A 24-week, Double Blind, Double Dummy, Randomized, Multicentre, 2-arm Parallel Group, Active Controlled Clinical Trial of Fixed Combination of Beclometasone Dipropionate Plus Formoterol Fumarate Administered Via pMDI (CHF 1535) Versus the Fixed Combination of Budesonide Plus Formoterol Fumarate (Symbicort® Turbohaler®) in Patients With Chronic Obstructive Pulmonary Disease
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 750
- 试验地点
- 53
- 主要终点
- Demonstration of the non-inferiority of CHF 1535 pMDI versus Symbicort® Turbohaler® in terms of pulmonary function
研究概览
简要总结
Primary Objective
To demonstrate that CHF 1535 pMDI is non-inferior to Symbicort® Turbohaler® in terms of pulmonary function (change from baseline in pre-dose morning FEV1 at Week 24) in patients with COPD.
Secondary Objectives
- To evaluate the effect of CHF 1535 pMDI on other lung function parameters, and patient reported outcomes (PROs);
- To assess the safety and the tolerability of the study treatments.
详细描述
This was a Phase III, multicenter, randomized, double-blind, double-dummy, active-controlled, 2-arm parallel-group study designed to evaluate the non-inferiority of CHF 1535 100/6 µg pMDI (400/24 µg/day) versus Symbicort® Turbohaler® 160/4.5 µg (640/18 µg/day) in patients with moderate-to-severe Chronic Obstructive Pulmonary Disease (COPD).
The study included the following phases:
- Screening and Run-in Phase (Visit 1, Weeks -6 to 0): Patients underwent eligibility assessments, including spirometry and medical history review. Eligible participants entered a 6-week open-label run-in period with Symbicort® Turbohaler® 160/4.5 µg (640/18 µg/day) to establish baseline parameters and standardize therapy before randomization.
- Randomization Phase (Visit 2, Week 0): Patients meeting eligibility criteria were randomized in a 1:1 ratio to receive either CHF 1535 100/6 µg pMDI (400/24 µg/day) or Symbicort® Turbohaler® 160/4.5 µg (640/18 µg/day) for 24 weeks. Randomization was performed via an Interactive Web Response System (IWRS) to ensure balanced treatment allocation.
- Investigational Phase (Treatment Period: Weeks 0-24): Patients attended scheduled visits at Weeks 4, 12, 18, and 24 to assess treatment efficacy and safety. Daily assessments included pre-dose morning Peak Expiratory Flow (PEF), rescue medication use, and COPD symptom scores, recorded using an electronic diary. At each visit, lung function (FEV1, FVC, IC, and PEF), COPD symptom scores, and rescue medication use were evaluated. Vital signs (heart rate, blood pressure), adverse events (AEs), serious adverse events (SAEs), and laboratory assessments were monitored throughout the study.
- Follow-Up Phase: A safety follow-up phone call was conducted 7-14 days after the final visit (Week 24) or early termination to assess any unresolved adverse events (AEs) or newly reported concomitant medications.
The total study duration per participant was 30 weeks, including the 6-week run-in period, 24-week treatment phase, and follow-up assessment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 40 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients had to meet all of the following criteria to be eligible for enrolment into the study:
- •Male and female adults aged ≥40 years, of Chinese ethnicity with written informed consent prior to any study-related procedure;
- •Patients with a diagnosis of COPD (according to the GOLD document [1], updated 2017) at least 12 months before the screening visit;
- •A smoking history of at least 10 pack-years [pack-years = (number of cigarettes per day x number of years)/20]. Current and ex-smokers were eligible; Note: Smoking cessation therapy had to be completed 6 months prior to screening visit;
- •A post-bronchodilator FEV1 <50% of the predicted normal value and a post-bronchodilator FEV1/FVC ratio <0.7, 10 to 15 minutes after 4 puffs (4 x 100 µg) of salbutamol pMDI; Note: If this criterion was not met at screening, the test could be repeated no more than 7 days before the randomisation visit;
- •A documented history of at least one exacerbation in the 12 months preceding the screening visit. COPD exacerbation was defined according to the following: "A sustained worsening of the patient's 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 necessitates a change in regular medication in a patient with underlying COPD that includes prescriptions of systemic corticosteroids and/or antibiotics or need for hospitalisation";
- •Patients in treatment for at least 2 months prior to screening with either:
- •ICS/LABA; or
- •ICS/LAMA; or
- •Inhaled LABA and inhaled LAMA; or
- •LABA; Note: Triple therapy was not allowed 2 months before the screening visit;
- •A cooperative attitude and ability to be trained to use correctly the study treatment inhalers (pMDI and Turbohaler®);
- •A cooperative attitude and ability to be trained to use correctly the COPD questionnaires.
