A Double Blind, Multicentre, Randomised Three-Period, Three-Treatment, Cross-Over Study To Evaluate The Effect of BGF MDI, BFF MDI and Placebo MDI on Exercise Parameters In Participants with Chronic Obstructive Pulmonary Disease (ATHLOS)
- Trial ID
- 2022-502274-16-00
- Protocol
- D5988C00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **Budesonide, Glycopyrronium, and Formoterol Fumarate** (BGF) metered dose inhaler (MDI) compared to Placebo MDI and Budesonide and Formoterol Fumarate (BFF) MDI on dynamic hyperinflation in participants with **Chronic Obstructive Pulmonary Disease** (COPD). Dynamic hyperinflation is a critical factor in COPD as it contributes to exercise limitation and dyspnea, impacting the quality of life and overall disease management.
Secondary objectives include:
- Assessing the effect of BGF MDI relative to Placebo MDI and BFF MDI on exercise endurance time in COPD participants.
- Evaluating the effect of BGF MDI compared to Placebo MDI on isotime dyspnea in COPD participants.
- Comparing the effect of BGF MDI to BFF MDI on isotime dyspnea and static lung volumes in COPD participants.
- Assessing the effect of BFF MDI relative to Placebo on exercise endurance time, isotime dyspnea, and static lung volumes in COPD participants.
- Evaluating the safety and tolerability of BGF MDI and BFF MDI.
Participants
The clinical trial involves a total of **139 participants** diagnosed with **Chronic Obstructive Pulmonary Disease (COPD)**. The study population comprises both male and female subjects, aged between **40 to 80 years**. Participants were selected based on specific criteria, including a confirmed diagnosis of COPD with a post-bronchodilator Forced Expiratory Volume in 1 second/Forced Vital Capacity (FEV1/FVC) ratio of less than 0.7, and a history of smoking with at least 10 pack-years. The trial includes individuals who are on stable mono- or dual inhaled maintenance COPD treatment. Participants are required to have a Body Mass Index (BMI) of less than 40 kg/m². The study considers lifestyle factors such as smoking history and current COPD treatment regimen. Both genders are included, with specific considerations for females regarding reproductive status and contraceptive use. The trial population is not limited to a vulnerable population, ensuring a diverse representation of individuals affected by COPD.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled, cross-over study to evaluate the effects of Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) metered dose inhaler (MDI) compared to a placebo MDI and Budesonide and Formoterol Fumarate (BFF) MDI on exercise parameters in participants with **Chronic Obstructive Pulmonary Disease (COPD)**. The trial is set to run from September 2023 to August 2025, with an estimated duration of 23 months. Participants will be involved in the study for a maximum of 12 weeks, during which they will undergo a series of study visits.
The sequence of study visits includes an initial screening visit to confirm eligibility based on specific inclusion criteria, such as age, smoking history, and COPD diagnosis. Following successful screening, participants will be randomized into one of the treatment groups. The trial consists of three treatment periods, each followed by a washout period to minimize carryover effects. During each treatment period, participants will receive one of the three interventions: BGF MDI, BFF MDI, or placebo MDI. The primary endpoint is the measurement of isotime inspiratory capacity, while secondary endpoints include exercise endurance time and static lung volumes.
Participants will attend regular follow-up visits to monitor their health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will occur after the final treatment period, where comprehensive assessments will be conducted to evaluate the overall effects of the interventions. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of serious adverse events. The trial aims to provide valuable insights into the management of COPD and the potential benefits of the investigational treatments.
Treatment
The clinical trial involves the administration of several treatments to evaluate their effects on exercise parameters in participants with **Chronic Obstructive Pulmonary Disease (COPD)**. The experimental medication, **Trixeo Aerosphere**, is a pressurised inhalation suspension containing a combination of **Budesonide**, **Glycopyrronium Bromide**, and **Formoterol Fumarate Dihydrate**. This medication is administered via inhalation, with a maximum daily dose of 4 dosage forms, and a maximum treatment period of 10 weeks. The device used for administration is a metered dose inhaler (MDI) with a white actuator for blinding purposes. Participant compliance is monitored through regular assessments and device usage tracking.
Another experimental treatment in the study is a combination of **Formoterol Fumarate** and **Budesonide**, also delivered as a pressurised inhalation suspension. This treatment is administered using an MDI, with a maximum daily dose of 4 dosage forms and a treatment period of up to 10 weeks. The inhalation route ensures targeted delivery to the lungs, and compliance is monitored similarly to the Trixeo Aerosphere treatment.
The study also includes the administration of **Salbutamol**, a selective beta-2-adrenoreceptor agonist, as an auxiliary treatment. Salbutamol is provided as a pressurised inhalation suspension, with a maximum daily dose of 800 micrograms and a treatment period of up to 12 weeks. This medication is administered via inhalation, and participant adherence is tracked through device usage and regular follow-ups.
