Functional Respiratory Imaging Study (DARWiIN)

Open Label, Prospective Study to Evaluate the Effect of Step-up From Non-extra Fine Inhaled Corticosteroids/Long Acting Beta2 Agonist (ICS/LABA) Dry Powder Inhaler (DPI) to Extra Fine Triple Therapy With CHF5993 DPI on Airway Geometry and Lung Ventilation Using Functional Respiratory Imaging (FRI) in Subjects With Advanced Chronic Obstructive Pulmonary Disease (COPD)

The objective of this clinical study was to evaluate the tolerability, safety, and efficacy of stepping up from fluticasone propionate (FP)/salmeterol (SLM) dry-powder inhaler (DPI) (SERETIDE™ DISKUS™) to extrafine beclometasone dipropionate (BDP)/formoterol fumarate (FF)/glycopyrronium bromide (GB) DPI (CHF5993) and to assess its effect on airway geometry and lung ventilation in subjects with advanced Chronic Obstructive Pulmonary Disease (COPD).

Primary Objectives:

• Untrimmed siVaw for distal region at TLC - actual value for V2 pre-dose and V3 pre-dose
• Trimmed siRaw for distal region at TLC - actual value for V2 pre-dose and V3 pre-dose

Secondary Objectives:

• Untrimmed siVaw for distal region at TLC and FRC - actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose
• Trimmed siRaw for distal region at TLC and FRC - actual value for V2 pre-dose, V2 post-dose, V3 pre-dose and V3 post-dose
• Safety assessment through the evaluation of treatment-emergent adverse events (TEAEs).

The study was an open-label, single-arm, prospective study of a duration of approximately 14 weeks per patient, aimed at evaluating the effect of step-up from non-extra fine ICS/LABA DPI to extra fine triple therapy with CHF5993 DPI on airway geometry and lung ventilation using Functional Respiratory Imaging (FRI) in subjects with advanced COPD.

All parameters assessed in this trial were evaluated at the following visits:

• Visit 1: Baseline Visit (Run-In Start): Screening and initiation of SERETIDE™ DISKUS™ DPI.
• Visit 2 (Transition to CHF5993 DPI): End of the 6-week run-in period.
• Visit 3 (End of Treatment): Completion of the 6-week CHF5993 DPI treatment phase.

The screening visit (V1) was followed by a 6-week run-in phase where participants were stabilized on SERETIDE™ DISKUS™ DPI 500/50μg, one inhalation twice daily (b.i.d.). This regimen provided a total daily dose of 1 mg of fluticasone propionate (FP) and 100 µg of salmeterol (SLM). At the screening visit (V1), patients received specific training on the proper use of the inhalation technique using In-Check Dial for both SERETIDE™ DISKUS™ and CHF5993 NEXThaler®. More precisely, to familiarize participants with the technique and ensure repeatable inhalations one assessment was set up for DISKUS™ resistance and the other for NEXThaler® resistance.

At the end of the run-in period (V2), patients transitioned to a 6-week treatment phase with CHF5993 DPI (until V3).

A follow-up call was conducted 2 weeks ± 2 days after V3 for males and women of non-childbearing potential, FRI, spirometry, and plethysmography were used to evaluate airway geometry, lung ventilation, and lung function.

Inclusion Criteria:

1. Patient's signed ICF obtained prior to any study-related procedure;

2. Male or female ≥40 years of age;

3. Current smokers or ex-smokers of at least 10 pack-years, calculated as (number of cigarettes/day * number of years)/20 (e-cigarettes smoking could not be used to calculate pack-year history);

4. Established diagnosis of COPD according to the 2020 GOLD Report, prior to the V1;

5. Post-BD FEV1/forced vital capacity (FVC) <0.7 and FEV1 ≤60% of predicted at V1 (Note: if the criterion was not met at screening, the measure could be repeated once before run-in Day 1);

6. On a stable dose of any non-extrafine ICS/LABA DPI twice daily regimen for at least 8 weeks before screening;

7. Presence of lung hyperinflation based on the increase of TLC exceeding either the ULN or 120% of predicted, and/or a plethysmographic FRC exceeding either ULN or 120% of predicted;

