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 effectiveness of continuous respiratory rate monitoring in predicting hypoxic and pyrexic events: a retrospective cohort study.

Respiratory rate (RR) is routinely used to monitor patients with infectious, cardiac and respiratory diseases and is a component of early warning scores used to predict patient deterioration. However, it is often measured visually with considerable bias and inaccuracy.Objectives. Firstly, to compare distribution and accuracy of electronically measured RR (EMRR) and visually measured RR (VMRR). Secondly, to determine whether, and how far in advance, continuous electronic RR monitoring can predict oncoming hypoxic and pyrexic episodes in infectious respiratory disease.Approach.A retrospective cohort study analysing the difference between EMRR and VMRR was conducted using patient data from a large tertiary hospital. Cox proportional hazards models were used to determine whether continuous, EMRR measurements could predict oncoming hypoxic (SpO2 < 92%) and pyrexic (temperature >38 °C) episodes.Main results.Data were gathered from 34 COVID-19 patients, from which a total of 3445 observations of VMRR (independent of Hawthorne effect), peripheral oxygen saturation and temperature and 729 117 observations of EMRR were collected. VMRR had peaks in distribution at 18 and 20 breaths per minute. 70.9% of patients would have had a change of treatment during their admission based on the UK's National Early Warning System if EMRR was used in place of VMRR. An elevated EMRR was predictive of hypoxic (hazard ratio: 1.8 (1.05-3.07)) and pyrexic (hazard ratio: 9.7 (3.8-25)) episodes over the following 12 h.Significance.Continuous EMRR values are systematically different to VMRR values, and results suggest it is a better indicator of true RR as it has lower kurtosis, higher variance, a lack of peaks at expected values (18 and 20) and it measures a physiological component of breathing directly (abdominal movement). Results suggest EMRR is a strong marker of oncoming hypoxia and is highly predictive of oncoming pyrexic events in the following 12 h. In many diseases, this could provide an early window to escalate care prior to deterioration, potentially preventing morbidity and mortality.

Patient-Selected Treatment Goals in Severe Asthma.

BACKGROUND: Goal-orientated health care accounts for patient preferences and values, not just physician treatment aims. The Global Initiative for Asthma (GINA) management strategy states that clinicians should elicit patients' own treatment goals as a central part of care. Despite this recommendation, data on patients' treatment goals are sparse among patients with severe asthma. OBJECTIVE: The objective of this study is to investigate the relationship between rates of treatment adherence and goal achievement, and patient-selected goals. METHODS: Thematic analysis was used to characterize patient-selected goals. Previously undescribed goal categories in asthma were identified, quantified, and related to clinical characteristics. Goal achievement was aligned with objectively measured treatment adherence. RESULTS: Three categories of patients-selected goals were identified from 2 randomized control trials: disease-specific (n = 98 [51%] and n = 92 [54%], respectively), function-related (n = 90 [48%] and n = 61 [36%]), and knowledge (n = 1 [1%] and n = 17 [10%]). Only 53% of goals aligned with clinician treatment goals. Patients who chose disease-specific goals were more likely to achieve both control and their specified goal (n = 98 [45%], odds ratio: 1.789, confidence interval: 1.066-3.001). Male participants are more likely to focus on disease-specific goals. Patients who achieved their goals were more likely to be T2-high, have an elevated fractional exhaled nitric oxide (FeNO) at their first visit, and have a lower FeNO value at their final visit. Interestingly, adherence rates decline significantly for those who achieve their goals. CONCLUSION: Almost half of patient-selected goals do not align with GINA clinical asthma management goals. Participants who chose goals that do align with clinicians were more likely to achieve them.

Personalized Biofeedback on Inhaler Adherence and Technique by Community Pharmacists: A Cluster Randomized Clinical Trial.

