Dry Powder Inhalers: From Bench to Bedside.

Dry powder inhalers (DPIs) are now widely prescribed and preferred by the majority of patients. These devices have many advantages over the traditional pressurized metered-dose inhaler (pMDI) but they do have disadvantages. The characteristics of the dose emitted from a DPI are affected by the inhalation manoeuvre used by a patient. Each patient is different and the severity of their lung disease varies from mild to very severe. This affects how they use an inhaler and so determines the type of dose they inhale. An understanding of the pharmaceutical science related to DPIs is important to appreciate the relevance of how patients inhale through these devices. Also, each type of DPI has its unique dose preparation routine, and thus it is essential to follow these recommended steps because errors at this stage may result in no dose being inhaled. All issues related to the inhalation manoeuvre and dose preparation are addressed in this chapter. The importance of the inhalation technique is highlighted with a realization of inhale technique training and checking. During routine patient management, devices should not be switched nor doses increased unless the patient has demonstrated that they can and do use their DPI.

Advancing Digital Solutions to Overcome Longstanding Barriers in Asthma and COPD Management.

Maintenance therapy delivered via inhaler is central to asthma and chronic obstructive pulmonary disease (COPD) management. Poor adherence to inhaled medication and errors in inhalation technique have long represented major barriers to the optimal management of these chronic conditions. Technological innovations may provide a means of overcoming these barriers. This narrative review examines ongoing advances in digital technologies relevant to asthma and COPD with the potential to inform clinical decision-making and improve patient care. Digital inhaler devices linked to mobile apps can help bring about changes in patients' behaviors and attitudes towards disease management, particularly when they build in elements of interactivity and gamification. They can also support ongoing technique education, empowering patients and helping providers maximize the value of consultations and develop effective action plans informed by insights into the patient's inhaler use patterns and their respiratory health. When combined with innovative techniques such as machine learning, digital devices have the potential to predict exacerbations and prompt pre-emptive intervention. Finally, digital devices may support an advanced precision medicine approach to respiratory disease management and help support shared decision-making. Further work is needed to increase uptake of digital devices and integrate their use into care pathways before their full potential in personalized asthma and COPD management can be realized.

A Predictive Machine Learning Tool for Asthma Exacerbations: Results from a 12-Week, Open-Label Study Using an Electronic Multi-Dose Dry Powder Inhaler with Integrated Sensors.

Purpose: Machine learning models informed by sensor data inputs have the potential to provide individualized predictions of asthma deterioration. This study aimed to determine if data from an integrated digital inhaler could be used to develop a machine learning model capable of predicting impending exacerbations. Patients and Methods: Adult patients with poorly controlled asthma were enrolled in a 12-week, open-label study using ProAir® Digihaler®, an electronic multi-dose dry powder inhaler (eMDPI) with integrated sensors, as reliever medication (albuterol, 90 µg/dose; 1-2 inhalations every 4 hours, as needed). Throughout the study, the eMDPI recorded inhaler use, peak inspiratory flow (PIF), inhalation volume, inhalation duration, and time to PIF. A model predictive of impending exacerbations was generated by applying machine learning techniques to data downloaded from the inhalers, together with clinical and demographic information. The generated model was evaluated by receiver operating characteristic area under curve (ROC AUC) analysis. Results: Of 360 patients included in the predictive analysis, 64 experienced a total of 78 exacerbations. Increased albuterol use preceded exacerbations; the mean number of inhalations in the 24-hours preceding an exacerbation was 7.3 (standard deviation 17.3). The machine learning model, using gradient-boosting trees with data from the eMDPI and baseline patient characteristics, predicted an impending exacerbation over the following 5 days with an ROC AUC of 0.83 (95% confidence interval: 0.77-0.90). The feature of the model with the highest weight was the mean number of daily inhalations during the 4 days prior to the day the prediction was made. Conclusion: A machine learning model to predict impending asthma exacerbations using data from the eMDPI was successfully developed. This approach may support a shift from reactive care to proactive, preventative, and personalized management of chronic respiratory diseases.

