A 24-week, Double Blind, Double Dummy, Randomized, Multinational, Multicentre, 2-arm Parallel Group,Active Controlled Clinical Trial of Fixed Combination of Beclometasone Dipropionate Plus Formoterol Fumarate Plus Glycopyrronium Bromide Administered Via pMDI (CHF 5993) Versus the Fixed Combination of Budesonide Plus Formoterol Fumarate (Symbicort® Turbuhaler®) in Patients With Chronic Obstructive Pulmonary Disease
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 708
- 试验地点
- 64
- 主要终点
- Change From Baseline in Pre-dose Forced Expiratory Volume Within the First Second (FEV1) at Week 24
研究概览
简要总结
Primary Objective
• To demonstrate the superiority of CHF 5993 pressurised metered dose inhaler (pMDI) over Symbicort® Turbuhaler® in terms of pulmonary function (change from baseline in pre-dose morning forced expiratory volume in the first second of a forced vital capacity manoeuvre [FEV1] and 2-hour post-dose morning FEV1 at Week 24).
Secondary Objectives
Key secondary objective:
• To demonstrate the superiority of CHF 5993 pMDI over Symbicort® Turbuhaler® in terms of pulmonary function (change from baseline in pre-dose morning FEV1 and 2-hour post-dose morning FEV1 at Week 24) in the subgroup of Chinese population.
Other secondary objectives:
- To evaluate the effect of CHF 5993 pMDI on other lung function parameters, patient's health status and clinical outcome measures;
- To collect data in order to assess the impact of study treatments on health economic outcomes;
- To assess the safety and the tolerability of the study treatments.
详细描述
This was a phase III, 24-week, randomised, double-blind, double-dummy, Multinational (China, South Korea, Taiwan), Multicentre, 2-arm parallel-group, active-controlled study in patients with COPD.
The study was designed to demonstrate the superiority of CHF 5993 pMDI over budesonide/formoterol in terms of pulmonary function (change from baseline in pre-dose morning FEV1 and 2-hour post-dose morning FEV1 at Week 24), both in the overall study population and in the Chinese population. The study lasted approximately 27 weeks for each patient, and a total of 7 clinic visits (Visit [V] 0 to V6) were performed during the study, plus a follow-up phone call.
A pre-screening visit (Visit [V] 0) was planned to occur no more than 7 days before a screening visit (V1, Week -2), followed by a 2-week open-label run-in period on Symbicort® Turbuhaler® (budesonide/formoterol fumarate [FF] 160/4.5 μg per inhalation), 2 inhalations twice daily (BID) (total daily dose: 640/18 μg budesonide/FF). The 2-week run-in period was deemed sufficient in order to 'standardise' the target population on the same treatment (Symbicort® Turbuhaler® [budesonide/FF 160/4.5 μg per inhalation]) prior to randomisation to study treatments, without leading to a deterioration in the disease.
At the randomisation visit (V2, Week 0), patients were randomised in a 1:1 ratio to one of the following two treatments for 24 weeks:
- CHF 5993 pMDI, 2 inhalations BID (total daily dose: 400/24/50 μg beclometasone dipropionate [BDP]/FF/glycopyrronium bromide [GB]);
- Symbicort® Turbuhaler®, 2 inhalations BID (total daily dose: 640/18 μg budesonide/FF).
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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 inclusion criteria to be eligible for enrolment into the study:
- •Male and female adults aged ≥ 40 years with written informed consent obtained prior to any study-related procedure;
- •Patients with a diagnosis of COPD (according to GOLD 2015 strategic document, updated January 2015) 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 at least 10-15 mins after 4 puffs (4 x 100 μg) of salbutamol pMDI;
- •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 under therapy for at least 2 months prior to screening with either:
- •ICS/LABA or
- •ICS/LAMA or
- •Inhaled LABA and inhaled LAMA or
- •A cooperative attitude and ability to be trained to use correctly the study treatment inhalers (pMDI and Turbuhaler®);
- •A cooperative attitude and ability to be trained to use correctly the COPD questionnaires.
- •All inclusion criteria were checked at screening (V1, Week -2). If criterion #4 was not met at V1, the test could be repeated once before the randomisation visit (V2, Week 0). Inclusion criteria #7 and #8 were to be re-checked at the randomisation visit (V2, Week 0).
