A 12-week double-blind, multicentre, randomised, active-controlled, 2-arm, parallel-group clinical trial to evaluate the safety of CHF5993 pMDI 200/6/12.5 µg HFA-152a, compared to CHF5993 pMDI 200/6/12.5 µg HFA-134a, in subjects with asthma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Chiesi Farmaceutici S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

15 Jan 2024 → 25 Feb 2026

Decision date (initial)

2023-11-20

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Chiesi Farmaceutici S.p.A.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

To compare the potential for bronchoconstriction with CHF5993 pMDI formulated using the HFA-152a propellant versus CHF5993 pMDI formulated using the HFA-134a propellant both at the 200/6/12.5 µg/actuation dosage.

Secondary objectives 1

1. To evaluate the safety and tolerability profile of HFA-152a propellant compared to HFA-134a propellant when administered as CHF5993 pMDI 200/6/12.5 µg in adults with moderate to severe controlled asthma

Conditions and MedDRA coding

Moderate to severe controlled asthma according to Step 4 and Step 5 of the Global Initiative for Asthma (GINA) 2022 Guidelines.

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Subject’s written informed consent obtained prior to any study related procedure;
2. Male and female adults aged ≥ 18 and ≤ 75;
3. Body mass index (BMI) within the range of 18.0 to 35.0 kg/m2 inclusive
4. Non-smokers or ex-smokers who smoked < 10 pack-years (pack-years = the number of cigarette packs per day x the number of years) and stopped smoking > 1 year (6 months for e-cigarettes) prior to screening;
5. Diagnosis of asthma: physician-diagnosed asthma for at least 6 months and with diagnosis before the age of 50 years;
6. Stable asthma therapy: a stable treatment with medium/high doses of inhaled corticosteroids (ICS) + long-acting β-agonist (LABA) + long-acting muscarinic antagonist (LAMA) (fixed or free combination) or medium/high doses of ICS+LABA (fixed or free combination) for at least 4 weeks before screening (medium and high-dose ICS defined as BDP non‑extrafine > 500-1000 µg and > 1000 µg respectively, or estimated clinical comparable dose). Subjects who inhale their pMDI medication with a spacer will be required to keep using a spacer for the study medication throughout the entire duration of the study
7. Asthma control: controlled or partly controlled based on an Asthma Control Questionnaire 7 items (ACQ-7) score < 1.5 at screening and at randomisation
8. Subjects with a pre-bronchodilator 40% < forced expiratory volume in 1 second (FEV1) < 90% of their predicted normal value, after appropriate wash‑out from bronchodilators, at the screening visit;
9. Subjects with a positive bronchodilator response at screening defined as an increase in FEV1 ≥ 12% and 200 mL over baseline within 30 minutes after inhalation of 400 μg salbutamol pMDI; Note: in case the bronchodilator (BD) response threshold is not met at screening, the spirometry test can be repeated no later than 1 day before randomisation at a second spirometry visit. In case the BD response is not met at this second spirometry visit, historical documentation of BD response can be provided. Historical documentation of BD response defined according to the 2005 American Thoracic Society (ATS)/European Respiratory Society (ERS) Task Force on interpretative strategies for lung function tests, or history of positive bronchial challenge test (methacholine) within 24 months prior to screening (copy of original printed spirometry to be included as source documentation) is also accepted.
10. Subjects must have a cooperative attitude and the ability to be trained to use correctly the pMDI inhalers and e-Diary, to be able to read/write, to be able to perform the required outcomes measurements (e.g., technically acceptable spirometry, e‑Diary completion) and the ability to understand the risks involved. Subjects who already use a spacer device will be asked to use one for inhalation of their pMDI medication;
11. Female subjects fulfilling one of the following criteria: a. Woman of childbearing potential (WOCBP) fulfilling one of the following criteria: • WOCBP with fertile male partners: they and/or their partner must be willing to use a highly effective birth control method from the signature of the informed consent and until the follow-up call or • WOCBP with non-fertile male partners (contraception is not required in this case). b. Female subject of non-childbearing potential (WONCBP) defined as physiologically incapable of becoming pregnant (i.e., post-menopausal or permanently sterile). Tubal ligation or partial surgical interventions are not acceptable. If indicated, as per Investigator’s request, post-menopausal status may be confirmed by follicle-stimulating hormone (FSH) levels (according to local laboratory ranges).