Investigating the Accuracy of the Digihaler, a New Electronic Multidose Dry-Powder Inhaler, in Measuring Inhalation Parameters.

Background: The Digihaler® is a Food and Drug Administration-approved, digital multidose dry powder inhaler with an integrated electronic module that provides patients and health care professionals with feedback on inhalation parameters, including usage, adherence, and technique. This study compared inhalation parameters measured using the Digihaler with readings made simultaneously using an inhalation profile recorder (IPR). Methods: This single-visit, open-label study enrolled children (4-17 years) and adults (18-55 years) with asthma, and adults (≥55 years) with chronic obstructive pulmonary disease (COPD). Participants made three separate inhalations using an empty Digihaler device, each measured simultaneously by the Digihaler and IPR. Inhalation profiles were downloaded from the devices at the end of the study. Inhalation parameters measured included peak inspiratory flow (PIF) and inhaled volume (inhV). The profile with the highest PIF and corresponding IPR profile were analyzed. Results: Overall, 150 participants were enrolled; inhalation data were available for 148 (50 children and 49 adults with asthma, and 49 with COPD). Mean (standard deviation [SD]) age was 39.1 (24.5) years; 51% of participants were male. Overall mean (SD) PIFs as measured by the Digihaler and IPR were 70.62 (17.73) L/min and 72.55 (19.42) L/min, respectively, with a mean percentage difference of -1.75% (95% confidence interval [CI]: -3.64 to 0.15). Mean percentage differences between the Digihaler and IPR measurements of PIF ranged from -2.97% among adults with COPD to 0.16% among children with asthma. Overall mean (SD) inhV for the Digihaler and IPR were 1.57 (0.69) L and 1.67 (0.73) L, respectively, with a mean percentage difference of -6.11 (95% CI: -8.08 to -4.13). There was a strong correlation between PIF and inhV measurements taken by the Digihaler and those taken by the IPR (Spearman's correlation coefficient = 0.96). Conclusions: Our findings confirm the ability of the Digihaler to provide accurate measurement of inhalation parameters when used by patients.

The Burden of Self-Reported Rhinitis and Associated Risk for Exacerbations with Moderate-Severe Asthma in Primary Care Patients.

PURPOSE: There is a dearth of research regarding the prevalence and nature of patient-reported rhinitis and its relationship with risk of asthma exacerbations. The aim of this study was to (i) determine the prevalence, severity and treatment of self-reported rhinitis symptoms among adults aged ≥18 years with asthma treated at Global Initiative for Asthma (GINA) Step 3 and above and (ii) compare the demographics, clinical characteristics, medication use, side-effects and healthcare practitioner review between patients who report rhinitis symptoms and those who do not and (iii) determine whether patient-reported rhinitis is associated with risk of asthma exacerbations in the total patient sample. PATIENTS AND METHODS: This analysis used data from the iHARP (Initiative Helping Asthma in Real-life Patients) asthma review service - a cross-sectional observational study (2011 and 2014) in seven countries that captured data on patient demographics, rhinitis symptoms, asthma symptoms, indicators of exacerbations, medication use, oropharyngeal effects and side-effects, using practitioner- and patient-reported questionnaires. Comparisons between patients with and without rhinitis were tested. Univariate logistic regression was used to identify variables associated with risk of exacerbations for entry into multivariable logistic regression. RESULTS: This report contains data from 4274 patients: 67.4% (2881/4274) reported rhinitis symptoms and of which 65.7% (1894/2881) had not received a doctor diagnosis; 36.5% (1052/2881) had moderate-severe rhinitis, 12.4% (358/2881) had used intranasal corticosteroids and 19.8% (569/2881) oral antihistamines. Patients with coexisting moderate-severe rhinitis were more likely to have GINA-defined uncontrolled asthma than those with mild rhinitis or no rhinitis. Moderate-severe rhinitis was associated with 40% increased risk of asthma exacerbations (OR=1.40, 95% CI: 1.02-1.90). CONCLUSION: This study identified a major gap in the diagnosis and management of rhinitis in a cohort of people with asthma treated at GINA Step 3 and above who are managed in general practice. It highlights the need for practitioners to identify, evaluate and optimally treat rhinitis in adults with asthma, which is a significant factor associated with exacerbation risk.