排除标准
- •If a patient met any of the following criteria, he/she was not enrolled into the study:
- •Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS are willing to use one or more of the following reliable methods of contraception:
- •Placement of an intrauterine device or intrauterine system;
- •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;
- •Male sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). Reliable contraception had to be maintained throughout the study until last study visit. "True abstinence" was acceptable only if it was in line with the preferred and usual lifestyle of the patient. Pregnancy testing was carried out during the course of the study in all women of childbearing potential: serum pregnancy test was performed at screening (V1) and end of treatment (V6); and urine pregnancy test was performed at all visits except V0 and V
- •Any postmenopausal women (physiologic menopause defined as "12 consecutive months of amenorrhea") or women permanently sterilised (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy) could have been enrolled in the study;
- •Diagnosis of asthma, history of allergic rhinitis or atopy (atopy which may raise contra-indications or impact the efficacy of the study according to Investigator's judgement);
- •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 E (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 hospitalisation during the run-in period;
- •Changes in dose, schedule, formulation or product of oral xanthine derivatives (e.g. theophylline) in the month prior to screening visit or during the run-in period. Stop of xanthines prior to screening visit was allowed;
- •Patients treated with non-cardioselective β-blockers in the week preceding the screening visit or during the run-in period;
- •Patients treated with long-acting antihistamines (e.g. astemizole, terfenadine) unless taken at stable regimen at least 2 months prior to screening and to be maintained constant during the study, or if taken as required (PRN);
- •Patients requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxaemia;
- •Known respiratory disorders other than COPD which may impact the efficacy of the study treatment according to the Investigator's judgement. This can include but is not limited to alfa-1 antitrypsin deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial lung disease;
- •Patients who had a clinically significant (CS) cardiovascular condition (such as but not limited to unstable ischaemic 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 (AF):
- •Paroxysmal (i.e. intermittent);
- •Persistent as defined by continuous AF 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 results in an active medical problem which may impact the safety of the patient according to Investigator's judgement. Patients whose ECG (12 lead) showed Fridericia-corrected QT interval (QTcF) > 450 ms for males or QTcF > 470 ms for females at screening and at randomisation visits were not eligible.
- •Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that in the opinion of the Investigator would prevent use of anticholinergic agents;
- •History of hypersensitivity to M3 antagonists, β2-agonist, corticosteroids or any of the excipients contained in any of the formulations used in the trial;
- •Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the efficacy or the safety of the study treatment according to Investigator's judgement;
- •Patients with serum potassium levels < 3.5 mEq/L (or 3.5 mmol/L) at screening;
- •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, or other which may impact the feasibility of the results of the study according to Investigator's judgement;
- •History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening visit;
- •Participation in another clinical trial where investigation drug was received less than 8 weeks prior to screening visit;
- •Patients treated with Traditional Chinese Medicines used for respiratory diseases.
- •All exclusion criteria except for criterion #4 were checked at screening (V1, Week -2).
- •The following exclusion criteria were to be re-checked at the randomisation visit (V2, Week 0): #1,
- •#4, #5, #6, #7, #10, #11, #12, #17, and #
- •For patients in South Korea (only), the following were added to the South Korea-specific protocol (version 3.0):
- •For exclusion criterion #14, it was additionally specified that patients with a history of lactose intolerance were to be excluded;
- •For exclusion criterion #17, it was additionally specified that patients with a known history of hypersensitivity to sympathomimetic amine were to be excluded;
- •An additional exclusion criterion (#21) was specified for patients with a known history of hypertrophic cardiomyopathy.
研究组 & 干预措施
CHF 5993 100/6/12.5 µg
Fixed combination of extrafine beclometasone dipropionate 100 µg plus formoterol fumarate 6 µg plus glycopyrronium bromide 12.5 µg (BDP/FF/GB), 2 inhalations bid, for a total daily dose of 400/24/50 μg BDP/FF/GB respectively, administered via pMDI.
If patients were used to inhaling their pMDI COPD medications with a spacer device, the AeroChamber PlusTM was used with the study pMDI treatments, dispensed to the patients at V2 (Week 0) and V4 (Week 12).
干预措施: CHF 5993 100/6/12.5 µg (Drug)
Symbicort Turbuhaler 160/4.5 µg
Fixed combination of 160 µg budesonide (BUD) + 4.5 µg formoterol fumarate (FF), 2 inhalations a day, for a total daily dose of 640/18 μg BUD/FF respectively, administered via dry powder inhaler (DPI).
干预措施: 160 µg budesonide + 4.5 µg formoterol fumarate (Drug)
结局指标
主要结局
Change From Baseline in Pre-dose Forced Expiratory Volume Within the First Second (FEV1) at Week 24
时间窗: Week 24 (Visit 6)
FEV1 measures the amount, or volume, exhaled by a patient in the first second of the expiration after a full inspiration. The lower the values, more severe the airflow limitation. For FEV1, the highest value from 3 technically acceptable attempts was recorded irrespective of the curve they were derived from. The chosen highest value had not to exceed the second highest by more than 150 mL; if the difference was larger, up to 8 measurements were performed and the largest value reported. Please note that the adjusted mean is reported with its 95%IC.