A **placebo** pressurised inhalation suspension is used as a comparator treatment in the study. The placebo is administered via inhalation, mimicking the administration schedule of the active treatments to maintain blinding and ensure the integrity of the study results. Compliance with the placebo treatment is monitored in the same manner as the active treatments, ensuring consistency across all study arms.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating the effect of Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) metered dose inhaler (MDI) relative to Placebo MDI and Budesonide and Formoterol Fumarate (BFF) MDI on dynamic hyperinflation in participants with **Chronic Obstructive Pulmonary Disease (COPD)**. The primary endpoint for efficacy assessment is the Isotime Inspiratory Capacity (IC). Secondary endpoints include constant work rate cycle ergometry endurance time, isotime dyspnea Numerical Rating Scale (NRS), static lung volumes such as Functional Residual Capacity (FRC), Total Lung Capacity (TLC), Residual Volume (RV), RV/TLC, specific airway conductance (sGaw), and Inspiratory Capacity (IC). Additionally, exercise endurance time and adverse events, including serious adverse events and adverse events leading to discontinuation of study intervention, will be monitored. Vital signs will also be recorded as part of the efficacy assessment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female, 40 to 80 years of age inclusive, at the time of signing the informed consent.
- Participant must have: (a) A diagnosis of Chronic obstructive pulmonary disease (COPD) confirmed by a post-bronchodilator Forced Expiratory Volume in 1 second/Forced Vital Capacity (FEV1/FVC) < 0.7 at Visit 1. (b) A post-bronchodilator Forced Expiratory Volume in 1 second (FEV1) ≥ 30% and < 80% predicted normal (moderate to severe Chronic obstructive pulmonary disease (COPD)) at Visit 1. (c) A score of ≥ 2 on the modified Medical Research Council (mMRC) at Visit 1. (d) Pre-bronchodilator Functional Residual Capacity (FRC) of > 120% of predicted normal FRC values at Visit 1.
- Participant must be on mono- or dual inhaled maintenance Chronic Obstructive Pulmonary Disease (COPD) treatment at a stable dose for 6 weeks (Long-Acting Muscarinic Antagonist (LAMA), Long-Acting Beta2-Agonist (LABA), Long-Acting Muscarinic Antagonist/ Long-Acting Beta2- Agonist (LAMA/LABA), or Inhaled Corticosteroid/ Long- Acting Beta2-Agonist (ICS/LABA)).
- Current or former smoker with a history of ≥ 10 pack-years of tobacco smoking.
- Willing and, in the opinion of the investigator, able to adjust current Chronic Obstructive Pulmonary Disease (COPD) therapy, as required by the protocol (including Placebo periods).
- Willing to visit at the study site as required per protocol to complete all visit assessments.
- A Body Mass Index (BMI) < 40 kg/m2 .
- A female is eligible to enter and participate in the study if the female is of: (a) Non-childbearing potential: either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. A female will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomization without an alternative medical cause. The following age-specific requirements apply: (i) Female < 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle-stimulating hormone levels in the postmenopausal range. (ii) Female ≥ 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment. (b) Childbearing potential, has a negative serum pregnancy test at Visit 1 and must use one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly. At enrollment, women of childbearing potential who are sexually active with a non-sterilized male partner should be stable on their chosen method of highly effective birth control, as defined below, and willing to remain on the birth control until at least 14 days after last dose of study intervention. Cessation of contraception after this point should be discussed with a responsible physician. (c) Highly effective birth control methods include: - Sexual abstinence as defined as complete abstinence from intercourse when it is the preferred and usual lifestyle of the participant (however, periodic abstinence eg, calendar, ovulation, symptothermal, post-ovulation methods, declaration of abstinence for the duration of exposure to study intervention, and withdrawal are not acceptable methods of contraception). - Contraceptive subdermal implant. - Intrauterine device or intrauterine system. - Oral contraceptive (combined or progesterone only). - Injectable progestogen. - Contraceptive vaginal ring. - Percutaneous contraceptive patches. - Male partner sterilization with documentation of azoospermia prior to the female participant’s entry into the study, and this male is the sole partner for that participant. The documentation on male sterility can come from the study site personnel’s review of participant’s medical records, medical examination and/or semen analysis or medical history interview provided by her or her partner. - Bilateral tubal ligation
- Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in the protocol.
Exclusion Criteria
- A current diagnosis of asthma, asthma-Chronic Obstructive Pulmonary Disease (COPD)-overlap, or any other chronic respiratory disease other than Chronic Obstructive Pulmonary Disease (COPD) such as alpha-1 antitrypsin deficiency, active tuberculosis, lung cancer, lung fibrosis, sarcoidosis, interstitial lung disease and pulmonary hypertension.
- Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular, hepatic, renal, hematological, neurological, endocrine, gastrointestinal, or pulmonary. 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 analyses.
- Participants on oxygen therapy or that desaturate significantly (<82%) during exercise.
