Safety Evaluation of CHF5993 pMDI Formulated with HFA-152a Versus HFA-134a in Moderate to Severe Asthma Patients
- Trial ID
- 2023-503333-22-00
- Protocol
- CLI-05993AB6-03
- Sponsor
- Chiesi Farmaceutici S.p.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to compare the potential for **bronchoconstriction** when using CHF5993 pressurised metered-dose inhaler (pMDI) formulated with the HFA-152a propellant versus the HFA-134a propellant, both at a dosage of 200/6/12.5 µg/actuation. This comparison is clinically relevant as it aims to determine the safety and efficacy of different propellants in managing moderate to severe controlled asthma, as per the Global Initiative for Asthma (GINA) 2022 Guidelines. Understanding the potential for bronchoconstriction is crucial for optimizing asthma management and ensuring patient safety.
Secondary objectives include evaluating the safety and tolerability profile of the HFA-152a propellant compared to the HFA-134a propellant when administered as CHF5993 pMDI 200/6/12.5 µg in adults with moderate to severe controlled asthma. This assessment is important to ensure that the new propellant does not introduce additional risks or adverse effects, thereby supporting its potential use in clinical practice.
Participants
The clinical trial involves a total of **100 participants** diagnosed with **moderate to severe controlled asthma** as per the Global Initiative for Asthma (GINA) 2022 Guidelines. The study population comprises both male and female adults aged between **18 and 75 years**. Participants were selected based on specific criteria, including a **body mass index (BMI)** ranging from 18.0 to 35.0 kg/m² and a history of asthma diagnosed by a physician for at least six months, with the diagnosis made before the age of 50. The trial includes non-smokers or ex-smokers who have smoked less than 10 pack-years and ceased smoking more than one year prior to screening. Participants are required to have stable asthma therapy with medium to high doses of inhaled corticosteroids (ICS) combined with long-acting β-agonist (LABA) and/or long-acting muscarinic antagonist (LAMA) for at least four weeks before screening. Asthma control is assessed using the Asthma Control Questionnaire (ACQ-7), with a score of less than 1.5 indicating controlled or partly controlled asthma. The trial does not include a vulnerable population, and participants must demonstrate a cooperative attitude and the ability to use inhalers and e-Diaries correctly. The study does not specify any particular lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is designed as a **randomized**, double-blind, active-controlled, 2-arm, parallel-group study 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 moderate to severe controlled **asthma**. The trial will span a duration of 12 weeks, with the primary objective being to compare the potential for bronchoconstriction between the two formulations. The study will involve multiple visits, including an initial screening visit, followed by study visits on Day 1, Day 7, Week 4, and Week 12, with a follow-up call post-study.
Participants will be involved in the study for approximately 12 weeks. The inclusion visit will involve screening for eligibility based on criteria such as age, asthma diagnosis, and stable asthma therapy. Participants must provide written informed consent and demonstrate the ability to use the pMDI inhalers and e-Diary correctly. The primary endpoint is the relative change from pre-dose in forced expiratory volume in 1 second (FEV1) at the 10-minute post-dose timepoint on Day 1. Secondary endpoints include changes in FEV1 at various post-dose timepoints, changes in asthma control, and the incidence of adverse events.
Study visits will be conducted to monitor the safety and efficacy of the treatments, with assessments including spirometry, vital signs, ECG parameters, and laboratory tests. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial is expected to conclude by December 2024, with recruitment starting in November 2023. The study is not classified as low intervention and is conducted under Phase 3 clinical trial guidelines.
Treatment
The clinical trial involves the administration of **SALBUTAMOL**, which is provided as an **inhalation solution**. The active substance, salbutamol, is of chemical origin. The maximum daily dose is 800 µg, with a total maximum dose of 81,600 µg over a treatment period of up to 102 days. The route of administration is via inhalation. Salbutamol serves as a rescue medication in this study, providing pharmacological therapy as needed.
Another treatment used in the trial is **Trimbow 172 micrograms/5 micrograms/9 micrograms pressurised inhalation, solution**. This medication contains three active substances: **glycopyrronium bromide**, **formoterol fumarate dihydrate**, and **beclometasone dipropionate anhydrous**, all of which are of chemical origin. The pharmaceutical form is a pressurised inhalation solution, and it is administered via inhalation use. The maximum daily dose is 874 µg, with a total maximum dose of 75,164 µg over a 12-week treatment period. This product is used as a comparator in the study.
