 µg plus formoterol 6 µg/unit dose) via a pressurized metered-dose inhaler (pMDI), twice daily (BID) as maintenance therapy and additional doses of Ventolin (Salbutamol, 100 μg per metered dose) as needed in response to symptoms as reliever therapy.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 47.8 Years STANDARD_DEVIATION 14.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 34 Participants |
| Race (NIH/OMB) White | 827 Participants |
| Region of Enrollment Bulgaria | 94 participants |
| Region of Enrollment Croatia | 22 participants |
| Region of Enrollment Czechia | 82 participants |
| Region of Enrollment France | 24 participants |
| Region of Enrollment Germany | 74 participants |
| Region of Enrollment Italy | 90 participants |
| Region of Enrollment Poland | 256 participants |
| Region of Enrollment Romania | 93 participants |
| Region of Enrollment Russia | 239 participants |
| Region of Enrollment Serbia | 44 participants |
| Region of Enrollment Spain | 0 participants |
| Region of Enrollment Turkey | 30 participants |
| Region of Enrollment Ukraine | 87 participants |
| Region of Enrollment United Kingdom | 1 participants |
| Sex: Female, Male Female | 1049 Participants |
| Sex: Female, Male Male | 331 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 854 | 2 / 854 |
| other Total, other adverse events | 370 / 854 | 360 / 854 |
| serious Total, serious adverse events | 32 / 854 | 41 / 854 |
Outcome results
None listed