- Participants who are enrolled or entering a pulmonary rehabilitation program during the study (from Visit 1 onwards). These participants will be allowed to re-screen after completion of the pulmonary rehabilitation program.
- Participants who have cancer that has not been in complete remission for at least 5 years. Note: Participants with squamous cell carcinoma of the skin, basal cell carcinoma of the skin in complete remission for 1 year are allowed in the study.
- Participants with a diagnosis of narrow-angle glaucoma that has not been adequately treated and/or change in vision that may be relevant, in the opinion of the investigator. All medications approved for control of intraocular pressures are allowed including topical ophthalmic non-selective beta-blockers and prostaglandin analogues.
- Participants with symptomatic prostatic hypertrophy or bladder neck obstruction/urinary retention that, in the opinion of the investigator, is clinically significant. Note: Participants with trans-urethral resection of prostate or full resection of the prostate within 6 months prior to Visit 1 are excluded from the study.
- Participants who have a history of hypersensitivity to β2-agonists, budesonide or any other corticosteroid components, glycopyrronium or other muscarinic anticholinergics, or any component of the metered dose inhaler (MDI) or dry powder inhaler.
- Participant with resting (5 minutes) oxygen saturation SaO2 in room air ≤ 85%.
- A Chronic Obstructive Pulmonary Disease (COPD) exacerbation that requires hospitalization within 12 months prior to Visit 1 or a COPD exacerbation that requires systemic corticosteroids or antibiotics within 4 months of Visit 1.
- Participants with contraindications to cardiopulmonary exercise testing, including (but not limited to): (a) Acute myocardial infarction (within 6 months prior to Visit 1). (b) Unstable angina. (c) Uncontrolled arrhythmias, including atrial fibrillation with uncontrolled ventricular rate. (d) Active endocarditis. (e) Acute myocarditis or pericarditis. (f) Symptomatic aortic stenosis. (g) Uncontrolled heart failure. (h) Pulmonary embolism, uncontrolled pulmonary edema. (i) Acute non-cardiac disorder that may affect exercise performance or be aggravated by exercise (eg, infection, renal failure, thyrotoxicosis, acute bleeding, electrolyte abnormalities). (j) Left main coronary stenosis or equivalent. (k) Moderate or severe stenotic valvular cardiac disease. (l) Severe untreated arterial hypertension (> 200 mmHg systolic, > 120 mmHg diastolic). (m) Severe pulmonary hypertension. (n) Syncope tachyarrhythmias or bradyarrhythmias. (o) Hypertrophic cardiomyopathy. (p) Mental impairment leading to limited ability to perform study procedures. (q) High degree atrioventricular block. (r) Deep venous thrombosis of lower extremities. (s) Suspected dissecting aneurysm. (t) Participants with uncontrolled Type I diabetes mellitus.
- Participants who have had a respiratory tract infection within 8 weeks prior to Visit 1 and/or during the screening period. . Participants who develop an upper or lower respiratory tract infection during the screening period will not be eligible, but will be permitted to be re-screened 8 weeks after the resolution of the respiratory tract infection.
- Participants with lung lobectomy, lung volume reduction (during the study and within 3 months of Visit 1), or lung transplantation.
- Unable to withhold short-acting bronchodilators for 6 hours prior to lung function testing at each study visit.
- Unable to abstain from protocol-defined prohibited medications.
- Participation in another clinical study with an investigational product administered in the last 30 days or 5 half-lives, whichever is longer prior to Visit 1 (any other investigational product that is not identified in this protocol is prohibited for use during the duration of the study).
- Participants with a known hypersensitivity to beta2-agonists, muscarinic antagonists, or corticosteroids, or any component of the metered dose inhaler (MDI).
- Participants with estimated Glomerular Filtration Rate (eGFR) ≤ 30 mL/minute/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.
- Any clinically relevant abnormal findings in physical examination, clinical chemistry, hematology, vital signs, or Electrocardiogram (ECG), which in the opinion of the investigator, may put the participant at risk because of his/her participation in the study. Note: Participants with Electrocardiogram QT Interval Corrected for Heart Rate (ECG QTcF) interval > 480 msec will be excluded. Participants with high degree atrioventricular block II or III, or with sinus node dysfunction with clinically significant pauses who are not treated with pacemaker will also be excluded.
- Investigatory safety concerns regarding the participant’s enrollment.
- Known history of drug or alcohol abuse within 12 months of Visit 1.
- Any regular recreational use of marijuana in the 12 months prior to Visit 1 and throughout the study, as per investigator’s discretion.
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
- Participants who have been previously randomized but subsequently withdrew from the study either by the investigator, sponsor, or self-withdrawal cannot be re-screened for the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 27 Sept 2023 | 109 |
 Spain | Not Recruiting | 27 Sept 2023 | 51 |
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 | 10 | PRD8600525 |
Placebo pressurized inhalation suspension | Placebo | N/A | — | — | — | N/A |
SALBUTAMOL | Other | — | INHALATION USE | 800 | 12 | SUB10422MIG |