Chronic Obstructive Pulmonary Disease
Conditions
Keywords
Lung functions, COPD, Symbicort Turbohaler
Brief summary
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.
Detailed description
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.
Interventions
DRUGCHF 1535 100/6 µg pMDI plus Symbicort® Turbohaler® Placebo
2 inhalations BID Total Daily Dose = 400/24µg
DRUGSymbicort® Turbohaler® plus CHF 1535 pMDI Placebo
2 inhalations BID Total Daily Dose = 640/18µg
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
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients had to meet all of the following criteria to be eligible for enrolment into the study: 1. Male and female adults aged ≥40 years, of Chinese ethnicity with written informed consent prior to any study-related procedure; 2. Patients with a diagnosis of COPD (according to the GOLD document \[1\], updated 2017) at least 12 months before the screening visit; 3. 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; 4. 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; 5. 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"; 6. 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 * LAMA; or * LABA; Note: Triple therapy was not allowed 2 months before the screening visit; 7. A cooperative attitude and ability to be trained to use correctly the study treatment inhalers (pMDI and Turbohaler®); 8. A cooperative attitude and ability to be trained to use correctly the COPD questionnaires.
Exclusion criteria
1. 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; 2. COPD exacerbation requiring prescriptions of systemic corticosteroids and/or antibiotics or hospitalization during the run-in period; 3. 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; 4. 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; 5. 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); 6. 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); 7. Patients requiring long-term (at least 12 hours daily) oxygen therapy for chronic hypoxemia; 8. History of hypersensitivity to β2-agonists, corticosteroids or any of the excipients contained in any of the formulations used in the study; 9. Patients treated with non-cardioselective β-blockers in the 4 weeks preceding the screening visit or during the run-in period; 10. 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); 11. 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); 12. 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; 13. 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; 14. 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; 15. Patients with serum potassium levels \<3.5 mEq/L (or 3.5 mmol/L); 16. History of alcohol abuse and/or substance/drug abuse within 12 months prior to the screening visit; 17. 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; 18. 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pre-dose Morning First Expiratory Volume in 1 Second (FEV1) in Patients With Chronic Obstructive Pulmonary Disease (COPD) | Baseline and week 24 | Forced Expiratory Volume in 1 second (FEV1) measures lung function by quantifying the volume of air forcefully exhaled during the first second of a forced expiratory maneuver. Spirometry was conducted at baseline and Week 24 to assess treatment effects in patients with moderate-to-severe COPD. Baseline FEV1, recorded during the run-in phase before randomization, was used as the reference for changes post-treatment. Tests were performed under controlled conditions using calibrated equipment. Patients inhaled deeply to full capacity and exhaled forcefully into the spirometer. Each completed at least three acceptable maneuvers, with the highest value recorded for analysis. FEV1 higher values indicate better lung function. An increase in FEV1 reflects improved airway patency, while a decrease suggests worsening obstruction, making it a key parameter in COPD management. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pre-dose Morning FEV1 at All the Other Clinic Visits in Patients With Chronic Obstructive Pulmonary Disease (COPD) | Baseline and week 4, week 12, week 18 | Forced Expiratory Volume in 1 second (FEV1) is a key measure of lung function that quantifies the volume of air a patient can exhale forcefully in the first second of a forced expiratory maneuver. Spirometry was conducted at baseline and at Weeks 4, 12, 18, and 24 to evaluate treatment effects in patients with moderate-to-severe COPD. Baseline FEV1, recorded during the run-in phase before randomization, served as a reference for post-treatment changes. Tests were performed under controlled conditions with calibrated equipment. Patients were seated, instructed to inhale deeply to full capacity, and exhale forcefully into the spirometer. At least three acceptable and repeatable maneuvers were completed, and the highest value was used for analysis. FEV1 is measured in liters (L), with higher values indicating better lung function. Increases in FEV1 reflect improved airway patency and reduced obstruction, while decreases indicate worsening airflow limitation. |
| Change From Baseline in Pre-dose Morning Force Vital Capacity (FVC) at All Timepoints | Baseline and week 4, week 12, week 18 and week 24 | Forced Vital Capacity (FVC) measures the total volume of air a patient can exhale forcefully after a full inhalation, offering key insights into lung function. Baseline FVC, recorded during the run-in phase before randomization, served as a reference for evaluating changes during treatment. Spirometry tests were conducted in controlled settings with calibrated, high-precision equipment to ensure accuracy and reliability. Patients performed the test while seated, inhaling deeply to full lung capacity and exhaling forcefully and completely into the spirometer. At least three acceptable maneuvers meeting predefined criteria for consistency were required, with the highest FVC value recorded for analysis. The procedure adhered to standardized protocols, including calibration of equipment before each test, coaching by trained technicians, and monitoring for quality control. FVC is measured in liters (L); higher values indicate improved lung capacity and reduced airway obstruction. |