The dry powder inhaler features of the Easyhaler that benefit the management of patients.

Introduction: Inhaled therapies are likely to continue to dominate asthma and chronic obstructive pulmonary disease treatment. Dry powder inhalers (DPIs) have several advantages over pressurized metered-dose inhaler (pMDIs), that are most frequently marketed world-wide, but often difficult to use. This literature search focus on DPI features, with respect to Easyhaler, that may affect their use and patients' clinical benefit.Areas covered: DPIs are breath-actuated, easy to use, convenient to use, and more environmentally friendly. During inhalation, the formulation in a DPI is disaggregated by a turbulent airflow energy to generate particles with the greatest likelihood of deposition into the airways. The resistance among DPIs varies from low to high and those with high resistance are wrongly considered as difficult to use. Multidose reservoir-type DPIs have been developed to efficiently deliver a wide range of medications, including the fixed-dose combination of budesonide and formoterol. Easyhaler® shares a similar shape with pMDIs and, as other DPIs, its performance is unaffected by environmental and storage conditions. Due to Easyhaler internal design, dose emission is consistent irrespective of the inhalation flow used by each patient.Expert opinion: Easyhaler® may be considered one of the most convenient inhalers, for daily use, in patients with asthma or COPD.

A multinational observational study identifying primary care patients at risk of overestimation of asthma control.

Factors related to the discrepancy between patient-perceived and actual disease control remain unclear. Identifying patients at risk of overestimation of asthma control remains elusive. This study aimed to (i) investigate the relationship between patient-reported and actual level of asthma control (ii), compare the characteristics between patients who believe their asthma is well controlled that accurately report 'well-controlled' asthma with those that do not, and (iii) identify factors associated with inaccurately reported 'well-controlled' asthma. A historical, multinational, cross-sectional study using data from the iHARP (initiative Helping Asthma in Real-life Patients) review service for adults with asthma prescribed fixed-dose combination therapy. Data from 4274 patients were analysed. A major discrepancy between patient-reported and Global Initiative for Asthma defined asthma control was detected; 71.1% of patients who reported 'well-controlled' asthma were inaccurate in their perception despite receiving regular maintenance therapy. Significant differences were noted in age, gender, body mass index, education level, medication use, side effects, attitudes to preventer inhaler use, inhaler technique review and respiratory specialist review between patients who accurately reported 'well-controlled' asthma and those who did not. Independent risk factors associated with inaccurately reported 'well-controlled' asthma were: having taken a maximum of 5-12 puffs or more of reliever inhaler on at least one day within the previous 4 weeks; being female; having seen a respiratory specialist more than a year ago (rather than in the previous year); and having required oral corticosteroids for worsening asthma in the previous year. The study highlighted the significant hidden burden associated with under-recognition of poor asthma control, on the part of the patient and the need for targeted interventions designed to address the continuing discrepancy between perceived and actual disease control.

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.

Real-life budesonide and formoterol dose emission from the medium and high strength fixed dosed combinations in a Spiromax® dry powder inhaler using inhalation profiles from patients with chronic obstructive pulmonary disease.

