A MULTICENTRE, RANDOMISED, DOUBLE-BLIND, ACTIVE-CONTROLLED, 3-WAY CROSS-OVER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF A FREE COMBINATION OF 3 DOSES OF CHF 5259 (GLYCOPYRROLATE) PLUS FOSTER® 100/6 µg (FIXED COMBINATION OF BECLOMETHASONE DIPROPIONATE PLUS FORMOTEROL) IN A METERED DOSE INHALER FOR THE TREATMENT OF PATIENTS WITH UNCONTROLLED ASTHMA UNDER MEDIUM DOSES OF INHALED CORTICOSTEROIDS PLUS LONG-ACTING β2-AGONISTS.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 211
- 试验地点
- 88
- 主要终点
- FEV1 AUC0-12h normalised by time on Day 42
研究概览
简要总结
Primary objective
The primary objective was to evaluate the efficacy of a free combination of CHF 5259 at 3 dose levels plus Foster® 100/6 μg in a pMDI by comparison with Foster® 100/6 μg in terms of forced expiratory volume in the first second (FEV1) area under the curve between time 0 and 12 hours (AUC0-12h) normalised by time on Day 42.
Key secondary objective
The key secondary objective was to evaluate the efficacy of the free combination CHF 5259 plus Foster® 100/6 μg by comparison with Foster® 100/6 μg in terms of peak FEV1 on Day 42.
Secondary objectives
The secondary objectives were:
- To evaluate the effect of the free combination of CHF 5259 plus Foster® 100/6 μg on other lung function parameters and on clinical outcome measures;
- To assess the safety and the tolerability of the study treatments.
详细描述
This was a dose-finding, phase II, multicentre, randomised, double-blind, active-controlled, 3-way cross-over of 6 weeks, balanced incomplete block and multiple dose study.
Since each patient serves as his/her own control, the cross-over design reduces the effect of potentially confounding variables and allows for greater statistical power with fewer subjects.
This study was designed to evaluate the efficacy of a free combination of CHF 5259 at 3 dose levels (25 μg, 50 μg or 100 μg daily) plus Foster vs. Foster alone, administered via pMDI over a 6-week treatment period in patients with uncontrolled asthma.
A total of 220 patients were targeted for randomisation to ensure that a minimum of 164 completed the study (assuming an estimated non-evaluable rate of 25%). There were 4 treatments, but as it was a cross-over incomplete block design, each patient took only 3 treatments out of 4, according to the randomisation list of sequences: A-C-B; B-D-C; C-A-D and D-B-A.
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研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •For inclusion into the study, patients were required to fulfil all of the following criteria:
- •Patient's written informed consent obtained prior to any study-related procedures;
- •Male or female patients aged ≥18;
- •Patients with uncontrolled asthma on medium doses of ICS+LABA (>500-1000 μg daily dose BDP non-extrafine or equivalent plus formoterol 24 μg or salmeterol 100 μg) at a stable dose for at least 4 weeks prior to Screening; Drug* Medium daily dose BDP non-extrafine >500 - 1000 μg BDP extrafine >250 - 500 μg Budesonide >400 - 800 μg Ciclesonide >160 - 320 μg Fluticasone >250 - 500 μg Mometasone ≥400 μg - < 800 μg
- •*In this table (adapted from GINA 2012) the recommendations for doses of inhaled glucocorticosteroids are given as "μg/day budesonide or equivalent"
- •Patients with a pre-bronchodilator FEV1 ≥40% and <80% of their predicted normal value, after appropriate wash-out from bronchodilators, at Screening and at the end of the run-in period;
- •Patients with a positive response to the reversibility test at Screening within 30 minutes after administration of 400 μg of salbutamol pMDI, defined as ΔFEV1 ≥12% and ≥200 mL over Baseline; Note: In case the reversibility threshold is not met, the test can be performed once before randomisation.
- •Patients with uncontrolled asthma evidenced by a score at the Asthma Control Questionnaire® (ACQ) ≥1.5 (criterion must be met at Screening and at the end of the run-in period);
- •Patients with a co-operative attitude and ability to be trained to correctly use the pMDI.
- •At pre-Screening visit (V0) the patient's written informed consent (criterion 1) was obtained and then at the Screening visit (V1), all the above-mentioned inclusion criteria were checked. At the Randomisation visit (Visit P1D1 [V2]), the following inclusion criteria were re-checked: 4, 6 and 7.
