Comparing once-daily combination inhalers with tiotropium to find which helps people with chronic obstructive pulmonary disease exercise longer

ISRCTN	ISRCTN94574860
DOI	https://doi.org/10.1186/ISRCTN94574860

Submission date: 26/10/2025
Registration date: 28/10/2025
Last edited: 28/10/2025

Recruitment status: No longer recruiting
Overall study status: Ongoing
Condition category: Respiratory

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
People with chronic obstructive pulmonary disease (COPD) often get short of breath and cannot exercise for long. Modern “combination” inhalers (two medicines in one) may help patients breathe more easily during exercise. This study compares three once-daily combination inhalers with tiotropium (a single-medicine inhaler) to see which helps people exercise for longer on a standard cycling test. The study also looks at breathing mechanics, fitness, symptoms, quality of life, blood levels of a muscle-related protein (myostatin), and body composition.

Who can participate?
Adults aged 40 years and older with stable COPD who can safely perform a cycling-based exercise test. Typical requirements include a history of smoking, moderate airflow limitation on breathing tests, and no recent COPD flare-ups. People with asthma, significant other lung diseases, or unstable heart conditions cannot take part.

What does the study involve?
This is a randomised, open-label, “crossover” study. Each participant tries four once-daily inhaler treatments in a random order.

Treatments: three combination inhalers (tiotropium/olodaterol; umeclidinium/vilanterol; indacaterol/glycopyrronium) and tiotropium alone (the comparator).

Duration: each treatment lasts 28 days, separated by a 7-day wash-out.

Visits and tests: at the start and end of each treatment period, participants do breathing tests (spirometry), a standard cycling test at a set effort (based on an initial test of their peak ability), symptom and quality-of-life questionnaires, a small blood sample (to measure myostatin), and body-composition measurements (e.g. fat-free mass). Inhaler technique is checked. Short-acting reliever inhalers are allowed if needed.

What are the possible benefits and risks of participating?
Some participants may notice easier breathing or longer exercise time, but personal benefit is not guaranteed. Risks are small but include temporary breathlessness or fatigue during exercise testing, rare heart-related events (tests are medically supervised with monitoring and clear stopping rules), common inhaler side effects (e.g. dry mouth, tremor, palpitations), minor discomfort or bruising from blood samples, and occasional light-headedness after exertion. Safety is monitored throughout.

Where is the study run from?
The study is run at a single academic centre: the Medical University of Białystok (Poland), 2nd Department of Lung Diseases, Lung Cancer and Internal Diseases.

When is the study starting and how long is it expected to run for?
The study started in March 2024 and ran until May 2025. It is retrospectively registered.

Who is funding the study?
This is an academic study supported by institutional resources from the Medical University of Białystok (grant); there is no specific external grant.

Who is the main contact?
Prof Robert M Mróz, 2nd Department of Lung Diseases, Lung Cancer and Internal Diseases, Medical University of Białystok, ul. Jana Kilińskiego 1, 15-089 Białystok, Poland; robert.mroz@umb.edu.pl

Contact information

Prof Robert Mroz
Principal investigator

Jana Kilińskiego 1
Białystok
15-089
Poland

ORCID ID	0000-0002-5826-7395
Phone	+48 85 831 6522
Email	robert.mroz@umb.edu.pl

Mr Jakub Mroz
Public, Scientific

Jana Kilinskiego 1
Bialystok
15-089
Poland

ORCID ID	0000-0002-0653-0833
Phone	+48 85 831 6395
Email	jakub.mroz@sd.umb.edu.pl

