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

Comparative Efficacy of Once-daily LAMA/LABA Combinations Versus Tiotropium on Constant-work-rate Cycle Endurance in COPD: Randomised Crossover Study (COMPETE)

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.

Study Overview

• Status: Suspended
• Conditions: COPD (Chronic Obstructive Pulmonary Disease)
• Intervention / Treatment: Drug: Tiotropium; Drug: Olodaterol; Drug: Umeclidinium; Drug: Vilanterol; Drug: Indacaterol; Drug: Glycopyrronium

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Poland
  • Podlaskie Voivodeship
    • Bialystok, Podlaskie Voivodeship, Poland, 15-540
      • II Department of Lung Diseases, Lung Cancer and Internal Diseases

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Signed informed consent for study participation

Diagnosis of COPD

Age ≥30 years and ≤70 years

Post-bronchodilator FEV₁ ≤80% and ≥30% predicted

BMI ≥15 kg/m² and <40 kg/m²

Exclusion Criteria:

• Lack of informed consent for study participation

No confirmed diagnosis of COPD

Age <30 years or >70 years

FEV₁ >80% or <30% predicted

BMI <15 kg/m² or ≥40 kg/m²

Inability to self-care or lack of long-term family or caregiver support

Recent myocardial infarction (within 3 months before enrollment)

Unstable angina

Uncontrolled arrhythmias detected on ECG at screening or immediately before CPET

Critical aortic stenosis at screening

Acute myocarditis or pericarditis

Acute cardiovascular conditions such as pulmonary embolism, aortic dissection, or endocarditis

Acute systemic conditions that may interfere with exercise testing or worsen under stress (e.g., infections, renal failure, thyrotoxicosis)

Deep vein thrombosis

Uncontrolled asthma

Physical disability preventing safe and adequate CPET performance

Cognitive impairment precluding cooperation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tiotropium (LAMA); Participants receive tiotropium 2.5 μg per actuation, 2 inhalations once daily (Spiriva Respimat®) for 28 days.	Drug: Tiotropium; Tiotropium bromide, long-acting muscarinic antagonist (LAMA). Administered as 2.5 μg per actuation, 2 inhalations once daily via Respimat inhaler for 28 days.; Other Names: Spiriva; Spiriva Respimat
Experimental: Tiotropium/Olodaterol (LAMA/LABA); Participants receive tiotropium 2.5 μg + olodaterol 2.5 μg per actuation, 2 inhalations once daily (Spiolto Respimat®) for 28 days.	Drug: Tiotropium; Tiotropium bromide, long-acting muscarinic antagonist (LAMA). Administered as 2.5 μg per actuation, 2 inhalations once daily via Respimat inhaler for 28 days.; Other Names: Spiriva; Spiriva Respimat; Drug: Olodaterol; Olodaterol, long-acting beta2-agonist (LABA). Administered as 2.5 μg per actuation, 2 inhalations once daily via Respimat inhaler for 28 days in combination with tiotropium.
Experimental: Umeclidinium/Vilanterol (LAMA/LABA); Participants receive umeclidinium 55 μg + vilanterol 22 μg, 1 inhalation once daily (Anoro Ellipta®) for 28 days.	Drug: Umeclidinium; Umeclidinium bromide, long-acting muscarinic antagonist (LAMA). Administered as 55 μg, 1 inhalation once daily via Ellipta inhaler for 28 days in combination with vilanterol.; Drug: Vilanterol; Vilanterol, long-acting beta2-agonist (LABA). Administered as 22 μg, 1 inhalation once daily via Ellipta inhaler for 28 days in combination with umeclidinium.
Experimental: Indacaterol/Glycopyrronium (LABA/LAMA); Participants receive indacaterol 110 μg + glycopyrronium 54 μg, 1 capsule inhaled once daily (Ultibro Breezhaler®) for 28 days.	Drug: Indacaterol; Indacaterol maleate, long-acting beta2-agonist (LABA). Administered as 110 μg, 1 capsule inhaled once daily via Breezhaler device for 28 days in combination with glycopyrronium.; Drug: Glycopyrronium; Glycopyrronium bromide, long-acting muscarinic antagonist (LAMA). Administered as 54 μg, 1 capsule inhaled once daily via Breezhaler device for 28 days in combination with indacaterol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endurance time during constant-work-rate cycle ergometry (CWRCE)	Change in endurance time (ET) during constant-work-rate exercise testing at 80% peak workload, measured by cardiopulmonary exercise testing (CPET).	Baseline and after 28 days of each treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak oxygen uptake (VO₂peak) during CPET	Change in peak oxygen uptake measured during cardiopulmonary exercise testing (CPET).	Baseline and after 28 days of each treatment period
Oxygen uptake (VO₂) at isotime during CPET	Change in oxygen uptake at isotime measured during cardiopulmonary exercise testing (CPET).	Baseline and after 28 days of each treatment period
Forced expiratory volume in 1 second (FEV₁)	Change in forced expiratory volume in 1 second (FEV₁).	Baseline and after 28 days of each treatment period
Forced vital capacity (FVC)	Change in forced vital capacity (FVC).	Baseline and after 28 days of each treatment period
Inspiratory capacity at rest during CPET	Change in inspiratory capacity at rest measured during cardiopulmonary exercise testing (CPET).	Baseline and after 28 days of each treatment period
Inspiratory capacity at isotime during CPET	Change in inspiratory capacity at isotime measured during cardiopulmonary exercise testing (CPET).	Baseline and after 28 days of each treatment period
Inspiratory capacity at peak exercise during CPET	Change in inspiratory capacity at peak exercise measured during cardiopulmonary exercise testing (CPET).	Baseline and after 28 days of each treatment period
St. George's Respiratory Questionnaire (SGRQ) total score	Change in St. George's Respiratory Questionnaire (SGRQ) total score. Scores range from 0 to 100, with lower scores indicating better health-related quality of life and higher scores indicating worse health-related quality of life.	Baseline and after 28 days of each treatment period
Dyspnoea intensity at isotime measured by the Modified Borg Dyspnoea Scale	Change in dyspnoea intensity at isotime measured by the Modified Borg Dyspnoea Scale. Scores range from 0 to 10, with lower scores indicating less dyspnoea and higher scores indicating more severe dyspnoea.	Baseline and after 28 days of each treatment period
COPD Assessment Test (CAT) total score	Change in COPD Assessment Test (CAT) total score. Scores range from 0 to 40, with lower scores indicating a better outcome and higher scores indicating a worse outcome.	Baseline and after 28 days of each treatment period
Veterans Specific Activity Questionnaire (VSAQ) score	Change in Veterans Specific Activity Questionnaire (VSAQ) score. Scores range from 1 to 13, with higher scores indicating greater exercise capacity.	Baseline and after 28 days of each treatment period
Duke Activity Status Index (DASI) total score	Change in Duke Activity Status Index (DASI) total score. Scores range from 0 to 58.2, with higher scores indicating better functional capacity.	Baseline and after 28 days of each treatment period
Dyspnoea intensity at peak exercise measured by the Modified Borg Dyspnoea Scale	Change in dyspnoea intensity at peak exercise measured by the Modified Borg Dyspnoea Scale. Scores range from 0 to 10, with lower scores indicating less dyspnoea and higher scores indicating more severe dyspnoea.	Baseline and after 28 days of each treatment period
Modified Medical Research Council (mMRC) Dyspnoea Scale score	Change in Modified Medical Research Council (mMRC) Dyspnoea Scale score. Scores range from 0 to 4, with lower scores indicating less dyspnoea and higher scores indicating more severe dyspnoea.	Baseline and after 28 days of each treatment period

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma myostatin concentration	Evaluation of circulating plasma myostatin levels as a biomarker of muscle metabolism and potential predictor of exercise capacity and treatment response in COPD patients.	Baseline V1 and after each 28-day treatment period
Body fat percentage assessed by bioelectrical impedance analysis	Change in body fat percentage assessed by bioelectrical impedance analysis performed under standardized conditions.	Baseline V1 and after 28 days of each treatment period
Fat-free mass assessed by bioelectrical impedance analysis	Change in fat-free mass assessed by bioelectrical impedance analysis performed under standardized conditions.	Baseline V1 and after 28 days of each treatment period
Skeletal muscle mass assessed by bioelectrical impedance analysis	Change in skeletal muscle mass assessed by bioelectrical impedance analysis performed under standardized conditions.	Baseline V1 and after 28 days of each treatment period
Visceral fat level assessed by bioelectrical impedance analysis	Change in visceral fat level assessed by bioelectrical impedance analysis performed under standardized conditions.	Baseline V1 and after 28 days of each treatment period

Collaborators and Investigators

• Sponsor: Medical University of Bialystok
• Investigators: Principal Investigator: Robert M Mroz, professor, Medical University of Bialystok

Publications and helpful links

General Publications

• Mejza F.: Postępowanie w przewlekłej obturacyjnej chorobie płuc. Podsumowanie wytycznych Global Initiative for Obstructive Lung Disease (GOLD) 2020. Med. Prakt., 2020; 2: 38-50
• 5. Koarai, A., Sugiura, H., Yamada, M. et al. Treatment with LABA versus LAMA for stable COPD: a systematic review and meta-analysis. BMC Pulm Med 20, 111 (2020). https://doi.org/10.1186/s12890-020-1152-8
• A. Bourdin, P-R Burgel, P. Chanez, G. Garcia, T. Perez, N. Roche Recent advances in COPD: pathophysiology, respiratory physiology and clinical aspects, including comorbiditiesEuropean Respiratory Review Dec 2009, 18 (114) 198-212;
• Bill B Brashier , Rahul Kodgule, Risk Factors and Pathophysiology of Chronic Obstructive Pulmonary Disease (COPD), The Journal of the Association of Physicians of India, 2012
• 1. World Health Organization. Chronic Obstructive Pulmonary Disease. Key Facts https://www.who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease- (copd)

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2024
• Primary Completion (Actual): February 7, 2025
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: April 7, 2026
• First Submitted That Met QC Criteria: April 16, 2026
• First Posted (Actual): April 21, 2026

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: exercise capacity; Chronic Obstructive Pulmonary Disease; bronchodilators; LABA/LAMA; copd; cardiopulmonary exercise testing; cpet; laba; lama; Pulmonary Disease Chronic Obstructive; uLAMA
• Additional Relevant MeSH Terms: Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pathological Conditions, Signs and Symptoms; Pulmonary Disease, Chronic Obstructive; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Alkaloids; Amines; Aza Compounds; Quaternary Ammonium Compounds; Onium Compounds; Pyrrolidines; Heterocyclic Compounds, Bridged-Ring; Tropanes; Azabicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Scopolamine Derivatives; Tiotropium Bromide; Glycopyrrolate; GSK573719; vilanterol; indacaterol; olodaterol
• Other Study ID Numbers: APK.002.200.300.2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: There are currently no plans to share individual participant data (IPD) due to resource and privacy constraints. However, summary results will be published in peer-reviewed journals

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No