排除标准
- •Patients were not enrolled if one or more of the following criteria were present:
- •Inability to carry out pulmonary lung function testing, to comply with study procedures or with study treatment intake;
- •History of near fatal asthma or of a past hospitalisation for asthma in intensive care unit or of frequent exacerbations which, in the judgement of the Investigator, may have placed the patient at undue risk;
- •Hospitalisation, emergency room admission or use of systemic corticosteroids for asthma exacerbation in the 4 weeks prior to Screening visit and during the run-in period;
- •Lower respiratory tract infection in the 4 weeks before the Screening visit or during the run-in period;
- •Patients who were in therapy for gastroesophageal reflux disease (GERD) and/or patients with a medical history of GERD that led to asthma symptoms;
- •Patients with a seasonal worsening of asthma and who were not able to complete the study outside the relevant allergen season;
- •History of cystic fibrosis, bronchiectasis or alpha-1 antitrypsin deficiency, or any other significant lung disease which may have interfered with data evaluation;
- •Patients who suffered from COPD as defined by the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines;
- •Current smokers or ex-smokers with total cumulative exposure equal or more than 10 pack-years and /or having stopped smoking one year or less prior to Screening visit;
- •Any change in dose, schedule, formulation of ICS + LABAs in the 4 weeks prior to Screening visit;
- •Patients used to be or treated with inhaled long-acting antimuscarinic drugs;
- •Patients treated with anti-IgE antibodies;
- •Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS were using one or more of the following reliable methods of contraception:
- •Placement of an intra uterine device (IUD) or intra uterine system (IUS);
- •Hormonal contraception (implantable, patch, oral);
- •Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical vaults/caps) with spermicidal foam/gel/film/cream/suppository. Reliable contraception was maintained throughout the study. Pregnancy tests were performed at study entry (a serum one at Screening visit and a urine one at Screening and Randomisation visits) in all women of childbearing potential. Any postmenopausal women (physiologic menopause defined as "12 consecutive months of amenorrhea") or women permanently sterilized (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy) were allowed to be enrolled in the study.
- •Patients who have received an investigational drug within 2 months before Screening visit;
- •Patients who had clinically significant (CS) cardiovascular condition according to Investigator's judgement, such as but not limited to: congestive heart failure (New York Heart Association [NYHA] class >3), acute ischemic heart disease in the last year prior to study Screening, history of sustained cardiac arrhythmias or sustained and nonsustained cardiac arrhythmias diagnosed in the last 6 months (sustained means lasting more than 30 seconds and or ending only with external action, and or leads to hemodynamic collapse; non-sustained means > 3 beats < 30 seconds, and or ending spontaneously, and or asymptomatic), impulse conduction blocks. Similarly, patients affected by permanent or paroxysmal atrial fibrillation were not considered for enrolment;
- •An abnormal and CS 12-lead electrocardiogram (ECG) that resulted in active medical problem which may have impacted the safety of the patient according to Investigator's judgement;
- •Patients whose electrocardiogram (12-lead ECG) showed Fridericia-Corrected QTc (QTcF) >450 millisecond (ms) for males or QTcF >470 ms for females at Screening or at Randomisation visits;
- •Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that, in the opinion of the Investigator, would have prevented use of anticholinergic agents;
- •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may have increased the risk associated with study participation or study drug administration and, in the judgment of the Investigator, would have made the patient inappropriate for entry into this study, placed the patients at undue risk or potentially compromised the results or interpretation of the study;
- •Patients having received a live-attenuated virus vaccination within two weeks prior to Screening or during the run-in (inactivated influenza vaccination was acceptable provided it was not administered less than 48 hours prior to Screening);
- •Patients mentally or legally incapacitated;
- •Patients with a history of alcohol or drug abuse;
- •Patients with known intolerance/hypersensitivity or contra-indication to treatment with ß2-agonists, inhaled corticosteroids, anti-cholinergics or propellant gases/excipients;
- •Patients with major surgery in the 3 months prior to Screening visit and/or planned surgery during the trial;
- •Patients treated with non-potassium sparing diuretics (association with potassium sparing diuretics was allowed), non-selective β-blocking drugs, quinidine, quinidine-like anti arrhythmics, or any medication with a QTc prolongation potential or a history of QTc prolongation;
- •Patients treated with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants;
- •Patients who were receiving any therapy that could have interfered with the study drugs according to Investigator's opinion.