BACKGROUND: Guidelines recommend that patients treated with inhalers receive adherence counseling and device training. Digital technologies that assess both inhaler adherence and technique have been developed. Using these technologies community pharmacists, who have regular contact with patients, are well placed to deliver personalized inhaler education. OBJECTIVE: To determine the impact of a pharmacist intervention, informed by digital technology, on inhaler technique and adherence of patients with asthma in the community. METHODS: A cluster randomized, parallel-group, multisite pharmacy study was conducted over 6 months. All study groups had an electronic device (inhaler compliance assessment device) attached to their maintenance inhaler. A biofeedback group received personalized inhaler training informed by data recorded by the device. The demonstration group received inhaler training, by physical demonstration with a placebo inhaler. The control group received usual care. The primary outcome was inhaler adherence, which was classified as "actual adherence" and expressed as the proportion of expected drug accumulation if adherence and technique had been perfect. Secondary outcomes were quality-of-life scores as measured by the St George's Respiratory Questionnaire, symptoms, and exacerbations. RESULTS: A total of 152 participants (n = 74 biofeedback, n = 56 demonstration, and n = 22 control) were recruited. Asthma was the predominant condition among participants (n = 83), with chronic obstructive pulmonary disease (n = 55) and asthma/chronic obstructive pulmonary disease overlap also reported (n = 8). In intention-to-treat analysis, adherence in the biofeedback group during month 2 was 62%, 18% higher (95% CI, 6 to 30) than that in the demonstration group (P = .004) and 24% higher (95% CI, 9 to 40) than that in the control group (P = .003). During month 6, adherence was 14% higher (95% CI, -1 to 30; P = .07) in the biofeedback group than in the demonstration group and 31% higher (95% CI, 13 to 48; P = .001) than in the control group. At the end of the study, the biofeedback group had a sustained fall in St George's Respiratory Questionnaire from baseline, -6.1 (95% CI, -9 to -0.4; P = .04) and had significantly improved daily respiratory symptoms. CONCLUSIONS: Community pharmacist-delivered inhaler training informed by a digital technology improved adherence and health status.

Inadequate assessment of adherence to maintenance medication leads to loss of power and increased costs in trials of severe asthma therapy: results from a systematic literature review and modelling study.

Adherence to inhaled maintenance therapy in severe asthma is rarely adequately assessed, and its influence on trial outcomes is unknown. We systematically determined how adherence to maintenance therapy is assessed in clinical trials of "add-on" therapy for severe asthma. We model the improvement in trial power that could be achieved by accurately assessing adherence.A systematic search of six major databases identified randomised trials of add-on therapy for severe asthma. The relationship between measuring adherence and study outcomes was assessed. An estimate of potential improvements in statistical power and sample size was derived using digitally recorded adherence trial data.87 randomised controlled trials enrolling 22 173 participants were included. Adherence assessment was not reported in 67 trials (n=13 931, 63%). Studies that reported adherence used a range of self-report and subjective methods. None of the studies employed an objective assessment of adherence. Studies that reported adherence had a significantly reduced pooled variance in forced expiratory volume in 1 s (FEV1) compared to those that did not assess adherence: s2=0.144 L2 versus s2=0.168 L2, p<0.0001. Power to detect clinically relevant changes in FEV1 was significantly higher in trials that reported adherence assessment (mean power achieved 59% versus 49%). Modelling suggests that up to 50% of variance in FEV1 outcomes is attributable to undetected variations in adherence. Controlling for such variations could potentially halve the required sample size.Few trials of add-on therapy monitor adherence to maintenance inhaled therapy, resulting in a greater variance in trial outcomes and inadequate power for determining efficacy.

Personalising adherence-enhancing interventions using a smart inhaler in patients with COPD: an exploratory cost-effectiveness analysis.

Four inhaler adherence clusters have been identified using the INCA audio device in COPD patients: (1) regular use/good technique, (2) regular use/frequent technique errors, (3) irregular use/good technique, and (4) irregular use/frequent technique errors. Their relationship with healthcare utilization and mortality was established, but the cost-effectiveness of adherence-enhancing interventions is unknown. In this exploratory study, we aimed to estimate the potential cost-effectiveness of reaching optimal adherence in the three suboptimal adherence clusters, i.e., a theoretical shift of clusters 2, 3, and 4 to cluster 1. Cost-effectiveness was estimated over a 5-year time horizon using the Irish healthcare payer perspective. We used a previously developed COPD health-economic model that was updated with INCA trial data and Irish national economic and epidemiological data. For each cluster, interventions would result in additional quality-adjusted life years gained at reasonable investment. Cost-effectiveness was most favorable in cluster 3, with possible cost savings of €845/annum/person.

A randomised clinical trial of feedback on inhaler adherence and technique in patients with severe uncontrolled asthma.

