Clinical trial NCT05563675: 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
Official title: Comparing Morning and Evening Dosing of Inhaled Long-Acting Muscarinic Antagonists for the Prevention of Hospitalization Requiring AECOPD or Death from All Causes - the LAMA by Night Study Utilizing a Comprehensive Nationwide Digital Platform for Recruitment Into a Pragmatic Randomized Controlled Trial Integrated with National Registries to Follow Outcomes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: COPD Exacerbation
Keywords: LAMA
Bedtime administration
Lead sponsor: Chronic Obstructive Pulmonary Disease Trial Network, Denmark
Sponsor class: OTHER
First posted: 2022-10-03
Enrollment: 10011
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized 1:1 to one of two treatment strategies by computer-generated allocation, to either LAMA administration in the morning or evening. Randomization groups will be allocated according to a computer-generated randomization. Data will be entered by participants directly into REDCap questionnaires. Consent and randomization will take place on day 0. The result of the randomization will be shown directly to the participant on their screen and sent to the participant's official electronic mailbox.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: COPD-related hospitalization-requiring (severe) exacerbations
timeFrame: 12 months from randomization
measure: All-cause mortality
timeFrame: 12 months from randomization
Secondary outcomes:
measure: Moderate, non-hospitalization-requiring COPD exacerbations
timeFrame: 12 months from randomization
measure: Number of admissions for all causes
timeFrame: 12 months from randomization
measure: Number of admissions in the intensive care unit (ICU) for all causes
timeFrame: 12 months from randomization
measure: Number of admissions requiring non-invasive ventilation (NIV) treatment
timeFrame: 12 months from randomization
measure: Mortality (all-cause)
timeFrame: 12 months from randomization
measure: Use of short-acting β2-agonists (SABA); pick-up rate
timeFrame: 12 months from randomization
measure: Change in COPD assesment test (CAT) score
timeFrame: 12 months from randomization
measure: Change in medical research council (MRC) score
timeFrame: 12 months from randomization
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Herlev-Gentofte Hospital
Study officials:
References: