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).

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.

Delivery Technologies for Orally Inhaled Products: an Update.

Orally inhaled products have well-known benefits. They allow for effective local administration of many drugs for the treatment of pulmonary disease, and they allow for rapid absorption and avoidance of first-pass metabolism of several systemically acting drugs. Several challenges remain, however, such as dosing limitations, low and variable deposition of the drug in the lungs, and high drug deposition in the oropharynx region. These challenges have stimulated the development of new delivery technologies. Both formulation improvements and new device technologies have been developed through an improved understanding of the mechanisms of aerosolization and lung deposition. These new advancements in formulations have enabled improved aerosolization by controlling particle properties such as density, size, shape, and surface energy. New device technologies emerging in the marketplace focus on minimizing patient errors, expanding the range of inhaled drugs, improving delivery efficiency, increasing dose consistency and dosage levels, and simplifying device operation. Many of these new technologies have the potential to improve patient compliance. This article reviews how new delivery technologies in the form of new formulations and new devices enhance orally inhaled products.

Long-Term Cost-Effectiveness of Digital Inhaler Adherence Technologies in Difficult-to-Treat Asthma.

BACKGROUND: Digital inhalers can monitor inhaler usage, support difficult-to-treat asthma management, and inform step-up treatment decisions yet their economic value is unknown, hampering wide-scale implementation. OBJECTIVE: We aimed to assess the long-term cost-effectiveness of digital inhaler-based medication adherence management in difficult-to-treat asthma. METHODS: A model-based cost-utility analysis was performed. The Markov model structure was determined by biological and clinical understanding of asthma and was further informed by guideline-based assessment of model development. Internal and external validation was performed using the Assessment of the Validation Status of Health-Economic (AdViSHE) tool. The INCA (Inhaler Compliance Assessment) Sun randomized clinical trial data were incorporated into the model to evaluate the cost-effectiveness of digital inhalers. Several long-term clinical case scenarios were assessed (reduced number of exacerbations, increased asthma control, introduction of biosimilars [25% price-cut on biologics]). RESULTS: The long-term modelled cost-effectiveness based on a societal perspective indicated 1-year per-patient costs for digital inhalers and usual care (ie, regular inhalers) of €7,546 ($7,946) and €10,752 ($11,322), respectively, reflecting cost savings of €3,207 ($3,377) for digital inhalers. Using a 10-year intervention duration and time horizon resulted in cost savings of €26,309 ($27,703) for digital inhalers. In the first year, add-on biologic therapies accounted for 69% of the total costs in the usual care group and for 49% in the digital inhaler group. Scenario analyses indicated consistent cost savings ranging from €2,287 ($2,408) (introduction biosimilars) to €4,581 ($4,824) (increased control, decreased exacerbations). CONCLUSIONS: In patients with difficult-to-treat asthma, digital inhaler-based interventions can be cost-saving in the long-term by optimizing medication adherence and inhaler technique and reducing add-on biologic prescriptions.

The emerging role of digital health in the management of asthma.

The most common reasons seen for lack of asthma control include misconceptions about disease control, low controller treatment adherence, poor inhaler technique, and the resulting underuse of controllers and overuse of short-acting beta2 agonists (SABAs). Narrowing these care gaps may be achieved through well-designed patient education that considers the patient's motivation, beliefs, and capabilities regarding their asthma and its management and empowers the patient to become an active participant in treatment decisions. Digital health technologies (DHTs) and digital therapeutic (DT) devices provide new opportunities to monitor treatment behaviors, improve communication between healthcare providers and patients, and generate data that inform educational interactions. DHT and DT have been proven effective in enhancing patient self-management in other chronic conditions, particularly diabetes. Accelerated integration of DHT and DT into the management of asthma patients is facilitated by the use of digital inhalers that employ sensor technology ("smart" inhalers). These devices efficiently provide real-time feedback on controller adherence, SABA use, and inhaler technique that have the strong potential to optimize asthma control.

The Current and Future Role of Technology in Respiratory Care.

Over the past few decades, technology and improvements in artificial intelligence have dramatically changed major sectors of our day-to-day lives, including the field of healthcare. E-health includes a wide range of subdomains, such as wearables, smart-inhalers, portable electronic spirometers, digital stethoscopes, and clinical decision support systems. E-health has been consistently shown to enhance the quality of care, improve adherence to therapy, and allow early detection of worsening in chronic pulmonary diseases. The present review addresses the current and potential future role of major e-health tools and approaches in respiratory medicine, with the aim of providing readers with trustful and updated evidence to increase their awareness of the topic, and to allow them to optimally benefit from the latest innovation technology. Collected literature evidence shows that the potential of technology tools in respiratory medicine mainly relies on three fundamental interactions: between clinicians, between clinician and patient, and between patient and health technology. However, it would be desirable to establish widely agreed and adopted standards for conducting trials and reporting results in this area, as well as to take into proper consideration potentially relevant pitfalls related to privacy protection and compliance with regulatory procedures.

Status of inhalable antimicrobial agents for lung infection: progress and prospects.

