Adherence to single inhaler triple therapy and digital inhalers in Chronic Obstructive Pulmonary Disease: a literature review and protocol for a randomized controlled trial (TRICOLON study)
Authors: Cuperus Liz J. A. , van der Palen Job , Aldenkamp Arnoud , van Huisstede Astrid , Bischoff Erik W. M. A. , van Boven Job F. M. , Brijker Folkert , Dik Stephan , van Excel Jeroen A. J. M. , Goosens Martijn , van Hal Peter Th. W. , Kuijvenhoven Jolanda C. , Kunz Lisette I. Z. , Vasbinder Erwin C. , Kerstjens Huib A. M. , in ’t Veen Johannes C. C. M. , van der Poel Marjo , Amelink Marijke , Rol Anke , de Graaf Jennifer , Hirmann Petra , van Tour Fleur , Jordens Elly , Alfing Lydia , Lenderink Gerda , Rupert Thecla , Rietveld Truus , van Campen Jasmijn , de Bruijn Jantine , ter Burg Janice , van Litsenburg Walter , Knoops Len , Eggermont-Schilt Margot , de Waard-Heijligers Manon , Paalvast-Schouten Ilonka , van Oord Sarah ,   the TRICOLON study group
Published: July 2024

Abstract
Background
Medication non-adherence is a significant problem in patients with Chronic Obstructive Pulmonary Disease (COPD). Efforts to address this issue are receiving increased attention. Simplifying treatment by prescribing single-inhaler triple therapy (SITT) as an alternative to multi-inhaler triple therapy (MITT) or with smart inhalers are often considered potential solutions. However, the actual impact of these innovations on adherence and clinical outcomes is unclear.

Methods
To address this knowledge gap we first conducted a literature review focusing on two research questions: 1) the difference in adherence between SITT and MITT users in COPD, and 2) the effect of smart inhalers on adherence in COPD. Separate searches were conducted in PubMed and two authors independently assessed the articles. In addition, we present a protocol for a study to acquire knowledge for the gaps identified.

Results
To address the first research question, 8 trials were selected for further review. All trials were observational, i.e. randomized controlled trials were lacking. Seven of these trials showed higher adherence and/or persistence in patients on SITT compared with patients on MITT. In addition, four studies showed a positive effect of SITT on various clinical outcomes. For the second research question, 11 trials were selected for review. While most of the studies showed a positive effect of smart inhalers on adherence, there was considerable variation in the results regarding their effect on other clinical outcomes.
The TRICOLON (TRIple therapy COnvenience by the use of one or multipLe Inhalers and digital support in ChrONic Obstructive Pulmonary Disease) trial aims to improve understanding regarding the effectiveness of SITT and smart inhalers in enhancing adherence. This open-label, randomized, multi-center study will enroll COPD patients requiring triple therapy at ten participating hospitals. In total, 300 patients will be randomized into three groups: 1) MITT; 2) SITT; 3) SITT with digital support through a smart inhaler and an e-health platform. The follow-up period will be one year, during which three methods of measuring adherence will be used: smart inhaler data, self-reported data using the Test of Adherence to Inhalers (TAI) questionnaire, and drug analysis in scalp hair samples. Finally, differences in clinical outcomes between the study groups will be compared.

Discussion
Our review suggests promising results concerning the effect of SITT, as opposed to MITT, and smart inhalers on adherence. However, the quality of evidence is limited due to the absence of randomized controlled trials and/or the short duration of follow-up in many studies. Moreover, its impact on clinical outcomes shows considerable variation. The TRICOLON trial aims to provide solid data on these frequently mentioned solutions to non-adherence in COPD. Collecting data in a well-designed randomized controlled trial is challenging, but the design of this trial addresses both the usefulness of SITT and smart inhalers while ensuring minimal interference in participants' daily lives.

Trial registration
NCT05495698 (Clinicaltrials.gov), registered at 08–08-2022. Protocol version: version 5, date 27–02-2023.