In severe asthma, poor control could reflect issues of medication adherence or inhaler technique, or that the condition is refractory. This study aimed to determine if an intervention with (bio)feedback on the features of inhaler use would identify refractory asthma and enhance inhaler technique and adherence.Patients with severe uncontrolled asthma were subjected to a stratified-by-site random block design. The intensive education group received repeated training in inhaler use, adherence and disease management. The intervention group received the same intervention, enhanced by (bio)feedback-guided training. The primary outcome was rate of actual inhaler adherence. Secondary outcomes included a pre-defined assessment of clinical outcome. Outcome assessors were blinded to group allocation. Data were analysed on an intention-to-treat and per-protocol basis.The mean rate of adherence during the third month in the (bio)feedback group (n=111) was higher than that in the enhanced education group (intention-to-treat, n=107; 73% versus 63%; 95% CI 2.8%-17.6%; p=0.02). By the end of the study, asthma was either stable or improved in 54 patients (38%); uncontrolled, but poorly adherent in 52 (35%); and uncontrolled, but adherent in 40 (27%).Repeated feedback significantly improved inhaler adherence. After a programme of adherence and inhaler technique assessment, only 40 patients (27%) were refractory and adherent, and might therefore need add-on therapy.

Reduction in exhaled nitric oxide tracks improved patient inhaler compliance in difficult asthma-a case study.

INTRODUCTION: Exhaled nitric oxide is believed be a useful surrogate for airways inflammation while non-adherence with therapy is known to be associated with worsening of asthma control. CASE: We present the case of a 49-year-old female with steroid-dependent asthma and an exacerbation rate of >20/year. She was enrolled in a 3-month-long prospective study using a validated diagnostic inhaler device that provided objective evidence of inhaler compliance. Fractional exhaled nitric oxide (FeNO), peak expiratory flow rates, asthma control questionnaires were measured throughout the study period. Peripheral eosinophil count was obtained prior to the study, during the study, and immediately afterwards. RESULTS: Improvement in compliance at the end of the study led to significant improvements in lung function peak expiratory flow rate (PEFR), and objective scores of asthma. There was an observed improvement in PEFR after 4 weeks, with an associated decrease in FeNO from 92 to 9 ppb that plateaued over the remainder of the study. Her eosinophil count was 0.79 × 109/litre prior to starting in the study, 0.37 × 109/litre after 2 months, and 0.1 × 109/litre at the end of the study. CONCLUSION: We believe that this is the first case study to objectively prove that improvements in compliance can lead to dramatic reductions in the overall inflammatory airway response and in particular that improvements in patient compliance are mirrored by marked reduction in FeNO levels. These changes occurred in tandem with an observed clinical improvement in our patient.

Colonisation of Irish patients with chronic obstructive pulmonary disease by Streptococcus pneumoniae and analysis of the pneumococcal vaccine coverage: a non-interventional, observational, prospective cohort study.

OBJECTIVES: To characterise the pattern of colonisation and serotypes of Streptococcus pneumoniae among patients with chronic obstructive pulmonary disease (COPD) who currently receive the 23-valent pneumococcal polysaccharide vaccine (PPV-23) according to vaccination status, use of antibiotics and steroids. To investigate the prevalence of PPV-23 and 13-valent pneumococcal conjugate vaccine (PCV-13) serotypes within the study cohort. DESIGN: A non-interventional, observational, prospective cohort study with a 12 -month follow-up period inclusive of quarterly study visits. SETTING: Beaumont Hospital and The Royal College of Surgeons in Ireland Clinical Research Centre, Dublin, Ireland. PARTICIPANTS: Patients with an established diagnosis of COPD attending a tertiary medical centre. PRIMARY OUTCOME MEASURE: Colonisation rate of S. pneumoniae in patients with COPD and characterisation of serotypes of S. pneumoniae with correlation to currently available pneumococcal vaccines. Sputum and oropharyngeal swab samples were collected for the isolation of S. pneumoniae. SECONDARY OUTCOME MEASURE: Seasonality of colonisation of S. pneumoniae and its relationship with the incidence of exacerbations of COPD. RESULTS: S. pneumoniae was detected in 16 of 417 samples, a colonisation incident rate of 3.8% and in 11 of 133 (8%) patients at least once during the study. The majority of S. pneumoniae isolates were identified in spring and were non-vaccine serotypes for either the PPV-23 or PCV-13 (63%). The colonisation incident rate of S. pneumoniae fluctuated over the four seasons with a peak of 6.6% in spring and the lowest rate of 2.2% occurring during winter. Antibiotic use was highest during periods of low colonisation. CONCLUSIONS: There is seasonal variation in S. pneumoniae colonisation among patients with COPD which may reflect antibiotic use in autumn and winter. The predominance of non-vaccine types suggests that PCV-13 may have limited impact among patients with COPD in Ireland who currently receive PPV-23. TRIAL REGISTRATION NUMBER: NCT02535546; post-results.

In patients with severe uncontrolled asthma, does knowledge of adherence and inhaler technique using electronic monitoring improve clinical decision making? A protocol for a randomised controlled trial.

INTRODUCTION: Many patients with asthma remain poorly controlled despite the use of inhaled corticosteroids and long-acting beta agonists. Poor control may arise from inadequate adherence, incorrect inhaler technique or because the condition is refractory. Without having an objective assessment of adherence, clinicians may inadvertently add extra medication instead of addressing adherence. This study aims to assess if incorporating objectively recorded adherence from the Inhaler Compliance Assessment (INCA) device and lung function into clinical decision making provides more cost-effective prescribing and improves outcomes. METHODS AND ANALYSIS: This prospective, randomised, multicentre study will compare the impact of using information on adherence to influence asthma treatment. Patients with severe uncontrolled asthma will be included. Data on adherence, inhaler technique and electronically recorded peak expiratory flow rate will be used to promote adherence and guide a clinical decision protocol to guide management in the active group. The control group will receive standard inhaler and adherence education. Medications will be adjusted using a protocol based on Global Initiativefor Asthma (GINA) recommendations. The primary outcome is the between-group difference in the proportion of patients who have refractory disease and are prescribed appropriate medications at the end of 32 weeks. A co-primary outcome is the difference between groups in the rate of adherence to salmeterol/fluticasone inhaler over the last 12 weeks. Secondary outcomes include changes in symptoms, lung function, type-2 cytokine biomarkers and clinical outcomes between both groups. Cost-effectiveness and cost-utility analyses of the INCA device intervention will be performed. The economic impact of a national implementation of the INCA-SUN programme will be evaluated. ETHICS AND DISSEMINATION: The results of the study will be published as a manuscript in peer-reviewed journals. The study has been approved by the ethics committees in the five participating hospitals. TRIAL REGISTRATION: NCT02307669; Pre-results.

The Impact of Common Inhaler Errors on Drug Delivery: Investigating Critical Errors with a Dry Powder Inhaler.

BACKGROUND: Researchers, using checklists, have identified that 30%-90% of patients make errors in inhaler use. It is not certain whether these errors affect the delivery of medication. We have developed an electronic monitor (INCA™) that records audio each time an inhaler is used, providing objective information on inhaler technique. The aim of this study was to assess the effect that correctly identified inhaler errors, with the INCA device, have on drug delivery. METHODS: This was a prospective study of healthy volunteers using a salbutamol Diskus™. The inclusion criteria allowed for the recruitment of healthy participants who were nonfrequent users of Salbutamol. Each participant was assigned to one control "phase" first and two/three subsequent error "phases." Each phase consisted of six doses of the drug taken 6 hours apart, and the participants' blood was drawn before and 25 minutes after doses one and six. This allowed us to sample their trough and peak serum salbutamol levels. RESULTS: Fourteen healthy volunteers were studied. The inhaler technique errors simulated in this study included exhaling into the device after drug priming but before inhalation, low inspiratory flow, multiple inhalations, low breath hold, missed doses, and wrong inhaler position. Only the exhalation error, low inspiratory flow, and missed doses led to a significant reduction in serum salbutamol levels. After six doses of the exhalation error, there was a 62% reduction in peak salbutamol levels. Low inspiratory flow led to a 52% reduction in peak salbutamol levels and a 78% reduction in trough levels. Missed doses led to a 37% reduction in trough salbutamol levels. CONCLUSIONS: These findings confirm that technique errors affect drug delivery. Furthermore, we were able to identify that the most critical technique errors with the Diskus inhaler are exhalation into the device before inhalation, poor inspiratory flow, and missing doses.

