Active Controlled Trial of CHF5993 Pressurized Metered-dose Inhaler ( pMDI) vs Symbicort®Turbuhaler® in Patients With Chronic Obstructive Pulmonary Disease ( COPD) (TRIVERSYTI)

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

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.

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).

The length of the treatment period (24 weeks) was considered as adequate to evaluate the long-term efficacy and safety of CHF 5993 pMDI 100/6/12.5 μg versus (vs) budesonide/formoterol in terms of lung function.

Salbutamol was purchased locally by the vendor and used as rescue medication on an as-needed basis during both the run-in and treatment periods.

Four subsequent visits were performed after 4 weeks (V3), 12 weeks (V4), 18 weeks (V5), and 24 weeks (V6) of treatment. A time window of ±3 days was allowed for the visit dates from V2 to V6. An early termination (ET) visit was to be performed in the event of premature study discontinuation, during which all efforts were made to perform the assessments that should have been done at Week 24 (V6). A safety follow-up phone call was scheduled with the patient 7-10 days after last study treatment intake or ET visit in order to check the status of any unresolved adverse events (AEs) at the last visit.

Following the outbreak of the coronavirus disease-19 (COVID-19) pandemic the conduct of the study was adapted to ensure the safety of the patients and staff as well as the study continuity (see Section 9.8.1.2). Sites were instructed that patient retention was privileged with continuity of investigational drug supply. As emergency measures, it was authorised to postpone planned patients' visits or conduct remote visits and have the investigational product delivered to patients' home. Specific process for performing and reporting of Remote Visits was followed to cover all remote visits conducted during the period of the COVID-19 outbreak.

Study assessments

During the study, from screening (V1, Week -2) to end of treatment (V6, Week 24):

• Concomitant medications, smoking status, AEs, and physical examination were recorded at all visits. Height and weight were measured at V1 (Week -2);
• Pregnancy tests (serum tests at V1 [Week -2] and V6 [Week 24], and urinary tests from V1 [Week -2] to V5 [Week 18]) were performed. Blood samples for haematology and blood chemistry were performed at V1 (Week -2), V4 (Week 12), V5 (Week 18), and V6 (Week 24);
• Vital signs (blood pressure) were recorded pre-bronchodilator at V1 (Week -2), and at pre-dose and 10 minutes (mins) post-dose at all visits from V2 (Week 0) to V6 (Week 24);
• A single 12-lead electrocardiogram (ECG) was recorded pre-bronchodilator at V1 (Week -2), triplicate 12-lead ECG was recorded pre-dose at V2 (Week 0), and single 12-lead ECGs were recorded post-dose at V2 (Week 0), and pre-dose and 10 mins post-dose at V4 (Week 12) and V6 (Week 24);
• COPD exacerbations were assessed by the Investigator at all visits; the COPD assessment test (CAT) was also completed at all visits;
• Lung function tests were carried out to assess FEV1, forced vital capacity (FVC), forced expiratory flow measured between 25% and 75% of a forced vital capacity (FEF25-75%), and inspiratory capacity (IC) pre-bronchodilator at V1 (Week -2) and pre-dose from V2 (Week 0) to V6 (Week 24). FEV1 and FVC were assessed 10-15 mins post-bronchodilator at V1 (Week -2) and 2 hours post-dose from V2 (Week 0) to V6 (Week 24);
• The patient diary was completed daily from V1 (Week -2) until the end of treatment (V6, Week 24) to record medication intake, including study treatment and rescue medication, and treatment compliance;
• The European Quality of Life-5-Dimensional-3-Level questionnaire (EQ-5D-3L) and St. George's Respiratory Questionnaire (SGRQ) were completed at V2 (Week 0), V4 (Week 12), and V6 (Week 24). Additionally, the health economic assessment was completed from V2 (Week 0) to V6 (Week 24).

The final analysis included a total of 1053 screened patients and 708 randomised patients (353 patients received CHF 5993 pMDI and 355 patients received budesonide/formoterol). This included 826 patients screened in China of whom 578 patients were randomised to one of two treatments: CHF 5993 pMDI (288 patients) and budesonide/formoterol (290 patients). Overall there were 612 evaluable patients, including 506 evaluable patients in China. Of the 708 randomised patients, 706 patients were included in the Intention-to-treat (ITT) population (CHF 5993 pMDI: n=351; budesonide/formoterol: n=355).

Inclusion criteria

Patients had to meet all of the following inclusion criteria to be eligible for enrolment into the study:

1. Male and female adults aged ≥ 40 years with written informed consent obtained prior to any study-related procedure;

2. Patients with a diagnosis of COPD (according to GOLD 2015 strategic document, updated January 2015) 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 at least 10-15 mins after 4 puffs (4 x 100 μg) of salbutamol pMDI;

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 under therapy 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.

7. A cooperative attitude and ability to be trained to use correctly the study treatment inhalers (pMDI and Turbuhaler®);

8. 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).

Exclusion Criteria:

If a patient met any of the following criteria, he/she was not enrolled into the study:

1. 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 V6.

   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;

2. 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);

3. 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;

4. COPD exacerbation requiring prescriptions of systemic corticosteroids and/or antibiotics or hospitalisation during the run-in period;

5. 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;

6. Patients treated with non-cardioselective β-blockers in the week preceding the screening visit or during the run-in period;

7. 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);

8. Patients requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxaemia;

9. 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;

10. 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;

11. 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);

12. 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.

13. 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;

14. History of hypersensitivity to M3 antagonists, β2-agonist, corticosteroids or any of the excipients contained in any of the formulations used in the trial;

15. 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;

16. Patients with serum potassium levels < 3.5 mEq/L (or 3.5 mmol/L) at screening;

17. 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;

18. History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening visit;

19. Participation in another clinical trial where investigation drug was received less than 8 weeks prior to screening visit;

20. 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 #20. 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.