Dry powder inhalers (DPIs) are passive devices used to administer inhaled medication for the management of asthma and chronic obstructive pulmonary disease (COPD). DPIs require patients to generate a sufficient internal turbulent airflow force during each inhalation to deaggregate the powdered drug formulation into an emitted dose containing particles with the greatest likelihood of lung deposition. This internal force is generated by the interaction between the user's inhalation flow and the resistance of the DPI. Traditional compendial in vitro methods of measuring dose emission use a vacuum pump to simulate inhalation. We have adapted this in vitro method by replacing the square wave inhalation profile generated by a vacuum pump with the inhalation profiles of patients using an empty DPI. This method enables accurate assessment of the actual dose they would have inhaled. In the present study, real-life inhalation profiles were selected from 15 patients with COPD who inhaled through an empty placebo Spiromax® DPI. Ex vivo dose emissions were measured for the medium (emitted dose of 160 µg/4.5 µg) and high-strength (320 µg/9 µg) budesonide/formoterol formulations from the Spiromax DPI. These profiles were used to investigate the effect of the primary inhalation parameter-peak inhalation flow (PIF). Some profiles were modified to isolate other inhalation parameters (namely, inhaled volume [Vin] and acceleration rate of the inhalation maneuver [ACIM]). Both the medium-strength and high-strength DuoResp Spiromax displayed flow-dependent dose emission. When the PIF of a patient's inhalation maneuver increased from 26.8 L/min to 69.7 L/min, there was a significant (p < 0.05) effect on the dose-emission characteristics of the medium-strength and high-strength DuoResp Spiromax. At each PIF, an increase in Vin from approximately 500 mL to 2000 mL had no effect on the dose-emission characteristics of either strength. However, at each Vin there was a significant (p < 0.05) effect on the dose-emission characteristics as PIF increased. The effect of ACIM on the dose-emission characteristics was small. The ex vivo methodology used in this study provides a practical approach to identify the actual dose a patient might inhale during routine real-life use of the DuoResp Spiromax.

Low-dose oral theophylline combined with inhaled corticosteroids for people with chronic obstructive pulmonary disease and high risk of exacerbations: a RCT.

BACKGROUND: Despite widespread use of therapies such as inhaled corticosteroids (ICSs), people with chronic obstructive pulmonary disease (COPD) continue to suffer, have reduced life expectancy and utilise considerable NHS resources. Laboratory investigations have demonstrated that at low plasma concentrations (1-5 mg/l) theophylline markedly enhances the anti-inflammatory effects of corticosteroids in COPD. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of adding low-dose theophylline to a drug regimen containing ICSs in people with COPD at high risk of exacerbation. DESIGN: A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial. SETTING: The trial was conducted in 121 UK primary and secondary care sites. PARTICIPANTS: People with COPD [i.e. who have a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) of < 0.7] currently on a drug regimen including ICSs with a history of two or more exacerbations treated with antibiotics and/or oral corticosteroids (OCSs) in the previous year. INTERVENTIONS: Participants were randomised (1 : 1) to receive either low-dose theophylline or placebo for 1 year. The dose of theophylline (200 mg once or twice a day) was determined by ideal body weight and smoking status. PRIMARY OUTCOME: The number of participant-reported exacerbations in the 1-year treatment period that were treated with antibiotics and/or OCSs. RESULTS: A total of 1578 people were randomised (60% from primary care): 791 to theophylline and 787 to placebo. There were 11 post-randomisation exclusions. Trial medication was prescribed to 1567 participants: 788 in the theophylline arm and 779 in the placebo arm. Participants in the trial arms were well balanced in terms of characteristics. The mean age was 68.4 [standard deviation (SD) 8.4] years, 54% were male, 32% smoked and mean FEV1 was 51.7% (SD 20.0%) predicted. Primary outcome data were available for 98% of participants: 772 in the theophylline arm and 764 in the placebo arm. There were 1489 person-years of follow-up data. The mean number of exacerbations was 2.24 (SD 1.99) for participants allocated to theophylline and 2.23 (SD 1.97) for participants allocated to placebo [adjusted incidence rate ratio (IRR) 0.99, 95% confidence interval (CI) 0.91 to 1.08]. Low-dose theophylline had no significant effects on lung function (i.e. FEV1), incidence of pneumonia, mortality, breathlessness or measures of quality of life or disease impact. Hospital admissions due to COPD exacerbation were less frequent with low-dose theophylline (adjusted IRR 0.72, 95% CI 0.55 to 0.94). However, 39 of the 51 excess hospital admissions in the placebo group were accounted for by 10 participants having three or more exacerbations. There were no differences in the reporting of theophylline side effects between the theophylline and placebo arms. LIMITATIONS: A higher than expected percentage of participants (26%) ceased trial medication; this was balanced between the theophylline and placebo arms and mitigated by over-recruitment (n = 154 additional participants were recruited) and the high rate of follow-up. The limitation of not using documented exacerbations is addressed by evidence that patient recall is highly reliable and the results of a small within-trial validation study. CONCLUSION: For people with COPD at high risk of exacerbation, the addition of low-dose oral theophylline to a drug regimen that includes ICSs confers no overall clinical or health economic benefit. This result was evident from the intention-to-treat and per-protocol analyses. FUTURE WORK: To promote consideration of the findings of this trial in national and international COPD guidelines. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 37. See the NIHR Journals Library website for further project information.