Objective Assessment of Adherence to Inhalers by Patients with Chronic Obstructive Pulmonary Disease.

RATIONALE: Objective adherence to inhaled therapy by patients with chronic obstructive pulmonary disease (COPD) has not been reported. OBJECTIVES: To objectively quantify adherence to preventer Diskus inhaler therapy by patients with COPD with an electronic audio recording device (INCA). METHODS: This was a prospective observational study. On discharge from hospital patients were given a salmeterol/fluticasone inhaler with an INCA device attached. Analysis of this audio quantified the frequency and proficiency of inhaler use. MEASUREMENTS AND MAIN RESULTS: Patients with COPD (n = 244) were recruited. The mean age was 71 years, mean FEV1 was 1.3 L, and 59% had evidence of mild/moderate cognitive impairment. By combining time of use, interval between doses, and critical technique errors, thus incorporating both intentional and unintentional nonadherence, a measure "actual adherence" was calculated. Mean actual adherence was 22.6% of that expected if the doses were taken correctly and on time. Six percent had an actual adherence greater than 80%. Hierarchical clustering found three equally sized well-separated clusters corresponding to distinct patterns. Cluster 1 (34%) had low inhaler use and high error rates. Cluster 2 (25%) had high inhaler use and high error rates. Cluster 3 (36%) had overall good adherence. Poor lung function and comorbidities were predictive of poor technique, whereas age and cognition with poor lung function distinguished those with poor adherence and frequent errors in technique. CONCLUSIONS: These data may inform clinicians in understanding why a prescribed inhaler is not effective and to devise strategies to promote adherence in COPD.

Irregular and Ineffective: A Quantitative Observational Study of the Time and Technique of Inhaler Use.

BACKGROUND: Cross-sectional observational studies suggest that between 50% and 60% of patients misuse a dry powder inhaler, whereas studies with electronic monitors indicate that patients sometimes overuse/underuse their inhalers. It is not known what impact errors and erratic use have on inhaler adherence. OBJECTIVES: The purpose of this study was to longitudinally quantify when and how patients adhered to a twice-daily preventer treatment by using a novel acoustic recording device attached to an inhaler (INhaler Compliance Assessment). METHODS: Patients with a history of asthma or chronic obstructive pulmonary disease (n = 123) from primary care and community pharmacies were given an INhaler Compliance Assessment-adapted inhaler for 1 month. Analysis of the audio files provided quantitative information on time and technique of inhaler use. RESULTS: Data were available for 103 patients. Twenty-one patients (20%) used their inhaler in the correct manner at the correct interval. There were 5045 audio files with attempted inhalations, of which 1204 had technique errors (24%). Errors included inadequate flow (27%), drug priming without inhalation (19%), exhalation into the inhaler (18%), and multiple inhalations (25%). On average, participants made errors 20% of the time. Of 60 doses expected to be taken in a month per person, on average 49 doses (82%) were attempted and when errors were accounted for, the average number of actual doses taken was 34 doses (57%; P < .01) comparing attempted to actual doses. DISCUSSION: These data highlight that ineffective and irregular inhaler use is common and when combined in a single calculation indicate that only 20% of participants used their inhaler correctly and on time.

A Method to Calculate Adherence to Inhaled Therapy that Reflects the Changes in Clinical Features of Asthma.

RATIONALE: Currently, studies on adherence to inhaled medications report average adherence over time. This measure does not account for variations in the interval between doses, nor for errors in inhaler use. OBJECTIVES: To investigate whether adherence calculated as a single area under the (concentration-time) curve (AUC) measure, incorporating the interval between doses and inhaler technique, was more reflective of patient outcomes than were current methods of assessing adherence. METHODS: We attached a digital audio device (INhaler Compliance Assessment) to a dry powder inhaler. This recorded when the inhaler was used, and analysis of the audio data indicated if the inhaler had been used correctly. These aspects of inhaler use were combined to calculate adherence over time, as an AUC measure. Over a 3-month period, a cohort of patients with asthma was studied. Adherence to a twice-daily inhaler preventer therapy using this device and clinical measures were assessed. MEASUREMENTS AND MAIN RESULTS: Recordings from 239 patients with severe asthma were analyzed. Average adherence that was based on the dose counter was 84.4%, whereas the ratio of expected to observed accumulated AUC, actual adherence, was 61.8% (P < 0.01). Of all the adherence measures, only adherence calculated as AUC reflected changes in asthma quality of life, ß-agonist reliever use, and peak expiratory flow over the 3 months (P < 0.05 compared with other measures of adherence). CONCLUSIONS: Adherence that incorporates the interval between doses and inhaler technique, and calculated as AUC, is more reflective of changes in quality of life and lung function than are the currently used measures of adherence. Clinical trial registered with www.clinicaltrials.gov (NCT 01529697).