8. Symptomatic patients with COPD Assessment Test (CAT) score ≥10 at V1 and V2;

9. Documented history of ≥1 moderate or severe COPD exacerbation in the previous 12 months prior to V1;

10. Had a cooperative attitude and the ability to be trained and use correctly the DPIs;

11. Had a cooperative attitude and the ability to perform the required outcomes measurements (e.g., spirometry manoeuvres in sitting and supine position) and the ability to understand the risks involved;

12. Women of childbearing potential (WOCBP) fulfilling one of the following criteria:

    1. WOCBP with fertile male partners: they and/or their partner had to be willing to use a highly effective birth control method from the signature of the informed consent and until the follow-up visit or
    2. WOCBP with non-fertile male partners (contraception was not required in this case).

13. Female patients of non-childbearing potential defined as physiologically incapable of becoming pregnant (i.e., post-menopausal or permanently sterile; e.g., amenorrhea for ≥12 consecutive months without alternative medical cause). Permanent sterilisation methods included hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. If indicated, as per Investigator's request, post-menopausal status could be confirmed by follicle-stimulating hormone (FSH) levels (according to local laboratory ranges).

Exclusion Criteria:

1. Pregnant or lactating woman;
2. Exacerbations defined as a sustained and acute deterioration of patient's symptoms and signs (dyspnoea, cough and/or sputum production/purulence) that were either moderate, i.e., required treatment with systemic (oral/intravenous [IV]/intramuscular [IM]) corticosteroids and/or antibiotics, or severe, i.e., required hospitalisation, if their associated treatment/hospitalisation occurred within the 30 days before V1 (or 4 weeks in case the event was treated with just systemic corticosteroids) or if the event was recorded during the run-in period;
3. A current asthma diagnosis;
4. Respiratory disorders other than COPD: patients with known respiratory disorders other than COPD that in the Investigator's opinion could affect efficacy and safety evaluation or place the patient at risk. This could include but was not limited to known α1-anti-trypsine deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, and interstitial lung disease;
5. Cardiovascular diseases: patients who had known clinically significant cardiovascular conditions such as but not limited to: unstable or acute ischaemic heart disease within one year prior to study entry, New York Heart Association (NYHA) class IV heart failure, history of atrial fibrillation, history of sustained, and non-sustained cardiac arrhythmias diagnosed within 6 months prior to study entry and not controlled with therapy according to the Investigator's opinion;
6. Evidence or history of other concurrent disease such as but not limited to hyperthyroidism, diabetes mellitus, or other endocrine disease; haematological disease; autoimmune disorders (e.g,. rheumatoid arthritis); significant renal impairment; significant neurological disease or other disease or condition that might, in the judgement of the Investigator, place the patient at undue risk or potentially compromise the results or interpretation of the study;
7. Medical history or current diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy, or bladder neck obstruction that in the opinion of the Investigator could have prevented use of anticholinergic agents;
8. History of lung transplant or lung reduction surgery;
9. Electrocardiogram (ECG) criteria: any clinically significant abnormal 12-lead ECG that in the Investigator's opinion could affect efficacy or safety evaluation or place the patients at risk. Male patients with a QTcF >450 ms and female patients with a QTcF >470 ms at V1 were not eligible;
10. Laboratory abnormalities: patients with clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease that could, in the judgement of the Investigator, place the patient at undue risk or potentially compromise the results or interpretation of the study;
11. Alcohol/drug abuse: patients with a known or suspected history of alcohol and/or substance/drug abuse within 12 months prior to screening; or had a positive drug test at screening or V2;
12. Participation in investigational study: patients who had received any investigational drug within the 30 days or a more appropriate time as determined by the Investigator (e.g., approximately five half-lives of the investigational drug, whatever was longer);
13. Contra-indications to investigational medicinal products (IMPs), based on Investigator judgement;
14. Hypersensitivity: history of hypersensitivity to any of the study medications components or a history of other allergy that in the opinion of the Investigator contraindicated the patient's participation;
15. Patients mentally or legally incapacitated or patients accommodated in an establishment as a result of an official or judicial order;
16. Documented Coronavirus disease 2019 (COVID-19) diagnosis or its complications which had not resolved within 14 days prior to screening;
17. Positive molecular COVID-19 test within the last 72 h before the remaining of screening activities.