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

NCT ID: NCT05563675

Last Updated: 2025-02-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 10011 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-01-27
• Study Completion Date: 2024-06-01

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.

Conditions

COPD Exacerbation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Morning administration of LAMA

Participants randomized to this group (with or without the combination of ICS and/or LABA) will be instructed to take their LAMA as usual in the morning between 6 and 12am.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Bedtime administration of LAMA

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.

Group Type: EXPERIMENTAL

Long acting muscarinic antagonists (LAMAs) in the evening

Intervention Type: DRUG

LAMAs administered at bedtime (8pm - 2am)

Interventions

Long acting muscarinic antagonists (LAMAs) in the evening

LAMAs administered at bedtime (8pm - 2am)

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chronic Obstructive Pulmonary Disease Trial Network, Denmark

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Herlev-Gentofte Hospital

Copenhagen, , Denmark

Countries

Denmark

References

Sivapalan P, Romer V, Wirenfeldt Klausen T, Dyrby Johansen N, Pareek M, Modin D, Mathioudakis A, Vestbo J, Eklof J, Jordan A, Hurst JR, Biering-Sorensen T, Jensen JU. AM/PM dosing of LAMA for COPD: a randomized controlled trial protocol using digital recruitment and registries. Front Med (Lausanne). 2024 Aug 6;11:1430169. doi: 10.3389/fmed.2024.1430169. eCollection 2024.

Reference Type: DERIVED

PMID: 39165373 (View on PubMed)

Other Identifiers

Protocol_LAMA

Identifier Type: -

Identifier Source: org_study_id