排除标准
- •Patients requiring use of the following medications:
- •Systemic steroids for COPD exacerbation in the 4 weeks prior to screening;
- •A course of antibiotics for COPD exacerbation longer than 7 days in the 4 weeks prior to screening;
- •Phosphodiesterase (PDE) inhibitors in the 4 weeks prior to screening;
- •Use of antibiotics for a lower respiratory tract infection (e.g. pneumonia) in the 4 weeks prior to screening;
- •COPD exacerbation requiring prescriptions of systemic corticosteroids and/or antibiotics or hospitalization during the run-in period;
- •Changes in dose, schedule, formulation or product of oral xanthine derivatives (e.g. theophylline) in the month prior to the screening visit or during the run-in period. Stop of xanthines prior to the screening visit was allowed;
- •Known respiratory disorders other than COPD which may have impacted the efficacy of the study treatment according to the Investigator's judgement. This could have included, but was not limited to, α-1 antitrypsin deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial lung disease;
- •Diagnosis of asthma, history of allergic rhinitis or atopy (atopy which may have risen contra-indications or impacted the efficacy of the study according to the Investigator's judgement);
- •Patients treated with long-acting antihistamines (e.g. astemizole, terfenadine) unless taken at stable regimen at least 2 months prior to screening and maintained constant during the study, or if taken as required (PRN);
- •Patients requiring long-term (at least 12 hours daily) oxygen therapy for chronic hypoxemia;
- •History of hypersensitivity to β2-agonists, corticosteroids or any of the excipients contained in any of the formulations used in the study;
- •Patients treated with non-cardioselective β-blockers in the 4 weeks preceding the screening visit or during the run-in period;
- •Patients who had a clinically significant (CS) active cardiovascular condition (such as, but not limited to, unstable ischemic heart disease, New York Heart Association [NYHA] Class III/IV, left ventricular failure, acute myocardial infarction, advanced atrio-ventricular conduction blocks);
- •Patients with atrial fibrillation:
- •Paroxysmal (i.e. intermittent);
- •Persistent as defined by continuous atrial fibrillation diagnosed for less than 6 months;
- •Persistent for at least 6 months with a resting ventricular rate ≥100/minute controlled with a rate control strategy (i.e. selective β-blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy);
- •An abnormal and CS 12-lead ECG that resulted in an active medical problem which may have impacted the safety of the patient or showed Fridericia-corrected QT interval (QTcF) >450 ms for males or QTcF >470 ms for females;
- •Unstable concurrent disease: e.g. uncontrolled hyperthyroidism, uncontrolled diabetes mellitus or other endocrine disease; uncontrolled gastrointestinal disease (e.g. active peptic ulcer); neurological disease; uncontrolled haematological disease; uncontrolled autoimmune disorders, significant hepatic impairment, significant renal impairment or other which may impact the feasibility of the results of the study according to the Investigator's judgment;
- •CS laboratory abnormalities indicating a significant or unstable concomitant disease which may have impacted the efficacy or the safety of the study treatment according to the Investigator's judgment;
- •Patients with serum potassium levels <3.5 mEq/L (or 3.5 mmol/L);
- •History of alcohol abuse and/or substance/drug abuse within 12 months prior to the screening visit;
- •Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS they were using one or more of the following highly effective contraceptive measures:
- •Placement of an intrauterine device or intrauterine hormone-releasing system;
- •Combined (oestrogen and progesterone-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal);
- •Progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable);
- •Bilateral tubal occlusion;
- •Vasectomised partner; Reliable contraception had to be maintained throughout the study; Any postmenopausal women (physiologic menopause defined as "12 consecutive months of amenorrhea without an alternative medical cause") or women permanently sterilised (e.g. bilateral oophorectomy, hysterectomy or bilateral salpingectomy) could be enrolled in the study; Pregnancy tests were performed at study entry (a serum test at the screening visit and a urine test at screening and randomisation visits) in all women of childbearing potential;
- •Participation in an interventional clinical trial with intake of the last dose of any investigational drug <12 weeks preceding baseline visit (last dose <5 half-lives prior to baseline visit for biologics).
研究组 & 干预措施
CHF 1535 100/6 µg pMDI
The experimental arm included 377 patients who received CHF 1535, a fixed-dose combination of beclometasone dipropionate (100 µg) and formoterol fumarate (6 µg). The treatment was administered as two inhalations twice daily (b.i.d.) via a pressurized metered-dose inhaler (pMDI), resulting in a total daily dose of 400 µg of beclometasone dipropionate and 24 µg of formoterol fumarate. During the initial 4-week run-in phase, patients in this group were treated with Symbicort® Turbohaler® 160/4.5 µg, administered as two inhalations b.i.d., to stabilize their clinical condition. After this period, patients transitioned to the randomized treatment phase, where they received CHF 1535 for 24 weeks.
To ensure blinding, the study employed a double-dummy design. Patients in the CHF 1535 group were also given a placebo Turbohaler®, while those in the Symbicort® group received a placebo pMDI, with both placebos administered as two inhalations b.i.d.
干预措施: CHF 1535 100/6 µg pMDI plus Symbicort® Turbohaler® Placebo (Drug)
Symbicort® Turbohaler®
The active comparator arm involved 373 patients treated with Symbicort® Turbohaler®, a fixed-dose combination of budesonide (160 µg) and formoterol fumarate (4.5 µg). Treatment in this group also involved two inhalations b.i.d., administered via a dry powder inhaler (Turbohaler®), providing a total daily dose of 640 µg of budesonide and 18 µg of formoterol fumarate. Similar to the experimental arm, these patients underwent a 4-week run-in phase with Symbicort® Turbohaler® 160/4.5 µg, followed by 24 weeks of randomized treatment with the same drug.
To ensure blinding, the study employed a double-dummy design. Patients in the CHF 1535 group were also given a placebo Turbohaler®, while those in the Symbicort® group received a placebo pMDI, with both placebos administered as two inhalations b.i.d.
干预措施: Symbicort® Turbohaler® plus CHF 1535 pMDI Placebo (Drug)
结局指标
主要结局
Demonstration of the non-inferiority of CHF 1535 pMDI versus Symbicort® Turbohaler® in terms of pulmonary function
时间窗: At week 24
Change from baseline in pre-dose morning First Expiratory Volume in 1 second (FEV1) in patients with Chronic Obstructive Pulmonary Disease (COPD)
次要结局
- Effect of CHF 1535 on change from baseline pre-dose morning FEV1(At week 4, week 12, week 18 and week 24)
- Effect of CHF 1535 on chnage from Baseline in pre-dose morning Force Vital Capacity (FVC)(At week 4, week 12, week 18 and week 24)
- Effect of CHF 1535 on change from baseline in the St. George's Respiratory Questionnaire (SGRQ) total scores and domains(At week 12, week 24)
- Effect of CHF 1535 on the rate of COPD exacerbations(Over 24 weeks of treatment)
- Number of subjects with abnormal Electrocardiogram (ECG) findings(At screening visit and week 24)
- Number of subjects with abnormal Haematology parameters(At screening visit and week 24)
- Effect of CHF 1535 on change from baseline in COPD Assessment Test (CAT)(Over 28 weeks)
- Assessment of blood pressure(Over 28 weeks (from Visit 1 to Visit 6))
- Number of patients with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)(Over 29 weeks (from Visit 0 to Visit 6))
- Number of subjects with abnormal Blood Chemistry parameters(At screening visit and week 24)