Predicting asthma exacerbations employing remotely monitored adherence.

This Letter investigated the efficacy of a decision-support system, designed for respiratory medicine, at predicting asthma exacerbations in a multi-site longitudinal randomised control trial. Adherence to inhaler medication was acquired over 3 months from patients with asthma employing a dose counter and a remote monitoring adherence device which recorded participant's inhaler use: n = 184 (23,656 audio files), 61% women, age (mean ± sd) 49.3 ± 16.4. Data on occurrence of exacerbations was collected at three clinical visits, 1 month apart. The relative risk of an asthma exacerbation for those with good and poor adherence was examined employing a univariate and multivariate modified Poisson regression approach; adjusting for age, gender and body mass index. For all months dose counter adherence was significantly (p < 0.01) higher than remote monitoring adherence. Overall, those with poor adherence had a 1.38 ± 0.34 and 1.42 ± 0.39 (remotely monitored) and 1.25 ± 0.32 and 1.18 ± 0.31 (dose counter) higher relative risk of an exacerbation in model 1 and model 2, respectively. However, this was not found to be statistically significantly different. Remotely monitored adherence holds important clinical information and future research should focus on refining adherence and exacerbation measures. Decision-support systems based on remote monitoring may enhance patient-physician communication, possibly reducing preventable adverse events.

The effect of providing feedback on inhaler technique and adherence from an electronic audio recording device, INCA®, in a community pharmacy setting: study protocol for a randomised controlled trial.

BACKGROUND: Poor adherence to inhaled medication may lead to inadequate symptom control in patients with respiratory disease. In practice it can be difficult to identify poor adherence. We designed an acoustic recording device, the INCA® (INhaler Compliance Assessment) device, which, when attached to an inhaler, identifies and records the time and technique of inhaler use, thereby providing objective longitudinal data on an individual's adherence to inhaled medication. This study will test the hypothesis that providing objective, personalised, visual feedback on adherence to patients in combination with a tailored educational intervention in a community pharmacy setting, improves adherence more effectively than education alone. METHODS/DESIGN: The study is a prospective, cluster randomised, parallel-group, multi-site study conducted over 6 months. The study is designed to compare current best practice in care (i.e. routine inhaler technique training) with the use of the INCA® device for respiratory patients in a community pharmacy setting. Pharmacies are the unit of randomisation and on enrolment to the study they will be allocated by the lead researcher to one of the three study groups (intervention, comparator or control groups) using a computer-generated list of random numbers. Given the nature of the intervention neither pharmacists nor participants can be blinded. The intervention group will receive feedback from the acoustic recording device on inhaler technique and adherence three times over a 6-month period along with inhaler technique training at each of these times. The comparator group will also receive training in inhaler use three times over the 6-month study period but no feedback on their habitual performance. The control group will receive usual care (i.e. the safe supply of medicines and advice on their use). The primary outcome is the rate of participant adherence to their inhaled medication, defined as the proportion of correctly taken doses of medication at the correct time relative to the prescribed interval. Secondary outcomes include exacerbation rates and quality of life measures. Differences in the timing and technique of inhaler use as altered by the interventions will also be assessed. Data will be analysed on an intention-to-treat and a per-protocol basis. Sample size has been calculated with reference to comparisons to be made between the intervention and comparator clusters and indicates 75 participants per cluster. With an estimated 10 % loss to follow-up we will be able to show a 20 % difference between the population means of the intervention and comparator groups with a power of 0.8. The Type I error probability associated with the test of the null hypothesis is 0.05. DISCUSSION: This clinical trial will establish whether providing personalised feedback to individuals on their inhaler use improves adherence. It may also be possible to enhance the role of pharmacists in clinical care by identifying patients in whom alteration of either therapy or inhaler device is appropriate. REGISTRATION: ClinicalTrials.gov NCT02203266 .

