Comparative Efficacy of Once-daily LAMA/LABA Combinations Versus Tiotropium on Constant-work-rate Cycle Endurance in COPD

Overview

This study is designed to directly compare the effects of widely available long-acting bronchodilator therapies in patients with chronic obstructive pulmonary disease (COPD). The trial evaluates three fixed-dose combinations of a long-acting beta-2 agonist and a long-acting muscarinic antagonist (LABA/uLAMA)-umeclidinium/vilanterol (Anoro® Ellipta), indacaterol/glycopyrronium (Ultibro® Breezhaler), and tiotropium/olodaterol (Spiolto® Respimat)-against tiotropium (Spiriva®), a long-acting muscarinic antagonist (LAMA) used as monotherapy. The primary aim is to assess their impact on exercise capacity, with additional evaluation of pharmacoeconomic outcomes. The study follows a prospective, randomized, open-label, four-period crossover design. Approximately 100 patients with stable COPD will be enrolled from the 2nd Department of Pulmonology and Tuberculosis, Medical University of Białystok, and the University Hospital Pulmonology Outpatient Clinic. Each treatment will last 28 days, separated by a 7-day wash-out period, so that every participant will receive each therapy. Assessments will include standard clinical examinations, lung function testing (spirometry, body plethysmography, DLCO, multiple-breath washout), cardiopulmonary exercise testing (CPET) on a cycle ergometer, the 6-minute walk test, validated questionnaires (SGRQ, CAT, mMRC, BODE index), laboratory tests, and imaging. These procedures are part of routine COPD evaluation and will allow detailed monitoring of respiratory function, exercise tolerance, and quality of life. The study aims to determine whether dual bronchodilation with LABA/uLAMA combinations provides superior improvements in exercise performance and overall efficiency compared to tiotropium alone. Results may help guide clinical decision-making and optimize cost-effectiveness in COPD management.