- •At the Screening visit (V1), all the above-mentioned exclusion criteria were checked. At the Randomisation visit (Visit P1D1 [V2], the following exclusion criteria were re-checked: 1, 3, 4, 5, 13, 16, 17, 19, 20, 24 and 27.
研究组 & 干预措施
Sequence A-C-B
Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block).
Treatment A (CHF 5259 12.5 μg + Foster 100/6 μg): total daily dose of GB 25 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 12.5 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.
Treatment C (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 100 μg + BDP 400 μg/FF 24 μg; Patients followed a schedule of two puffs of CHF 5259 25 μg BID and two puffs of Foster 100/6 μg BID.
Treatment B (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 50 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 25 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.
干预措施: CHF 5259 plus Foster 100/6 µg (Drug)
Sequence A-C-B
Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block).
Treatment A (CHF 5259 12.5 μg + Foster 100/6 μg): total daily dose of GB 25 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 12.5 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.
Treatment C (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 100 μg + BDP 400 μg/FF 24 μg; Patients followed a schedule of two puffs of CHF 5259 25 μg BID and two puffs of Foster 100/6 μg BID.
Treatment B (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 50 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 25 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.
干预措施: Foster 100/6 µg (four puffs BID) (Drug)
Sequence B-D-C
Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block).
Treatment B (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 50 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 25 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.
Treatment D, Foster 400 μg/24 μg (daily dose): Patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID.
Treatment C (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 100 μg + BDP 400 μg/FF 24 μg; Patients followed a schedule of two puffs of CHF 5259 25 μg BID and two puffs of Foster 100/6 μg BID.
干预措施: CHF 5259 plus Foster 100/6 µg (Drug)
Sequence B-D-C
Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block).
Treatment B (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 50 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 25 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.
Treatment D, Foster 400 μg/24 μg (daily dose): Patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID.
Treatment C (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 100 μg + BDP 400 μg/FF 24 μg; Patients followed a schedule of two puffs of CHF 5259 25 μg BID and two puffs of Foster 100/6 μg BID.
干预措施: Foster 100/6 µg (four puffs BID) (Drug)
Sequence C-A-D
Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block).
Treatment C (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 100 μg + BDP 400 μg/FF 24 μg; Patients followed a schedule of two puffs of CHF 5259 25 μg BID and two puffs of Foster 100/6 μg BID.
Treatment A (CHF 5259 12.5 μg + Foster 100/6 μg): total daily dose of GB 25 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 12.5 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.
Treatment D, Foster 400 μg/24 μg (daily dose): Patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID.
干预措施: CHF 5259 plus Foster 100/6 µg (Drug)
Sequence C-A-D
Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block).
Treatment C (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 100 μg + BDP 400 μg/FF 24 μg; Patients followed a schedule of two puffs of CHF 5259 25 μg BID and two puffs of Foster 100/6 μg BID.
Treatment A (CHF 5259 12.5 μg + Foster 100/6 μg): total daily dose of GB 25 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 12.5 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.
Treatment D, Foster 400 μg/24 μg (daily dose): Patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID.
干预措施: Foster 100/6 µg (four puffs BID) (Drug)
Sequence B-D-A
Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block).
Treatment B (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 50 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 25 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.
Treatment D, Foster 400 μg/24 μg (daily dose): Patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID.
Treatment A (CHF 5259 12.5 μg + Foster 100/6 μg): total daily dose of GB 25 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 12.5 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.
干预措施: CHF 5259 plus Foster 100/6 µg (Drug)
Sequence B-D-A
Each subject was allocated to 3 out of the 4 possible treatments performed in sequence during a cross over design (incomplete block).
Treatment B (CHF 5259 25 μg + Foster 100/6 μg): total daily dose of GB 50 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 25 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.
Treatment D, Foster 400 μg/24 μg (daily dose): Patients followed a schedule of two puffs of CHF 5259 placebo BID and two puffs of Foster 100/6 μg BID.