A method to assess adherence in inhaler use through analysis of acoustic recordings of inhaler events.

RATIONALE: Poor adherence to inhaler use can be due to poor temporal and/or technique adherence. Up until now there has been no way of reliably tracking both these factors in everyday inhaler use. OBJECTIVES: This paper introduces a device developed to create time stamped acoustic recordings of an individual's inhaler use, in which empirical evidence of temporal and technique adherence in inhaler use can be monitored over time. The correlation between clinical outcomes and adherence, as determined by this device, was compared for temporal adherence alone and combined temporal and technique adherence. FINDINGS: The technology was validated by showing that the doses taken matched the number of audio recordings (r2 = 0.94, p<0.01). To demonstrate that audio analysis of inhaler use gives objective information, in vitro studies were performed. These showed that acoustic profiles of inhalations correlated with the peak inspiratory flow rate (r2 = 0.97, p<0.01), and that the acoustic energy of exhalations into the inhaler was related to the amount of drug removed. Despite training, 16% of participants exhaled into the mouthpiece after priming, in >20% of their inhaler events. Repeated training reduced this to 7% of participants (p = 0.03). When time of use was considered, there was no evidence of a relationship between adherence and changes in AQLQ (r2 = 0.2) or PEFR (r2 = 0.2). Combining time and technique the rate of adherence was related to changes in AQLQ (r2 = 0.53, p = 0.01) and PEFR (r2 = 0.29, p = 0.01). CONCLUSIONS: This study presents a novel method to objectively assess how errors in both time and technique of inhaler use impact on clinical outcomes. TRIAL REGISTRATION: EudraCT 2011-004149-42.

The acoustic features of inhalation can be used to quantify aerosol delivery from a Diskus™ dry powder inhaler.

PURPOSE: Some patients are unable to generate the peak inspiratory flow rate (PIFR) necessary to de-agglomerate drug particles from dry powder inhalers (DPIs). In this study we tested the hypothesis that the acoustic parameters of an inhalation are related to the PIFR and hence reflect drug delivery. METHODS: A sensitivity analysis of the relationship of the acoustics of inhalation to simultaneously recorded airflow, in a cohort of volunteers (n = 92) was performed. The Next Generation Impactor (NGI) was used to assess in vitro drug delivery from salmeterol/fluticasone and salbutamol Diskus™ DPIs. Fine particle fraction, FPF, (<5 µm) was measured at 30-90 l/min for 2-6 s and correlated with acoustically determined flow rate (IFRc). In pharmacokinetic studies using a salbutamol (200 µg) Diskus™, volunteers inhaled either at maximal or minimal effort on separate days. RESULTS: PIFRc was correlated with spirometrically determined values (R (2) = 0.88). In in vitro studies, FPF increased as both flow rate and inhalation duration increased for the salmeterol/fluticasone Diskus™ (Adjusted R (2) = 0.95) and was proportional to flow rate only for the salbutamol Diskus™ (Adjusted R (2) = 0.71). In pharmacokinetic studies, blood salbutamol levels measured at 20 min were significantly lower when PIFRc was less than 60 l/min, p < 0.0001. CONCLUSION: Acoustically-determined PIFR is a suitable method for estimating drug delivery and for monitoring inhalation technique over time.

Automatic identification and accurate temporal detection of inhalations in asthma inhaler recordings.

Asthma is chronic airways disease characterized by recurrent attacks of breathlessness and wheezing. Adherence to medication regimes is a common failing for asthmatic patients and there exists a requirement to monitor such patients' adherence. The detection of inhalations from recordings of inhaler use can provide empirical evidence about patients' adherence to their asthma medication regime. Manually listening to recordings of inhaler use is a tedious and time consuming process and thus an algorithm which can automatically and accurately carry out this task would be of great value. This study employs a recording device attached to a commonly used dry powder inhaler to record the acoustic signals of patients taking their prescribed medication. An algorithm was developed to automatically detect and accurately demarcate inhalations from the acoustic signals. This algorithm was tested on a dataset of 255 separate recordings of inhaler use in real world environments. The dataset was obtained from 12 asthma outpatients who attended a respiratory clinic over a three month period. Evaluation of the algorithm on this dataset achieved sensitivity of 95%, specificity of 94% and an accuracy of 89% in detecting inhalations compared to manual inhalation detection.