Rationale and Objectives Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation, exertional dyspnea, and exercise intolerance, with dynamic and static hyperinflation as key physiological determinants of symptoms and functional limitation. Long-acting bronchodilators are a cornerstone of COPD management. Fixed-dose combinations of a long-acting β2-agonist with an ultra-long-acting muscarinic antagonist (LABA/uLAMA) may reduce hyperinflation more effectively than LAMA monotherapy, but direct, head-to-head evidence across the marketed combinations remains limited, particularly with objective exercise endpoints. Primary objective: to compare the effect of marketed LABA/uLAMA combinations versus tiotropium (LAMA) on exercise capacity in patients with COPD. Key secondary aim: to compare pharmacoeconomic efficiency (cost and cost-effectiveness metrics) among these therapies. Design Overview Prospective, randomized, open-label, four-period crossover (head-to-head) study conducted at a single academic center. Each treatment period lasts 28 days, separated by a 7-day wash-out. Every participant receives each study treatment according to a randomized sequence. The crossover design allows within-patient comparisons that limit between-subject variability. (Enrollment numbers, dates, allocation, and arm details are provided in the structured fields.) Setting and Eligibility Single-center study at the 2nd Department of Pulmonology and Tuberculosis, Medical University of Białystok, and the affiliated University Hospital Pulmonology Outpatient Clinic. Adults with a confirmed diagnosis of COPD were eligible per protocol-specified spirometric criteria and clinical stability. Key exclusions included major cardiovascular instability (e.g., recent myocardial infarction, unstable angina, uncontrolled arrhythmia), critical valvular disease, acute inflammatory or metabolic conditions that would confound exercise testing, inability to safely perform exercise testing, and conditions precluding informed cooperation. (Complete inclusion/exclusion lists are captured in the Eligibility section.) Interventions (all are approved, marketed medicines used within labeled dosing schedules) Indacaterol/glycopyrronium (Ultibro® Breezhaler) Umeclidinium/vilanterol (Anoro® Ellipta) Tiotropium/olodaterol (Spiolto® Respimat) Tiotropium (Spiriva® Respimat; monotherapy comparator) Each treatment is administered once daily for 28 days. Devices and dosing follow local marketing authorizations. Study drugs are provided at no cost during participation. Inhaler technique is checked at the start of each period. Assessments and Procedures To minimize duplication, instrument names and schedules are summarized here; specific timepoints and windows are in the Outcomes and Arms modules. Assessments reflect routine COPD evaluation augmented by objective exercise testing. Clinical and patient-reported measures: blood pressure; anthropometrics (height, weight, BMI); Saint George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), modified Medical Research Council (mMRC) dyspnea scale, and BODE index. Pulmonary function: spirometry with bronchodilator testing; body plethysmography (including IC, FRC, TLC, RV as applicable); diffusing capacity (DLCO); multiple-breath washout (MBW) with lung clearance index (LCI). Exercise capacity: cardiopulmonary exercise testing (CPET) on a cycle ergometer (incremental test to determine peak work rate; constant-work-rate endurance testing at a fixed fraction of peak); 6-minute walk test (6MWT). CPET includes standard gas-exchange and ventilatory measurements with safety monitoring and predefined termination criteria. Imaging (baseline or as clinically indicated): chest radiography; transthoracic echocardiography. Laboratory tests: complete blood count with differential, hsCRP, cardiac biomarkers (troponin, NT-proBNP), arterial blood gas, serum electrolytes, renal function (creatinine), miostatin and thyroid function (TSH, fT3, fT4). Endpoints (summary) Primary endpoint: change in exercise capacity assessed by constant-work-rate CPET endurance time (ET) at a standardized submaximal workload. Key physiologic endpoints: inspiratory capacity (IC) during CPET (dynamic hyperinflation), static IC and FRC by plethysmography, and standard ventilatory/metabolic CPET variables (e.g., VO₂, VCO₂, RER). Patient-reported and functional: SGRQ, CAT, mMRC, BODE, and 6MWT distance. Pharmacoeconomic endpoints (post-hoc analysis): direct drug costs (local currency), incremental cost-effectiveness ratio (ICER), threshold prices versus ICER and therapy cost differences, and subgroup effects by clinical phenotype. (Primary and secondary outcome measures with time frames are specified in the Outcomes module; MCID thresholds and analysis populations are described in Statistical Analysis.) Randomization and Sequence Participants are randomized to balanced treatment sequences to ensure that each drug is received in a distinct period by each participant. Wash-out periods (7 days) aim to reduce carryover. The open-label approach reflects real-world device use; outcome assessors follow standardized procedures. Safety and Test Termination Exercise testing follows accepted safety standards with continuous monitoring and predefined termination criteria (e.g., patient request, inability to maintain cadence, concerning ECG changes, presyncope). Clinical laboratory and imaging evaluations identify conditions that could contraindicate testing. Adverse events and COPD exacerbations are recorded throughout. Statistical Considerations (summary) Analyses emphasize within-patient comparisons across periods using mixed-effects models adjusted for period and baseline values. Multiplicity is handled with step-down procedures where applicable. Analytic populations include intention-to-treat and per-protocol sets. Minimal clinically important differences (MCIDs) for endurance outcomes guide interpretation. Pharmacoeconomic outcomes are analyzed post-hoc using standard cost-effectiveness methods. (Full statistical methods are summarized in the Statistical Analysis section of the record.) Ethics The study protocol received approval from the Bioethics Committee at the Medical University of Białystok (approval ID provided in the Administrative Information section). All participants provide written informed consent prior to any study-specific procedure. All products are approved/marketed; no U.S. FDA IND/IDE applies. Notes on Data Entry Original planning anticipated enrollment up to approximately 100 COPD patients; actual enrollment, study dates, and status are reported in the structured fields (to avoid duplication here). Drug names, devices, and dosing schedules are provided under Arms/Interventions. Detailed inclusion/exclusion criteria are listed in Eligibility.