Study information

Study design	Single-centre interventional randomized open-label active-controlled four-period crossover trial
Primary study design	Interventional
Secondary study design	Randomised cross over trial
Study setting(s)	Hospital, Laboratory, University/medical school/dental school
Study type	Diagnostic, Efficacy, Quality of life, Safety, Treatment
Participant information sheet	48289 Patient information sheet ENG.pdf
Scientific title	Comparative efficacy of once-daily LAMA/LABA combinations versus tiotropium on constant-work-rate cycle endurance in COPD: a randomized crossover study
Study acronym	COMPETE
Study objectives	Primary objective: To determine whether once-daily combination bronchodilators (tiotropium/olodaterol, umeclidinium/vilanterol, indacaterol/glycopyrronium) increase cycling endurance time during a constant-work-rate test (set at 80% of baseline peak work) more than tiotropium after 28 days of treatment in adults with stable chronic obstructive pulmonary disease. Primary hypothesis: Each combination bronchodilator increases endurance time more than tiotropium (within-patient comparison in a crossover design). Secondary objectives: 1. Compare dynamic hyperinflation (inspiratory capacity at rest, at the same time point during exercise [isotime], and at peak; summarised as change from baseline) across treatments and versus tiotropium. 2. Compare spirometry (forced expiratory volume in 1 s; forced vital capacity) and ventilatory efficiency (ventilatory equivalent for carbon dioxide at the ventilatory/lactate threshold). 3. Compare oxygen-related measures (peak oxygen uptake; oxygen uptake at threshold; oxygen pulse; oxygen saturation) and peak heart rate. 4. Compare patient-reported outcomes (health status and symptoms; dyspnoea; functional capacity). 5. Estimate and compare the proportion of “endurance responders”, defined a priori as a gain in endurance time ≥ minimal clinically important difference (planned range 60–105 seconds). 6. Assess safety and tolerability. 7. Biomarker: Compare plasma myostatin levels pre- and post-treatment within each period and across treatments. 8. Body composition: Compare body-composition indices (e.g. fat-free mass, fat mass, skeletal muscle mass, fat-free mass index; plus anthropometry such as body mass index and waist circumference) pre- and post-treatment within each period and across treatments. Secondary hypotheses: Combination therapy will (a) reduce dynamic hyperinflation, (b) improve lung function more than tiotropium, (c) increase peak oxygen uptake and oxygen pulse, (d) show higher responder rates (≥ MCID) than tiotropium, (e) produce minimal changes in ventilatory efficiency, (f) have similar safety, (g) favourably change plasma myostatin and body-composition measures. Exploratory objective and hypothesis (mechanism): Changes in inspiratory capacity at isotime will partly mediate the treatment effect on endurance time; baseline and on-treatment myostatin and body composition may be associated with changes in endurance, oxygen uptake and patient-reported outcomes.
Ethics approval(s)	Approved 22/09/2022, Bioethics Committee of the Medical University of Bialystok (ul. Jana Kilińskiego 1, Bialystok, 15-089, Poland; +48 857485407; komisjabioetyczna@umb.edu.pl), ref: APK.002.200.300.2022
Health condition(s) or problem(s) studied	Stable chronic obstructive pulmonary disease in adult outpatients, focusing on exercise capacity/endurance assessed by constant-work-rate cycle testing.
Intervention	Interventional, randomised, open-label, four-period crossover trial: each participant receives four once-daily inhaled regimens in a balanced random order, each for 28 days with a 7-day washout between periods— 1. Tiotropium/olodaterol (Respimat®): 2 inhalations once daily (2.5 µg tiotropium + 2.5 µg olodaterol per actuation); 2. Umeclidinium/vilanterol (Ellipta®): 55/22 µg, 1 inhalation once daily; 3. Indacaterol/glycopyrronium (Breezhaler®): 110/54 µg, 1 capsule inhaled once daily; 4. Tiotropium (Respimat®) — active control: 2 inhalations once daily (2.5 µg per actuation). Randomisation: computer-generated balanced sequences (within-patient comparisons); no masking. Short-acting bronchodilators permitted as rescue; inhaler technique checked at the start of each period.
Intervention type	Drug
Pharmaceutical study type(s)	Pharmacodynamic, Therapeutic - Efficacy; Safety/Tolerability
Phase	Phase III/IV
Drug / device / biological / vaccine name(s)	Tiotropium bromide/olodaterol hydrochloride — Respimat® soft-mist inhaler, Umeclidinium bromide/vilanterol trifenatate — Ellipta® dry-powder inhaler, Indacaterol maleate/glycopyrronium bromide — Breezhaler® dry-powder inhaler (capsule), Tiotropium bromide — Respimat® soft-mist inhaler, Short-acting bronchodilators such as salbutamol/albuterol were permitted as rescue medication but were not protocol-assigned study treatments
Primary outcome measure	Cycling endurance time (seconds) measured using constant-work-rate cycle ergometry at 80% of baseline peak work during cardiopulmonary exercise testing (CPET; electronically braked cycle ergometer, breath-by-breath system—COSMED Quark CPET) at pre-treatment (Day 0) and post-treatment (Day 28) in each period; primary endpoint = change (post − pre) within period.
Secondary outcome measures	1. Dynamic hyperinflation (ΔΔIC) was measured using inspiratory capacity manoeuvres during constant-work-rate cycle ergometry (CWRCE) at 80% of baseline W_peak within CPET at Day 0 and Day 28 of each period. The summary metric was (IC_peak−IC_rest)_post − (IC_peak−IC_rest)_pre, with IC captured at rest, isotime, and peak. 2. Forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC) were measured using spirometry according to ATS/ERS standards at Day 0 and Day 28 of each period. 3. Ventilatory efficiency (VE/VCO₂ at the ventilatory/lactate threshold) was measured using breath-by-breath CPET, with the threshold determined by V-slope and ventilatory equivalents at Day 0 and Day 28 of each period. 4. Peripheral oxygen saturation (SpO₂) was measured using pulse oximetry during CPET at rest, isotime, and peak on Day 0 and Day 28 of each period. 5. Peak heart rate (HR_max) was measured using a 12-lead ECG signal within CPET at Day 0 and Day 28 of each period. 6. Peak oxygen uptake (VO₂peak; in mL·min⁻¹ and mL·kg⁻¹·min⁻¹, % predicted) was measured using breath-by-breath CPET at Day 0 and Day 28 of each period. 7. Oxygen uptake at ventilatory/lactate threshold (VO₂@VT₁/LT₁) was measured using CPET with VT₁/LT₁ determination at Day 0 and Day 28 of each period. 8. Oxygen pulse (VO₂/HR at peak) was derived from CPET by dividing VO₂peak by peak HR at Day 0 and Day 28 of each period. 9. Health status (SGRQ total score) and symptoms (CAT) were measured using validated questionnaires at Day 0 and Day 28 of each period. 10. Functional capacity (DASI, VSAQ) was measured using validated questionnaires at Day 0 and Day 28 of each period. 11. Dyspnoea was measured using the modified Medical Research Council scale (mMRC) at Day 0 and Day 28 of each period. 12. Plasma myostatin concentration was measured using enzyme-linked immunosorbent assay (ELISA) at Day 0 and Day 28 of each period. 13. Body composition indices including fat-free mass, fat mass, skeletal muscle mass, fat-free mass index, BMI, and waist circumference were measured using multi-frequency bioelectrical impedance analysis (BIA) and standard anthropometry at Day 0 and Day 28 of each period. 14. Safety and tolerability including adverse events, serious adverse events, and withdrawals due to adverse events were monitored using standardised AE recording throughout each 28-day treatment period and the subsequent 7-day washout.
Overall study start date	05/09/2022
Completion date	31/12/2025