Treatment A (CHF 5259 12.5 μg + Foster 100/6 μg): total daily dose of GB 25 μg + BDP 400 μg/FF 24 μg; patients followed a schedule of one puff of CHF 5259 12.5 μg BID, one puff of CHF 5259 placebo BID, two puffs of Foster 100/6 μg BID.
干预措施: Foster 100/6 µg (four puffs BID) (Drug)
结局指标
主要结局
FEV1 AUC0-12h normalised by time on Day 42
时间窗: Day 42
FEV1 AUC0-12h Normalised by Time on Day 42
时间窗: Day 42
FEV1 = Forced expiratory volume in the first second. AUC0-12h = area under the curve between the time 0 and 12 hours. Post-dose FEV1 on Day 42 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h,8h, 11h30 and 12h post-study drug intake. The baseline FEV1 was the average FEV1 recorded on Day 1 at 45 and 10 minutes prior to study intake.
次要结局
- Peak FEV1 on Day 42(Day 42)
- Adverse Events and Adverse Drug Reactions(Up at Week 24 (study end))
- Change From Baseline in Peak FEV1 on Day 42(Day 42)
- FEV1 AUC0-3h Normalised by Time on Day 1(Day 1)
- FEV1 AUC0-3h Normalised by Time on Day 42(Day 42)
- Change From Baseline in FEV1 Pre-dose on Day 14(Day 14)
- Change From Baseline in FEV1 Pre-dose on Day 42(Day 42)
- Change From Baseline in Through FEV1 at 12 h Post-dose on Day 1(Day 1)
- Change From Baseline in Through FEV1 at 12 h Post-dose on Day 42(Day 42)
- Change From Baseline in Peak FEV1 on Day 1(Day 1)
- FEV1 AUC0-12h Normalised by Time on Day 1(Day 1)
- Change From Baseline in Asthma Control Questionnaire (ACQ) Total Score on Day 42(Day 42)
- Change From Baseline in Pre-dose FVC on Day 14(Day 14)
- Change From Baseline in Pre-dose FVC on Day 42(Day 42)
- Change From Baseline in Peak FVC on Day 1(Day 1)
- Change From Baseline in Peak FVC on Day 42(Day 42)
- Change From Baseline in Forced Vital Capacity (FVC) 12h Post-dose on Day 1(12h post-dose on Day 1)
- Change From Baseline in Forced Vital Capacity (FVC) at 2h Post-dose on Day 14(2h Post-dose on Day 14)
- Secondary: Change From Baseline in Forced Vital Capacity (FVC) 12h Post-dose on Day 42(12h post-dose on Day 42)
- Mean Changes From Baseline in FEV1 Percentage of Predicted Normal Value 12h Post-dose on Day 1(12h post-dose on Day 1)
- Mean Changes From Baseline in FEV1 Percentage of Predicted Normal Value 2h Post-dose on Day 14(2h post-dose on Day 14)
- Mean Changes From Baseline in FEV1 Percentage of Predicted Normal Value 12h Post-dose on Day 42(12h post-dose on Day 42)
- Average Daily Morning Peak Expiratory Flow (PEF)(From run-in (weeks 0-2±2 days) throughout the three treatment periods (Weeks 2-8, Weeks 9-15, and Weeks 16-22))
- Average Daily Evening Peak Expiratory Flow (PEF)(From run-in (weeks 0-2±2 days) throughout the three treatment periods (Weeks 2-8, Weeks 9-15, and Weeks 16-22))
- Total Average Daily Asthma Symptoms, Morning(Daily, from Screening Visit (V1, week 0) till end of the third treatment period (V10, week 22))
- Average Total Daily Asthma Symptoms, Evening(From Screening Visit (V1, week 0) till end of the third treatment period (V10, week 22))
- Percentage of Asthma Control Days During the Treatment Period(Between V1 (D1) and V3 (D42) of the 6-week treatment period)
- Average Use of Rescue Medication (Number of Puffs/Day)(Daily during run-in/wash-out & treatment periods (from V1 [week 0] to V10 [week 22]))
- Average Use of Rescue Medication (Number of Times/Day)(Daily during run-in/wash-out & treatment periods (from V1 [week 0] to V10 [week 22]))
- Number of Participants With at Least One Adverse Event (TEAE) or Adverse Drug Reaction (ADR)(Throughout the study up to Week 24 (end of study))