Assessment of Lung Function Equivalence of Budesonide, Glycopyrronium Bromide, and Formoterol Fumarate MDI HFO vs. MDI HFA in COPD Patients Aged 40-80
- Trial ID
- 2023-506565-57-00
- Protocol
- D5985C00002
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **equivalence** of Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) delivered by MDI HFO compared to BGF delivered by MDI HFA on lung function in participants with moderate to severe **Chronic Obstructive Pulmonary Disease (COPD)**. This evaluation is clinically relevant as it aims to determine if the new propellant, HFO, is as effective as the existing HFA propellant in maintaining lung function, which is crucial for the management of COPD.
Secondary objectives include:
- Assessing the **safety** and tolerability of BGF MDI HFO compared to BGF MDI HFA in participants with COPD.
- Determining the responsiveness to the study intervention for treatment period 1.
- Evaluating the time to onset of action for each study intervention.
- Assessing the superiority of BGF MDI HFO relative to placebo MDI HFA on lung function, both pre- and post-dose, in participants with COPD.
Participants
The clinical trial involves a total of **191 participants** diagnosed with **Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)**. The study population includes both male and female subjects, aged between **40 to 80 years**. Participants were selected based on specific criteria, including a documented history of physician-diagnosed COPD and a smoking history of at least 10 pack-years. The trial includes individuals who are either current or former smokers. Participants must have a pre-bronchodilator FEV1 of less than 80% predicted normal and a post-bronchodilator FEV1/FVC ratio of less than 0.70. The study population is required to have been on certain inhaled maintenance therapies for at least four weeks prior to the trial or be treatment-naïve. Additionally, participants must demonstrate acceptable MDI administration and spirometry techniques. The trial includes a vulnerable population, and all participants are required to provide informed consent. Lifestyle considerations such as smoking history are significant, and participants must be willing to adjust their current COPD therapy as per the protocol requirements.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled, multi-center, 4-week, 3-way crossover pharmacodynamic study. The primary objective is to assess the equivalence of Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) delivered by MDI HFO compared with BGF delivered by MDI HFA in participants with moderate to severe **Chronic Obstructive Pulmonary Disease (COPD)**. The trial will also demonstrate assay sensitivity via the superiority of BGF MDI HFA relative to placebo MDI HFA on lung function. The trial is expected to start recruitment on January 24, 2024, and conclude by September 5, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, smoking history, and lung function parameters. The trial includes multiple treatment periods, each followed by a washout period, to ensure the crossover design's integrity. Follow-up visits will be conducted to monitor safety and efficacy endpoints, including changes in FEV(1) and vital signs. The end-of-study visit will assess the overall outcomes and any adverse events experienced by participants.
The expected length of participant involvement is approximately 4 weeks, with conditions for early termination including non-compliance with study protocols, adverse events, or withdrawal of consent. Participants must demonstrate acceptable MDI administration and spirometry techniques and remain compliant with placebo run-in administrations. The trial will ensure rigorous monitoring to maintain the study's scientific validity and participant safety.
Treatment
The clinical trial involves the administration of **SALBUTAMOL**, a short-acting selective beta-2-adrenoreceptor agonist, as an auxiliary treatment. The pharmaceutical form of SALBUTAMOL is a pressurised inhalation suspension. It is administered via inhalation, with a maximum treatment period of 12 weeks. The dosage and frequency of administration are not specified, as the maximum daily and total dose amounts are indicated as zero, suggesting its use as a rescue medication rather than a scheduled treatment. Participant compliance with SALBUTAMOL administration will be monitored throughout the trial.
The experimental treatment in this trial is **Trixeo Aerosphere**, which contains a combination of **BUDESONIDE**, **GLYCOPYRRONIUM BROMIDE**, and **FORMOTEROL FUMARATE DIHYDRATE**. This medication is provided in a pressurised inhalation suspension form and is administered via inhalation. The maximum daily dose is 4 micrograms, with a total dose not exceeding 4 micrograms per day. The treatment period is limited to 4 weeks. Trixeo Aerosphere is used to assess the equivalence of the new propellant HFO (hydrofluoroolefin) compared to the traditional HFA (hydrofluoroalkane) propellant. Compliance with the dosing schedule will be closely monitored to ensure accurate assessment of the treatment's efficacy and safety.