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	40 Years
Upper age limit	75 Years
Sex	All
Target number of participants	100
Total final enrolment	16
Key inclusion criteria	1. Adults aged 40 years and older 2. Stable chronic obstructive pulmonary disease (COPD), GOLD stage II–III, managed as outpatients 3. Smoking history of at least 10 pack-years 4. Post-bronchodilator FEV₁/FVC ratio less than 0.70, measured by spirometry according to ATS/ERS standards 5. Post-bronchodilator FEV₁ between 35% and 70% of predicted value 6. Clinically stable at enrolment, with no acute deterioration requiring a change in treatment 7. Able to perform cardiopulmonary exercise testing (CPET) on an electronically braked cycle ergometer, including both incremental and constant-work-rate tests at 80% W_peak 8. Willing and able to comply with all study procedures across four 28-day treatment periods and associated wash-out phases 9. Provided written informed consent prior to any study-related procedures
Key exclusion criteria	1. Age less than 40 or greater than 75 years 2. Post-bronchodilator FEV₁/FVC ratio equal to or greater than 0.70, which does not meet the COPD airflow-limitation criterion 3. Post-bronchodilator FEV₁ less than 35% or greater than 70% of predicted, outside the target GOLD II–III range 4. Smoking history less than 10 pack-years 5. Recent COPD instability, including acute exacerbation, lower respiratory infection, or change in maintenance therapy within 4 weeks before screening 6. Frequent exacerbator phenotype, defined as two or more moderate or at least one severe exacerbation in the prior 12 months 7. Asthma or asthma–COPD overlap, including physician-diagnosed asthma or marked bronchodilator reversibility compatible with asthma (e.g. FEV₁ increase of 400 mL or more and 15% or more) 8. Significant non-COPD lung disease, such as interstitial lung disease, clinically relevant bronchiectasis, active pulmonary tuberculosis, or untreated obstructive sleep apnoea with daytime instability 9. Active malignancy, except adequately treated non-melanoma skin cancer, or other uncontrolled systemic inflammatory or autoimmune disease 10. Unstable cardiovascular disease, including recent myocardial infarction within 6 months, unstable angina, decompensated heart failure, clinically significant arrhythmia, symptomatic severe valvular disease, or uncontrolled hypertension greater than 180/110 mmHg 11. Contraindications to exercise testing per ATS/ACCP guidelines, including conditions that make CPET unsafe such as acute pulmonary embolism or severe aortic stenosis 12. Resting hypoxaemia requiring unstable oxygen therapy or any condition that makes CPET unsafe in the investigator’s judgement 13. Neuromuscular, musculoskeletal, or neurological limitation that precludes safe cycling or completion of CPET or CWRCE 14. Pregnancy or breastfeeding, or women of childbearing potential not using effective contraception 15. Known hypersensitivity or intolerance to tiotropium, olodaterol, indacaterol, glycopyrronium, umeclidinium, vilanterol, or inhaler excipients 16. Use of prohibited medications or procedures, including investigational drugs within 30 days, chronic systemic corticosteroids over 10 mg prednisolone equivalent per day, initiation or change of LABA/LAMA/ICS within 4 weeks, or pulmonary rehabilitation started within 4 weeks prior to baseline 17. Severe uncontrolled comorbidity, such as end-stage renal or hepatic failure or uncontrolled thyroid disease, that could confound outcomes or increase risk 18. Inability to give informed consent or comply with study procedures due to cognitive impairment or substance misuse interfering with adherence
Date of first enrolment	11/03/2024
Date of final enrolment	07/10/2025

