Once Daily Long-Acting Muscarinic Antagonists Administered in the Evening for Prevention of Chronic Obstructive Pulmonary Disease Exacerbations Requiring Hospitalization or Death from Any Cause

Phase 4

Completed

• Conditions: COPD Exacerbation
• Interventions: Drug: Long acting muscarinic antagonists (LAMAs) in the evening

• Registration Number: NCT05563675
• Lead Sponsor: Chronic Obstructive Pulmonary Disease Trial Network, Denmark

Brief Summary

To examine, among once-daily LAMA using COPD patients, whether evening administration of LAMA is superior with respect to the incidence of hospitalization requiring AECOPD or death from all causes than the more conventional morning administration.

Detailed Description

One of the most feared complications associated with chronic obstructive pulmonary disease (COPD) is acute exacerbation (AECOPD). On average, each COPD patient experiences 0.5 to 3.5 acute exacerbations per year, which is an important reason for the hospitalization, disease progression and mortality as well as decline in health status and lung function(1,2).

Treatment with a long-acting muscarinic antagonist (LAMA) reduces dyspnoea and the risk of exacerbations in patients with COPD by binding to muscarinic receptors in bronchial smooth musculature and thus inhibiting cholinergic bronchial constriction. LAMAs are given as inhalation therapy once daily (most often) or twice daily(3).

Most COPD-patients experience their worst symptoms and experience exacerbations in early morning hours, before getting out of bed(4). This might be explained by the physiological diurnal changes in the activity of the parasympathetic homeostasis system since this is most active at night to improve digestion and other secretions(5).

Correspondingly, the activity of the sympathetic system is physiologically suppressed at night, and stimulation of β-2 receptors is thus also low (and opposite for M-3 receptors). Taken together, the balance of sympathetic-parasympathetic tone is shifted significantly towards the latter. Most available LAMA treatments are dosed once daily in the morning.

Thus, for a COPD patient, being at a trough level of LAMA (which antagonizes the para-sympathetic system) at late night/early morning, may carry a hazard for the patient.

Studies have found that lung function measured as forced expiratory volume in 1 second (FEV1) improvement peaks approximately 2 hours after LAMA administration, and that FEV1 is still significantly improved at 7 hours post treatment but decreases towards the trough level of the LAMA(6). However, as a corollary to the above, when the medicine is probably most needed (02.00 a.m. to 07.00 a.m.), the effect is at its lowest level, which may not be desirable, since a low effect of the most important preventive medicine against AECOPD at this time, may lead to more exacerbations.

Evening administration, on the contrary, would lead to a greater and more certain effect regarding bronchodilation and reduced secretion in the early morning hours, and a maximum effect should be expected during the entire night.

Study Timeline

• Study First Submitted: 2022-09-23
• Study First Submitted QC: 2022-09-28
• Study First Posted: 2022-10-03
• Study Start: 2023-01-27
• Primary Completion: 2024-06-01
• Study Completion: 2024-06-01
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-16
• Last Update Posted: 2025-02-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10011

Inclusion Criteria

1. Age more than or equal to 30 years
2. Current treatment with LAMA once daily (as recorded in the Danish National Prescription Registry and confirmed by the participant via questionnaire)
3. Self-reported COPD

Exclusion Criteria

1. Patients who decline to participate.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bedtime administration of LAMA	Long acting muscarinic antagonists (LAMAs) in the evening	Participants randomized to this group (with or without the combination of inhaled corticosteroids (ICS) and/or long-acting beta2-agonists (LABA)) will be instructed to take their LAMA-containing inhalation between 8pm. and 2am.

Primary Outcome Measures

Name	Time	Method
COPD-related hospitalization-requiring (severe) exacerbations	12 months from randomization
All-cause mortality	12 months from randomization

Secondary Outcome Measures

Name	Time	Method
Moderate, non-hospitalization-requiring COPD exacerbations	12 months from randomization
Number of admissions for all causes	12 months from randomization
Number of admissions requiring non-invasive ventilation (NIV) treatment	12 months from randomization
Use of short-acting β2-agonists (SABA); pick-up rate	12 months from randomization	Data collected from the Danish National Prescription Registry
Number of admissions in the intensive care unit (ICU) for all causes	12 months from randomization
Mortality (all-cause)	12 months from randomization
Change in COPD assesment test (CAT) score	12 months from randomization	Measured by questionnaire at 6 and 12 months post-randomization. Measured on a scale from 0 to 40. Score of 0-9 means low impact of COPD and score of 31-40 means very high impact.
Change in medical research council (MRC) score	12 months from randomization	Measured by questionnaire at 6 and 12 months post-randomization. Measures baseline functional disability due to dyspnoea on a scale from 0 to 5, 0 meaning no disability and 5 meaning significant disability due to COPD.

Trial Locations

Locations (1)

Herlev-Gentofte Hospital; 🇩🇰 Copenhagen, Denmark