Optimal Inhalation Therapy for Chronic Obstructive Pulmonary Disease(COPD) Patients

Study Overview
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Brief Summary
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The primary objective of the study is to examine whether long-acting muscarinic antagonist (LAMA) administration at bedtime versus in the morning leads to a reduction in severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) among COPD-patients who are already receiving treatment with LAMAs. The hypothesis is that bedtime administration of LAMA, as opposed to morning administration, will lead to fewer severe AECOPD. Further, bedtime administration of LAMA will lead to fewer moderate AECOPD´s, fewer ICU admissions and a lower mortality in COPD patients who are already using LAMAs.

Detailed Description
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The study is a pragmatic, registry-based, open-label, randomized controlled trial combining the utilization of the Danish nationwide health registries and the official Danish electronic letter system (Digital Post/e-Boks) into an innovative, decentralized trial requiring no study visits from participants. The nationwide health registries will be used for identification of potential participants and data collection including baseline information and follow-up data, while the electronic letter system will be used for sending recruitment letters and communicating with participants. Study participants will provide electronic informed consent from home before inclusion and randomization. The study aims to include approximately minimum 20,000 participants. Participants will be individually randomized 1:1 to either LAMA administration at bedtime or in the morning for 12 months. Adherence with the intervention will be assessed using questionnaires at months 6 and 12. The study will comply with the standards of the CONSORT statement. This study will be conducted by the Chronic Obstructive Pulmonary Disease Trial Network (COP:TRIN) at the Section of Respiratory Medicine, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark, who will be responsible for all processes in the study including recruitment, inclusion, randomization, follow-up, and communication with participants. Registry data will be obtained through the Danish Health Data Authority and accessed through an encrypted remote-access server environment. The trial is expected to start in January/February 2023 and run for 12 months. Via links sent to their official electronic mailbox (Digital Post/e-Boks), trial participants will provide consent and answer questionnaires. Data obtained from these include personal identification number (the CPR-number), electronic signature, select sociodemographic and lifestyle-related variables, and information on compliance with the intervention. All data stemming from these processes will be stored in a REDCap database. All other data collection will be done using the Danish nationwide registries. In collaboration with the Danish Health Data Authority, the personal identification numbers of each participant will be used to link the study database to the Danish nationwide administrative health registries. The Danish National Patient Registry contains information on all in- and outpatient visits in the Danish public health system. The Danish National Prescription Registry contains claimed prescriptions at all pharmacies in Denmark. The Danish Civil Registration System contains information on date of birth, deaths, immigration, and emigration. The Danish Registry of Causes of death can be used to retrieve specific causes of death. Baseline information will be collected from the previously mentioned registries from the date of inclusion up to 10 years prior to the randomization date as has been done in most previous Danish registry-based studies.

Official Title
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Randomized Comparisons of Morning Versus Bedtime Drug Administration: Optimal Inhalation Therapy for COPD- and Asthma Patients

Conditions
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COPD Exacerbation

Intervention / Treatment
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* Drug: Long acting muscarinic antagonists (LAMAs) at bedtime


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age more than or equal to 30 years Current treatment with LAMA once daily (as recorded in the Danish National Prescription Registry and confirmed by the participant via questionnaire) Exclusion Criteria: 1. Patients who declined to participate.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be individually randomized 1:1 to either LAMA administration at bedtime or in the morning for 12 months. Randomization groups will be allocated according to a computer-generated randomization list with random permuted blocks. The result of the randomization will be shown directly to the participant on their screen and sent to the participant's official electronic mailbox.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Morning administration of LAMA<br>Patients randomized to this group will be instructed to take their LAMA medication as per usual in the morning (approx. 6-9 AM). | |
| Experimental: Bedtime administration of LAMA<br>Patients randomized to this group will be instructed to take their LAMA medication at bedtime (approx. 8-10 PM) | Drug: Long acting muscarinic antagonists (LAMAs) at bedtime<br>* LAMAs administered at bedtime (approx 8-10pm)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LAMA, Bedtime administration