A placebo, designed to match the BGF MDI HFA, is also used in this study as a comparator. The placebo is administered in a manner identical to the active treatment to maintain the double-blind nature of the trial. The placebo is used to demonstrate assay sensitivity by comparing the effects of the active treatment against a non-active control. The placebo administration will follow the same inhalation route and dosing schedule as the active treatment, ensuring consistency across the study arms.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating the equivalence of Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) delivered by MDI HFO compared to BGF delivered by MDI HFA in participants with **Chronic Obstructive Pulmonary Disease** (COPD). The primary endpoints include assessing the change from baseline in FEV(1) AUC(0-4) and morning pre-dose trough FEV(1) to determine the equivalence of BGF MDI HFO relative to BGF MDI HFA. Additionally, the trial aims to demonstrate assay sensitivity by showing the superiority of BGF MDI HFA relative to placebo MDI HFA on these same parameters.
Secondary endpoints will focus on safety, including adverse events and vital signs such as systolic and diastolic blood pressure and pulse rate. Exploratory endpoints will further assess changes from baseline in FEV(1) AUC(0-4) at specific timepoints, time to onset of action, and assay sensitivity via superiority of BGF MDI HFO relative to placebo MDI HFA on change from baseline in FEV(1) AUC(0-4) and morning pre-dose trough FEV(1) at Day 29.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 1 Participants must be 40 to 80 years inclusive at the time ofsigning the ICF.
- 10 Females must not be of childbearing potential or must use aform of highly effective birth control.
- 11 Capable of giving signed informed consent as described inAppendix A which includes compliance with the requirements and restrictions listed in the ICFand in this protocol.
- 12 Participants with calculated eGFR > 30 mL/min/1.73 m2 usingthe CKD-EPI formula.
- 13 Participants who demonstrate acceptable MDI administrationand spirometry techniques.
- 14 Participants who remain compliant with placebo run-inadministrations, defined as ≥ 80% of planned doses over the last 7 days prior to Visit 3, based onePRO diary data.
- 2 Participants who have a documented history of physician-diagnosed COPD as defined by the ATS/ERS (Celli et al 2004).
- 3 Participants who have been receiving LABA, LAMA, LAMA/LABA, or ICS/LABA inhaled maintenance therapies for the management of their COPDfor at least 4 weeks prior to Visit 1, OR Participants who have been receiving SABA, SAMA, or SABA/SAMAeither scheduled or as needed for at least 4 weeks prior to Visit 1, OR Participants who are COPD treatment-naïve or have not received previously prescribed COPD treatment in the 4 weeks prior to Visit 1.
- 4 At Visit 1: Participants with a blood eosinophil count < 300 cells/μL.
- 5 At Visit 1: Participants with a pre-bronchodilator FEV1 of < 80%predicted normal.
- 6 At Visit 2: Participants with a post-bronchodilator FEV1/FVC ratioof < 0.70 and a postbronchodilator FEV1 of ≥ 40% to < 80% predicted normal.
- 7 At Visit 3 (TP 1 Day 1): Participants with a pre-dose FEV1 of <80% predicted normal that is within ± 20% or 200 mL of their Visit 2 pre-bronchodilatorFEV1 and an FEV1/FVC ratio of < 0.70.
- 8 Current or former smokers with a history of at least 10 pack-years of tobacco smoking (1 pack-year = 20 cigarettes smoked per day for one year).
- 9 Participants who are willing and, in the opinion of the Investigator, able to adjust current COPD therapy, as required by the protocol.
- 15 Participants who are willing to remain at the study centre as required per protocol to complete all visit assessments.
Exclusion Criteria
- 1.Confirmed diagnosis of asthma, in the opinion of the Investigator based on thorough review of medical history and medical records.
- 2.COPD due to α1-antitrypsin deficiency.
- 3.A COPD exacerbation treated with systemic corticosteroids or antibiotics within 4 months prior to Visit 1 or during the Screening Period.
- 4.A COPD exacerbation that required hospitalisation within 12 months prior to Visit 1 or during the Screening Period.
- 5.A respiratory infection ending within 4 weeks prior to Visit 1 or beginning or ending during the Screening Period, per the Investigator’s judgement.
- 6.Life-threatening COPD (eg, need for mechanical ventilation) at any time prior to Visit 1 or during the Screening Period.
- 7.A SARS CoV 2 infection in the 8 weeks prior to Visit 1 or during the Screening Period, or that required hospitalisation at any time prior to Visit 1 or during the Screening Period.
- 8.Sleep apnoea that, in the opinion of the Investigator, is uncontrolled.
- 9.Other respiratory disorders including, but not limited to, known active tuberculosis, lung cancer, cystic fibrosis, significant bronchiectasis (high-resolution CT evidence of bronchiectasis that causes repeated acute exacerbations), severe neurological disorders affecting control of the upper airway, sarcoidosis, primary ciliary dyskinesia, idiopathic interstitial pulmonary fibrosis, primary pulmonary hypertension, or pulmonary thromboembolic disease.
- 10.Significant or unstable ischaemic heart disease, arrhythmia, cardiomyopathy, heart failure, uncontrolled hypertension as defined by the Investigator, or any other relevant cardiovascular disorder as judged by the Investigator.
- 11.Diagnosis of narrow-angle glaucoma that has not been adequately treated, or a change in vision that may be relevant, in the opinion of the Investigator. Note: All medications approved for control of intraocular pressures are allowed, including topical ophthalmic nonselective beta-blockers and prostaglandin analogues.
- 12.Symptomatic prostatic hypertrophy or bladder neck obstruction/urinary retention that, in the opinion of the Investigator, is clinically significant.
- 13.Unresectable cancer that has not been in complete remission for at least 5 years prior to Visit 1. Note: Squamous cell and basal cell carcinomas of the skin are allowed.
- 14.Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular, hepatic, renal, haematological, neurological, endocrine, gastrointestinal, or pulmonary. Immune deficiency disorders (ie, HIV infection) should be excluded even if controlled. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the participant at risk through participation, or that could affect the efficacy or safety analysis if the disease/condition is exacerbated during the study.
- 15.Participants with a known hypersensitivity to beta2-agonists, muscarinic antagonists, or corticosteroids, or any component of the MDI.
- 16.Known history of drug or alcohol abuse within 12 months of Visit 1 or known abuse at any time during the study.
- 17.History of QT prolongation associated with another medication that required discontinuation of that medication.
- 18.Unable to abstain from short-acting bronchodilators within 6hours prior to lung function testing at each study visit.
- 19.Pulmonary resection or lung volume reduction surgery during the 6 months prior to Visit 1 (ie, lobectomy, bronchoscopic lung volume reduction [endobronchial blockers, airway bypass, endobronchial valves, thermal vapour ablation, biological sealants, and airway implants]).
- 20.Long-term-oxygen therapy or nocturnal oxygen therapy required for greater than 15 hours per day. Note: As-needed oxygen use is allowed.
- 21.Trans-urethral resection of the prostate or full resection of the prostate within 6 months prior to Visit 1.
- 22.Unable to abstain from any protocol-defined prohibited medications during the Screening or Treatment Periods (see Section 6.9).
- Participants with ECG QTcF interval > 480 milliseconds.
- Participants with high-degree atrioventricular block II or III, or with sinus node dysfunction with clinically significant pauses who are not treated with pacemaker.
- Any clinically relevant abnormal findings in physical examination, clinical chemistry, haematology, urinalysis, vital signs, or ECG which, in the opinion of the Investigator, may put the participant at risk because of their participation in the study.
- Planned hospitalisation during the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 24 Jan 2024 | 24 |
 Hungary | Not Recruiting | 24 Jan 2024 | 15 |
 Poland | Not Recruiting | 24 Jan 2024 | 10 |
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 |
|---|---|---|---|---|---|---|
Trixeo Aerosphere 5 micrograms/7.2 micrograms/160 micrograms pressurised inhalation, suspension | Test | PRESSURISED INHALATION, SUSPENSION | INHALATION USE | 4 | 4 | PRD8600543 |
SALBUTAMOL | Other | — | INHALATION USE | 0 | 12 | SUB10422MIG |
Placebo MDI HFA to match BGF MDI HFA | Placebo | N/A | — | — | — | N/A |
Trixeo Aerosphere 5 micrograms/7.2 micrograms/160 micrograms pressurised inhalation, suspension | Comparator | PRESSURISED INHALATION, SUSPENSION | INHALATION USE | 4 | 4 | PRD8600526 |