| Change From Baseline in Pre-dose Morning Inspiratory Capacity (IC) at All Timepoints | Baseline and week 4, week 12, week 18 and week 24 | Inspiratory Capacity (IC) measures the maximum volume of air a patient can inhale after a normal exhalation, providing key insights into lung expansion and respiratory mechanics. Baseline IC, recorded during the run-in phase before randomization, was used as a reference for treatment-related changes. Spirometry tests were performed in controlled conditions using calibrated, high-precision equipment to ensure accuracy. Patients exhaled to their functional residual capacity, then inhaled deeply into the spirometer. At least three acceptable maneuvers were completed, and the highest IC value was recorded. The procedure followed standardized protocols, including pre-test calibration, technician coaching, and quality control monitoring. IC is measured in liters (L), with higher values indicating improved lung capacity, reduced restriction, and enhanced respiratory function. |
| Change From Baseline in Pre-dose Maximal Mid-expiratory Flow (MMEF) at All Timepoints | Baseline and week 4, week 12, week 18 and week 24 | Maximal Mid-Expiratory Flow (MMEF) measured the mean expiratory flow during the middle 50% of a forced vital capacity (FVC) maneuver, reflecting airflow through small airways. It was an important indicator of small airway function, often impaired in diseases like COPD. MMEF was measured using spirometry under standardized conditions with calibrated equipment. Patients inhaled deeply to full lung capacity and exhaled forcefully into the spirometer. The highest value from at least three acceptable maneuvers was recorded. MMEF was expressed in liters per second (L/sec), with lower values indicating increased resistance in small airways, a hallmark of COPD and asthma. The parameter was particularly sensitive to detecting early changes in small airway function that may not yet be apparent in larger airway measurements like FEV1 or FVC. This sensitivity made MMEF valuable for assessing treatment efficacy and progression in diseases affecting small airway mechanics. |
| Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score and Domain Scores at Week 12 and Week 24 | Baseline, week 12, week 24 | The SGRQ is a validated tool used to assess health-related quality of life in patients with chronic respiratory diseases. It consists of 76 items across 3 domains: * Symptoms (0-100; the lower the score, the better the heath), evaluating frequency and severity of respiratory issues (coughing, sputum production, breathlessness etc); * Activity (0-100; idem), measuring limitations in physical activities due to breathlessness; * Impacts (0-100; idem), examining psychological \& social effects (feelings of stigma, loss of control, and daily life disruption etc). Each domain score = sum of the weights of the positive items of that domain / sum of the weights of all items of that domain)\*100. Total score (0 - 100) is calculated by combining the weighted scores from each domain, with higher scores indicating a greater burden of disease and poorer quality of life. A reduction of 4 points or more in the total score is considered clinically significant. |
| Change From Baseline in COPD Assessment Test (CAT) | At week 4, week 12, week 18 and week 24 | The COPD Assessment Test (CAT) is a validated eight-item questionnaire designed to assess the impact of Chronic Obstructive Pulmonary Disease (COPD) on a patient's health status. It evaluates symptoms and quality of life, including cough, phlegm production, chest tightness, breathlessness during physical activity, sleep quality, and energy levels. Each item is scored from 0 (no impact) to 5 (severe impact), resulting in a total score range of 0 to 40, where higher scores indicate a greater disease burden and worse health status. The CAT was completed at baseline and during scheduled clinic visits throughout the treatment period. Scores were calculated by summing the responses to all eight items. A reduction in the CAT score reflects improvement in the patient's condition, with a change of 2 points or more considered clinically significant. This outcome captures changes in the patient's quality of life and provides a direct measure of the perceived impact of COPD on daily living. |
| Rate of Moderate and Severe COPD Exacerbations Over 24 Weeks of Treatment. - Moderate Exacerbations Require Treatment With Systemic Corticosteroids and/or Antibiotics - Severe Exacerbations Require Hospitalisation or Result in Death | Over 24 weeks of treatment | This outcome measures the frequency of moderate and severe exacerbations of Chronic Obstructive Pulmonary Disease (COPD) during the treatment period. A moderate exacerbation is defined as a worsening of respiratory symptoms requiring treatment with systemic corticosteroids, antibiotics, or both, without hospitalization. A severe exacerbation is defined as a worsening of symptoms requiring hospitalization or resulting in death. Exacerbations were recorded from the start of treatment to the final scheduled visit, using data from patient-reported symptom diaries, healthcare provider assessments, and verified medical records. |
| Number of Patients With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Over 29 weeks (from Visit 0 to Visit 6) | An AE is "any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment". A SAE is defined as any untoward medical occurrence or effect that, at any dose may result in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment. |
Countries
China
Contacts
PRINCIPAL_INVESTIGATORProfessor Fuqiang WEN, M.D., Ph.D.
West China Hospital
Participant flow
Recruitment details
Recruitment occurred across 50 centers in China, where 1,182 patients were screened, and 750 were randomized to CHF 1535 (377) or Symbicort® (373). Pre-screening evaluated eligibility, followed by screening with medical history review, spirometry, and inclusion/exclusion criteria confirmation. Eligible patients entered a 6-week run-in phase with open-label Symbicort® Turbohaler® to standardize therapy before randomization
Pre-assignment details
After enrollment, participants entered a 6-week run-in phase with open-label Symbicort® Turbohaler® (budesonide/formoterol) to standardize baseline therapy. During this phase, spirometry, adherence, and rescue medication use were monitored to ensure eligibility and compliance. Participants who failed to meet inclusion criteria or demonstrated protocol violations were excluded before randomization. This phase ensured consistency in baseline conditions prior to treatment assignment.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 65.7 years STANDARD_DEVIATION 6.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 373 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment China | 373 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 361 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 377 | 3 / 373 |
| other Total, other adverse events | 179 / 377 | 172 / 373 |
| serious Total, serious adverse events | 45 / 377 | 47 / 373 |
Outcome results
None listed