Introduction: Available parenteral and oral administration of antimicrobial agents (AMAs) in respiratory infections often show less penetration into the lung parenchyma. Due to inappropriate dose availability, the rate of antibiotic resistance is increasing gradually. Inhaled antibiotics intensely improve the availability of drugs at the site of respiratory infections. This targeted delivery minimizes systemic exposure and associated toxicity.Area covers: This review was performed by searching in the scientific database like PubMed and several trusted government sites like fda.gov, cdc.gov, ClinicalTrials.gov, etc. For better understanding, AMAs are classified in different stages of approval. Mechanism and characterization of pulmonary drug deposition section helps to understand the effective delivery of AMAs to the respiratory tract. There is a need for proper adoption of delivery devices for inhalable AMAs. Thus, delivery devices are extensively explained. Inspiratory flow has a remarkable impact on the delivery device that has been explained in detail.Expert opinion: Pulmonary delivery restricts the bulk administration of drugs in comparison with other routes. Therefore, novel AMAs with higher bactericidal activity at lower concentrations need to be synthesized. Extensive research is indeed in developing innovative delivery devices that would able to deliver higher doses of AMAs through the pulmonary route.

Global burden of medication non-adherence in chronic obstructive pulmonary disease (COPD) and asthma: a narrative review of the clinical and economic case for smart inhalers.

Medication non-adherence to asthma and chronic obstructive pulmonary disease therapy poses a significant burden for patients and societies. Non-adherence encompasses poor initiation, implementation (including poor inhalation technique) and non-persistence. Globally, non-adherence is associated with poor clinical outcomes, reduced quality of life and high healthcare and societal costs. Costs are mainly caused by excess hospitalizations and impaired work productivity. Multiple intervention programs to increase adherence in patients with asthma and chronic obstructive pulmonary disease have been conducted. However, these intervention programs are generally not as effective as intended. Additionally, adherence outcomes are mostly examined with non-objective or non-granular measures (e.g., self-report, dose count, pharmacy records). Recently developed smart inhalers could be the key to objectively diagnose and manage non-adherence effectively in patients with asthma and chronic obstructive pulmonary disease. Smart inhalers register usage of the inhaler, record time and date, send reminders, give feedback about adherence and some are able to assess inhaler technique and predict exacerbations. Still, some limitations need to be overcome before smart inhalers can be incorporated in usual care. For example, their cost-effectiveness and budget impact need to be examined. It is likely that smart inhalers are particularly cost-effective in specific asthma and chronic obstructive pulmonary disease subgroups, including patients with asthma eligible for additional GINA-5 therapy (oral corticosteroids or biologics), patients with severe asthma in GINA-5, patients with asthma with short-acting beta2 agonists overuse, patients with asthma and chronic obstructive pulmonary disease with frequent exacerbations and patients with asthma and chronic obstructive pulmonary disease of working-age. While there is high potential and evidence is accumulating, a final push seems needed to cost-effectively integrate smart inhalers in the daily management of patients with asthma and chronic obstructive pulmonary disease.

Inhaler with electrostatic sterilizer and use of cationic amphiphilic peptides may accelerate recovery from COVID-19.

We explore the design of a smart inhaler with electrostatic sterilizer and propose the utilization of cationic amphiphilic peptides, independently or in conjunction with a bronchodilator, for COVID-19 patients to quickly improve wellbeing while maintaining a strategic distance to protect healthcare personnel from virus-containing aerosol or droplets during the process of inhalation.

Real-life inhaler adherence and technique: Time to get smarter!

Smart inhalers, connected to smartphones, can provide real-life objective information about the patterns of a patient's adherence and their inhaler technique during routine use. The e-modules contain the battery and measuring sensors. Many of these are add-on modules attached externally whilst others are integrated inside the inhaler. Smart inhalers that identify a dose has either been actuated or prepared do not confirm the dose was inhaled but they can send missed dose reminders and clinical studies have highlighted their potential to improve adherence and outcomes. The e-modules that measure an inhalation profile confirm a dose has been inhaled together with providing useful information about the inhaler technique. Studies confirm that the sensors are accurate and confirm their usefulness to provide information about real-life inhaler use. Add-on e-modules are generic whereas integrated smart inhalers can be approved containing active agents and, therefore, prescribed and instructed under healthcare guidance. Real-life studies need to be carried out to demonstrate their potential to improve disease control and prevent exacerbations to justifying their increased cost.

Effective deployment of technology-supported management of chronic respiratory conditions: a call for stakeholder engagement.

BACKGROUND: Healthcare systems are under increasing strain, predominantly due to chronic non-communicable diseases. Connected healthcare technologies are becoming ever more capable and their components cheaper. These innovations could facilitate both self-management and more efficient use of healthcare resources for common respiratory diseases such as asthma and chronic obstructive pulmonary disease. However, newer technologies can only facilitate major changes in practice, and cannot accomplish them in isolation. FOCUS OF REVIEW: There are now large numbers of devices and software offerings available. However, the potential of such technologies is not being realised due to limited engagement with the public, clinicians and providers, and a relative paucity of evidence describing elements of best practice in this complex and evolving environment. Indeed, there are clear examples of wasted resources and potential harm. We therefore call on interested parties to work collaboratively to begin to realize the potential benefits and reduce the risks of connected technologies through change in practice. We highlight key areas where such partnership can facilitate the effective and safe use of technology in chronic respiratory care: developing data standards and fostering inter-operability, making collaborative testing facilities available at scale for small to medium enterprises, developing and promoting new adaptive trial designs, developing robust health economic models, agreeing expedited approval pathways, and detailed planning of dissemination to use. CONCLUSION: The increasing capability and availability of connected technologies in respiratory care offers great opportunities and significant risks. A co-ordinated collaborative approach is needed to realize these benefits at scale. Using newer technologies to revolutionize practice relies on widespread engagement and cannot be delivered by a minority of interested specialists. Failure to engage risks a costly and inefficient chapter in respiratory care.