The experimental medication, **CHF5993 pmDI-152a**, is also a pressurised inhalation solution containing the same active substances as Trimbow: glycopyrronium bromide, formoterol fumarate dihydrate, and beclometasone dipropionate anhydrous. The maximum daily dose and total dose are identical to those of Trimbow, with a maximum treatment period of 12 weeks. The route of administration is inhalation use. This product is the test medication in the trial, formulated with the HFA-152a propellant, and is compared against the same formulation using the HFA-134a propellant to evaluate safety and potential for bronchoconstriction.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **forced expiratory volume in 1 second (FEV1)**, a key parameter for evaluating lung function in subjects with asthma. The primary endpoint is the relative change from pre-dose in FEV1 at the 10-minute post-dose timepoint on Day 1. Secondary endpoints include relative and absolute changes from pre-dose in FEV1 at various post-dose timepoints across study visits, including Day 1, Day 7, and Week 12, as well as the area under the curve from time zero to 2 hours (AUC0-2h) on these days.
Additional secondary endpoints involve changes from baseline in morning and evening peak expiratory flow (PEF), the percentage of days without rescue medication use, and the average daily use of rescue medication. Symptom changes, as measured by the Asthma Control Questionnaire 7 items (ACQ-7), will also be evaluated at each study visit. Safety and tolerability will be monitored through adverse events (AEs), adverse drug reactions (ADRs), and specific AEs of interest such as cough and severe asthma exacerbations. Vital signs, 12-lead ECG parameters, and standard laboratory tests will further support the assessment of efficacy and safety.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject’s written informed consent obtained prior to any study related procedure;
- Male and female adults aged ≥ 18 and ≤ 75;
- Body mass index (BMI) within the range of 18.0 to 35.0 kg/m2 inclusive
- 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;
- Diagnosis of asthma: physician-diagnosed asthma for at least 6 months and with diagnosis before the age of 50 years;
- 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
- Asthma control: controlled or partly controlled based on an Asthma Control Questionnaire 7 items (ACQ-7) score < 1.5 at screening and at randomisation
- 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;
- 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.
- 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;
- 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
- 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;
- 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);
- Non-permanent asthma: exercise-induced, seasonal asthma (as the only asthma-related diagnosis) not requiring daily asthma control medicine;
- Asthma subjects currently treated with chronic SCS, anti-immunoglobulin E (IgE), or any other biologic therapy;
- 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;
- Lung resection: subjects with a history of lobectomy, pneumonectomy, or other sizable lung volume resection (total volume of lung removed > 25%);
- 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);
- 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;
- 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;
- 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;
- Contra-indications to investigational medicinal products. For warnings, eligibility will be judged by the Investigator;
- 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;
- 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;
- 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);
- Prohibited medication: subjects receiving treatment with one or more drugs listed in the non-permitted concomitant medications section (see section below);
- Clinical evidence of candidiasis at the oropharyngeal examination at screening or randomisation (to be re-checked prior to randomisation);
- 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);
- 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);
- 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);
- 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;
- e-Diary completion compliance < 60% at randomisation
- Vaccination: subjects having received a vaccination within 2 weeks prior to screening or during the run-in.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 13 Nov 2023 | 97 |
 Czechia | Not Recruiting | 13 Nov 2023 | 50 |
 Germany | Not Recruiting | 13 Nov 2023 | 90 |
 Greece | Not Recruiting | 13 Nov 2023 | 40 |
 Hungary | Not Recruiting | 13 Nov 2023 | 35 |
 Italy | Not Recruiting | 13 Nov 2023 | 40 |
 The Netherlands | Not Recruiting | 13 Nov 2023 | — |
 Poland | Not Recruiting | 13 Nov 2023 | 125 |
 Romania | Not Recruiting | 13 Nov 2023 | 65 |
 Slovakia | Not Recruiting | 13 Nov 2023 | 50 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CHF5993 pMDI -152a | Test | PRESSURISED INHALATION, SOLUTION | INHALATION USE | 874 | 12 | PRD10209273 |
SALBUTAMOL | Other | — | INHALATION | 800 | 102 | SUB10422MIG |
Trimbow 172 micrograms/5 micrograms/9 micrograms pressurised inhalation, solution | Comparator | PRESSURISED INHALATION, SOLUTION | INHALATION USE | 874 | 12 | PRD8686790 |