Chronic obstructive pulmonary disease (COPD) is a long-term lung disease that cannot be cured. The main symptom is shortness of breath on exertion. In the UK, about 1.2 million people have COPD. It is a major cause of death and costs the NHS > £1B a year. Sudden 'flare-ups' of symptoms often need emergency treatment, shorten life expectancy and reduce people's ability to get on with their lives. Theophylline is a drug that has been around for decades. In the past, it was used in high doses to treat COPD by opening up airways. However, its benefits were limited and it often caused unpleasant side effects. High-dose theophylline has been replaced by drugs administered by inhalers, such as inhaled corticosteroids (ICSs). Recent work in the laboratory and in animal models suggests that, at low dose, theophylline could make ICSs work better in COPD with none of the side effects of high-dose theophylline. The Theophylline With Inhaled CorticoSteroid (TWICS) trial tested whether or not adding low-dose theophylline reduces flare-ups in people with COPD taking ICSs. A total of 1578 people with COPD from 121 centres all over the UK took part. Participants were randomly divided into two groups: one group took low-dose theophylline and the other took dummy placebo pills. Participants were asked to attend visits at 6 and 12 months. A total of 791 participants were prescribed low-dose theophylline and 787 were prescribed dummy placebo pills. Although not everyone took the tablets for a whole year, it was possible to count the number of flare-ups in 98% of those taking part. In total, there were 3430 flare-ups. On average, the people taking low-dose theophylline had 2.24 flare-ups and the people taking placebo had 2.23 flare-ups. Overall, the trial showed that, for people with COPD, taking low-dose theophylline on top of steroid inhalers makes no real difference.

Bioavailability of Beclometasone From Two HFA-BDP Formulations With a Spacer.

BACKGROUND: The drug delivery characteristics of each inhaler/spacer combination are unique. The spacer size as well as the presence of electrostatic charge greatly influence the inhaler dose emission and in vivo delivery. Using a previously developed urinary pharmacokinetic method, we have measured the relative lung and systemic bioavailability of beclometasone dipropionate (BDP) after inhalation from 2 hydrofluroalkane-beclometasone dipropionate (HFA-BDP) formulations when used with a spacer. METHODS: 12 healthy volunteers received 8 randomized doses, separated by 7 d, of inhaled of BDP with either the Clenil pressurized metered-dose inhaler (pMDI; 250 µg) or the breath-actuated Qvar Easi-Breathe inhaler (100 µg), used alone or with a spacer. The urinary amounts of BDP excreted and retained in the spacer were assayed using a liquid chromatographic mass spectrometer. The spacer was assessed after washing with a detergent solution that was either rinsed or not rinsed with water. In addition, the aerodynamic characterization of each inhaler/spacer combination was assessed using the Andersen Cascade Impactor operated at 28 L/min using a 4-L inhalation volume. The amount of BDP deposited in the induction port, spacer, and various Anderson Cascade Impactor stages were determined. RESULTS: The in vivo 30-min urinary excretion and the in vitro fine particle dose results were only slightly affected by adding the spacer to the Clenil pMDI or the Qvar Easi-Breathe inhaler. However, the spacer significantly reduced drug particle impaction in the oropharynx and minimized deposition in the gastrointestinal tract. Therefore, using spacers with BDP inhalers is associated with a more favorable therapeutic ratio because it has little effect on lung dose, but it significantly reduced throat deposition. An improved lung deposition was achieved with non-rinsed spacers compared to spacers rinsed with water. CONCLUSION: The difference in the BDP particle size between formulations as well as spacer size greatly affected drug deposition in different regions of the respiratory tract.

