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

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

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.

Study Overview

• Status: Recruiting
• Conditions: COPD Exacerbation
• Intervention / Treatment: Drug: Long acting muscarinic antagonists (LAMAs) in the evening

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 Type: Interventional
• Enrollment (Estimated): 20000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jens Ulrik Stæhr Jensen, Professor; Phone Number: +4538673057; Email: jens.ulrik.jensen@regionh.dk
• Study Contact Backup: Name: Pradeesh Sivapalan, MD, PhD; Phone Number: +4529880601; Email: pradeesh.sivapalan.02@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Recruiting
    • Herlev-Gentofte Hospital
    • Contact: Jens-Ulrik Jensen, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: 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.
Experimental: 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.	Drug: Long acting muscarinic antagonists (LAMAs) in the evening; LAMAs administered at bedtime (8pm - 2am)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
COPD-related hospitalization-requiring (severe) exacerbations	12 months from randomization
All-cause mortality	12 months from randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Moderate, non-hospitalization-requiring COPD exacerbations		12 months from randomization
Number of admissions for all causes		12 months from randomization
Number of admissions in the intensive care unit (ICU) for all causes		12 months from randomization
Number of admissions requiring non-invasive ventilation (NIV) treatment		12 months from randomization
Mortality (all-cause)		12 months from randomization
Use of short-acting β2-agonists (SABA); pick-up rate	Data collected from the Danish National Prescription Registry	12 months from randomization
Change in COPD assesment test (CAT) score	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.	12 months from randomization
Change in medical research council (MRC) score	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.	12 months from randomization

Collaborators and Investigators

• Sponsor: Chronic Obstructive Pulmonary Disease Trial Network, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2023
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: September 23, 2022
• First Submitted That Met QC Criteria: September 28, 2022
• First Posted (Actual): October 3, 2022

Study Record Updates

• Last Update Posted (Estimated): February 9, 2024
• Last Update Submitted That Met QC Criteria: February 8, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: LAMA; Bedtime administration
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Respiratory Aspiration; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Antagonists; Muscarinic Antagonists; Cholinergic Agents
• Other Study ID Numbers: Protocol_LAMA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Both negative, positive, and inconclusive results will be submitted for publication in peer-reviewed journals and presented at international scientific conferences.

Participant-level data and statistical code will not be published.

Drug and device information, study documents

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