Locations

Countries of recruitment

Poland

Study participating centre

2nd Department of Lung Diseases, Lung Cancer and Internal Diseases, Medical University of Bialystok, Poland

Żurawia 14
Białystok
15-540
Poland

Sponsor information

Medical University of Białystok
University/education

Jana Kilińskiego
Białystok
15-089
Poland

Phone	+48 85 748 55 12
Email	kancelaria@umb.edu.pl
Website	https://www.umb.edu.pl/index.php
"ROR"	https://ror.org/00y4ya841

Funders

Funder type

University/education

Uniwersytet Medyczny w Białymstoku
Private sector organisation / Trusts, charities, foundations (both public and private)

Alternative name(s): Medical University of Bialystok, UMB
Location: Poland

Results and Publications

Intention to publish date	01/12/2025
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Study protocol: The full protocol has been submitted to a peer-reviewed journal and is currently with an assigned editor. Upon acceptance, we plan open-access publication so the design is publicly available. Primary results (physiology): We plan a first results manuscript focusing on exercise physiology and lung function (constant-work-rate cycle endurance, cardiopulmonary exercise testing, and spirometry) comparing the once-daily combination inhalers with tiotropium. Secondary results (biomarker/body composition): We plan a second results manuscript reporting plasma myostatin levels and body-composition measurements (e.g. fat-free mass, skeletal muscle mass) in relation to the study treatments. Conference dissemination: Key findings will be presented at international respiratory and cardiopulmonary meetings (e.g. ERS, ATS) as abstracts, posters, or oral presentations.
IPD sharing plan	The datasets will be availble upon request from Jakub Henryk Mroz jakub.mroz@sd.umb.edu.pl

Study outputs

Output type	Details	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	in English	28/10/2025	No	Yes
Participant information sheet	in Polish	28/10/2025	No	Yes
Protocol file		28/10/2025	No	No

Additional files

48289 Patient information sheet PL.pdf: in Polish
48289 Patient information sheet ENG.pdf: in English
48289 Protocol J.M - Comparative efficacy of LABALAMA.pdf

Editorial Notes

28/10/2025: Trial's existence confirmed by Bioethics Committee of the Medical University of Bialystok.