Exclusion criteria 22

1. History of near fatal asthma, hospitalisation for asthma in intensive care unit which in the judgement of the Investigator may place the subject at undue risk, emergency room access for asthma in the previous 6 months before enrolment;
2. Asthma exacerbation requiring systemic corticosteroids (SCS) or emergency room admission or hospitalisation within 4 weeks prior to study entry and/or during the run-in period (to be checked again prior to randomisation);
3. Non-permanent asthma: exercise-induced, seasonal asthma (as the only asthma-related diagnosis) not requiring daily asthma control medicine;
4. Asthma subjects currently treated with chronic SCS, anti-immunoglobulin E (IgE), or any other biologic therapy;
5. Any concomitant respiratory disease that, in the opinion of the Investigator and/or Medical Monitor, will interfere with the evaluation of the investigational product or interpretation of subject safety or study results. This can include but is not limited to: diagnosis of chronic obstructive pulmonary disease (COPD) as defined by the current guidelines (e.g., Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2023 guidelines), known alpha‑1 antitrypsin deficiency, active tuberculosis, bronchiectasis, sarcoidosis, pulmonary hypertension and interstitial lung disease/pulmonary fibrosis;
6. Lung resection: subjects with a history of lobectomy, pneumonectomy, or other sizable lung volume resection (total volume of lung removed > 25%);
7. Lower respiratory tract infection: subjects with lower respiratory tract infection that required use of antibiotics, if unresolved within 4 weeks prior to screening or if occurring during the run-in period (to be re-checked prior to randomisation);
8. Subjects with active cancer or a history of cancer with less than 5 years disease-free survival time (whether there is evidence of local recurrence or metastases). Localised carcinoma (e.g., basal cell carcinoma, in situ carcinoma of the cervix adequately treated) is acceptable;
9. Electrocardiogram (ECG) criteria: any clinically significant (CS) abnormal 12-lead ECG that in the Investigator’s opinion would affect efficacy or safety evaluations or place the subjects at risk. Male subjects with a QT interval corrected using Fridericia’s formula (QTcF) > 450 msec and female subjects with a QTcF > 470 msec at screening visit are not eligible (not applicable for subjects with permanent atrial fibrillation and for subjects with pacemaker); the average of the three measurements will be considered to check the criterion;
10. Previous medical history, evidence of an uncontrolled, severe, intercurrent illness, or any clinically relevant abnormal findings in haematology, clinical chemistry, or urinalysis that in the opinion of the Investigator and/or Medical Monitor may compromise the safety of the subject in the study or interfere with evaluation of the investigational product or reduce the subject’s ability to participate in the study. Subjects with well‑controlled comorbid disease (e.g., hypertension, hyperlipidaemia, gastroesophageal reflux disease) on a stable treatment regimen for 15 days prior to screening are eligible;
11. Contra-indications to investigational medicinal products. For warnings, eligibility will be judged by the Investigator;
12. History of hypersensitivity to any of the study medications components or a history of other allergy that in the opinion of the Investigator contraindicates the subject’s participation;
13. Subjects with a medical history or current diagnosis of narrow-angle glaucoma, symptomatic prostatic hypertrophy, urinary retention bladder neck obstruction that, in the opinion of the Investigator, would prevent use of anticholinergic agents;
14. Subjects using SCS medication in the 4 weeks prior to screening (6 weeks prior to randomisation) or slow-release corticosteroids in the 12 weeks before screening (14 weeks prior to randomisation);
15. Prohibited medication: subjects receiving treatment with one or more drugs listed in the non-permitted concomitant medications section (see section below);
16. Clinical evidence of candidiasis at the oropharyngeal examination at screening or randomisation (to be re-checked prior to randomisation);
17. Documented coronavirus disease 2019 (COVID-19) diagnosis within the previous 2 weeks, or associated complications/symptoms, which have not resolved within 14 days prior to screening (to be re-checked prior to randomisation);
18. Alcohol/drug abuse: subjects with a known or suspected history of alcohol and/or substance/drug abuse within 12 months prior to screening (to be re-checked prior to randomisation);
19. Participation in other investigational trial(s): subjects who have received any investigational drug within the 30 days (60 days for biologics) or a more appropriate time as determined by the Investigator (e.g., approximately 5 half‑lives of the investigational drug whatever is longer) (to be re‑checked prior to randomisation);
20. Pregnant or lactating women. Pregnancy is defined as the state of a female after conception and until termination of the gestation, confirmed by a positive pregnancy test. Serum and urine pregnancy tests will be performed at the screening visit. The urine pregnancy test will be repeated at the randomisation visit;
21. e-Diary completion compliance < 60% at randomisation
22. Vaccination: subjects having received a vaccination within 2 weeks prior to screening or during the run-in.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Relative change from pre-dose* in FEV1 at the 10 min post‑dose timepoint on Day 1.

Secondary endpoints 17

1. Relative change from pre-dose* in FEV1 at all the post-dose timepoints at each study visit (Day 1, Day 7 and Week 12: 20 min, 30 min, 1 h and 2 h post-dose; Day 7, Week 4 and Week 12: 10 min post-dose);
2. Absolute change from pre-dose* in FEV1 at all post-dose timepoints at each study visit (Day 1, Day 7, and Week 12: 10 min, 20 min, 30 min, 1 h, and 2 h post-dose; Week 4: 10 min post-dose);
3. Number and percentage of subjects with a relative decrease from pre-dose* in FEV1 at each post-dose timepoint and at any post-dose timepoint > 15% at each study visit (Day 1, Day 7, and Week 12: 10 min, 20 min, 30 min, 1 h, and 2 h post-dose; Week 4: 10 min post-dose);
4. Absolute and relative changes from baseline (i.e., pre-dose* FEV1 at Day 1) in pre-dose* FEV1 at all clinical visits;
5. Change from pre-dose* in FEV1 area under the curve from time zero to 2 h (AUC0-2h) on Day 1, Day 7 and Week 12;
6. Change from baseline at each inter-visit period and over the entire treatment period in morning and evening PEF;
7. Change from baseline at each inter-visit period and over the entire treatment period in the percentage of days without intake of rescue medication;
8. Change from baseline at each inter-visit period and over the entire treatment period in the average daily use of rescue medication (number of inhalations/day);
9. Change from baseline at each inter-visit period and over the entire treatment period in the average daily symptoms
10. Change from baseline in ACQ-7 at each study visit;
11. AEs and adverse drug reactions (ADRs);
12. AEs of particular interest: cough, dysphonia, paradoxical bronchospasm, hypersensitivity reactions, severe asthma exacerbations according to ATS/ERS criteria
13. Vital signs (systolic and diastolic blood pressure);
14. 12-lead ECG parameters: heart rate (HR), QTcF, PR interval (PR) and QRS interval (QRS);
15. 12-lead ECG abnormalities
16. Standard haematology and blood chemistry (including serum potassium and glucose);
17. Chemistry in urine (quantitative [proteins] and qualitative [ketones and microscopic examination of the sediments]).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Chiesi Farmaceutici S.p.A.

Sponsor organisation

Chiesi Farmaceutici S.p.A.

Address

Via Palermo 26 A

City

Parma

Postcode

43122

Country

Italy

Scientific contact point

Organisation

Chiesi Farmaceutici S.p.A.

Contact name

GLOBAL CLINICAL DEVELOPMENT

Public contact point

Organisation

Chiesi Farmaceutici S.p.A.

Contact name

GLOBAL CLINICAL DEVELOPMENT

Third parties 7

Locations

11 EU/EEA countries · 121 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 49 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

26 submissions — initial application plus substantial / non-substantial modifications