Change From Baseline in 2-hour Post-dose FEV1 at Week 24
时间窗: Week 24 (Visit 6)
FEV1 measures the amount, or volume, exhaled by a patient in the first second of the expiration after a full inspiration. The lower the values, more severe the airflow limitation. For FEV1, the highest value from 3 technically acceptable attempts was recorded irrespective of the curve they were derived from. The chosen highest value had not to exceed the second highest by more than 150 mL; if the difference was larger, up to 8 measurements were performed and the largest value reported. Please note that the adjusted mean is reported with its 95%IC.
次要结局
- Change From Baseline in Pre-dose Morning FEV1 at All the Other Clinic Visits(Pre-dose morning at week 4 (visit 3), week 12 (visit 4), week 18 (visit 5), week 24 (visit 6))
- Change From Baseline at 2-hour Post-dose FEV1 at All the Clinic Visits(2-hour post-dose morning at week 0 (V2), week 4 (V3), week 12 (V4), week 18 (V5), week 24 (V6))
- Change From Baseline in Pre-dose FEV1 ≥ 100 mL at Week 24(Week 24 (V6))
- Changes From Pre-Dose to the 2-Hour Post-Dose Value of FEV1 at Each Visit From Visit 3 Onwards(Week 4 (V3), week 12 (V4), week 18 (V5), week 24 (V6))
- Adjusted Rate Per Patient Per Year of Moderate or Severe COPD Exacerbations Over 24 Weeks of Treatment(Over the 24-week treatment period)
- Time to First Moderate or Severe COPD Exacerbation Over 24 Weeks of Treatment(From baseline to week 24 (EOT))
- Change From Baseline in Pre-dose Morning Forced Expiratory Flow Measured Between 25% and 75% of a Forced Vital Capacity (FEF25-75%) at All Clinic Visits(Pre-dose morning at week 4 (V3), week 12 (V4), week 18 (V5) and week 24 (V6))
- Change From Baseline in Pre-Dose Morning Forced Vital Capacity (FVC) at All Clinic Visits(Pre-dose morning, week 4 (V3), week 12 (V4), week 18 (V5), week 24 (V6))
- Change From Baseline in 2-Hour Post-Dose Morning FVC at All Clinic Visits(2-hour post dose, week 4 (V3), week 12 (V4), week 18 (V5), week 24 (V6))
- Change From Pre-Dose to the 2-Hour Post-Dose Value of FVC at Each Visit From Visit 3 Onwards(From Pre-Dose to the 2-Hour Post-Dose at week 4 (V3), week 12 (V4), week 18 (V5) and week 24 (V6))
- Pre-Dose FEV1/FVC at All Clinic Visits(Pre-dose at baseline (V1), week 0 (V2), week 4 (V3), week 12 (V4), week 18 (V5), week 24 (V6))
- Change From Baseline in Pre-dose Morning Inspiratory Capacity (IC) at All Clinic Visits(Pre-dose morning at week 4 (V3), week 12 (V4), week 18 (V5) and week 24 (V6))
- Change From Baseline in the Saint George's Respiratory Questionnaire (SGRQ) Total Score at Week 12 and Week 24(At weeks 12 and 24)
- Change From Baseline in the Number of Patients With SGRQ Total Score ≤ -4 (Defined as "Responders") at Week 24(At week 24)
- Changes From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) at All Clinical Visits(At week 4 (V3), week 12 (V4), week 18 (V5) and week 24 (V6))
- Change From Baseline to Each Inter-Visit Period and to the Entire Randomised Treatment Period in the Percentage of Days Without Intake of Rescue Medication(Weeks 1-4 (V2-V3); Weeks 5-12 (V3-V4); Weeks 13-18 (V4-V5); Weeks 19-24 (V5-V6); Weeks 1-24 (randomised treatment period))
- Change From Baseline to Each Inter-Visit Period and to the Entire Treatment Period in the Average Use of Rescue Medication (Number of Puffs/Day)(Weeks 1-4 (V2-V3); Weeks 5-12 (V3-V4); Weeks 13-18 (V4-V5); Weeks 19-24 (V5-V6); Weeks 1-24 (randomised treatment period))
- EQ-5D-3L Index at All Clinic Visits(At week 0 (V2), week 12 (V4) and week 24 (V6))
- EQ-5D-3L VAS Scores at All Clinic Visits(At week 0 (V2), week 12 (V4) and week 24 (V6))
- Total Number of Hospital Admissions Due to COPD and to Other Causes(From baseline to week 24 (V6))
- Total Number of Oxygen Therapy Use Due to COPD(From baseline to week 24 (V6))
- Total Number of Unplanned Diagnostic or Instrumental Tests Performed Due to COPD(From baseline to week 24 (V6))
- Number of Adverse Events (AEs) and Adverse Drug Reactions (ADRs)(From baseline to week 24 (V6))