Use of inspiratory profiles from patients with chronic obstructive pulmonary disease (COPD) to investigate drug delivery uniformity and aerodynamic dose emission of indacaterol from a capsule based dry powder inhaler.

Most patients using dry powder inhalers (DPIs) are unable to achieve the inhalation parameters recommended for pharmacopoeial in-vitro dose emission testing. The dose emission characteristics of indacaterol Breezhaler (IB) have been measured using COPD patients' inhalation profiles (IPs) when using IB and replayed in-vitro using a breath simulator attached to an Andersen Cascade Impactor. The peak inhalation flow (PIF) of the profiles ranged from 28.3 to 87.8 L/min and inhaled volumes (Vin) from 0.7 to 3 L. The indacaterol total emitted doses (TED), fine particle dose (FPD) and mass median aerodynamic diameter (MMAD) were measured. TED varied between 61% to 83% of the 150 µg nominal dose, the FPD was found to vary between 19% and 30% and the MMAD from 3.7 µm to 2.3 µm with the increase of the profiles' PIF and Vin. The mean (SD) values were 113.4(8.9) µg, 39.7(5.0) µg and 2.7(0.5) µm, respectively. The quantity and the quality of the emitted dose from the indacaterol Breezhaler® are dependent on the capability of a patient generating an optimal inhalation profile. Therefore, when using the IB patients should be encouraged to inhale as fast as they can from the start of their inhalation and for as long as possible.

ARIA pharmacy 2018 "Allergic rhinitis care pathways for community pharmacy": AIRWAYS ICPs initiative (European Innovation Partnership on Active and Healthy Ageing, DG CONNECT and DG Santé) POLLAR (Impact of Air POLLution on Asthma and Rhinitis) GARD Demonstration project.

Pharmacists are trusted health care professionals. Many patients use over-the-counter (OTC) medications and are seen by pharmacists who are the initial point of contact for allergic rhinitis management in most countries. The role of pharmacists in integrated care pathways (ICPs) for allergic diseases is important. This paper builds on existing studies and provides tools intended to help pharmacists provide optimal advice/interventions/strategies to patients with rhinitis. The Allergic Rhinitis and its Impact on Asthma (ARIA)-pharmacy ICP includes a diagnostic questionnaire specifically focusing attention on key symptoms and markers of the disease, a systematic Diagnosis Guide (including differential diagnoses), and a simple flowchart with proposed treatment for rhinitis and asthma multimorbidity. Key prompts for referral within the ICP are included. The use of technology is critical to enhance the management of allergic rhinitis. However, the ARIA-pharmacy ICP should be adapted to local healthcare environments/situations as regional (national) differences exist in pharmacy care.

Systematic review of association between critical errors in inhalation and health outcomes in asthma and COPD.

Inhaled medications are the cornerstone of treatment and management of asthma and COPD. However, inhaler device errors are common among patients and have been linked with reduced symptom control, an increased risk of exacerbations, and increased healthcare utilisation. These observations have prompted GINA (Global INitiative for Asthma) and GOLD (Global initiative for chronic Obstructive Lung Disease) to recommend regular assessment of inhaler technique in a bid to improve therapeutic outcomes. To better define the relationship between device errors and health outcomes (clinical outcomes, quality of life, and healthcare utilisation) in asthma and COPD, we conducted a systematic review of the literature, with a particular focus on the methods used to assess the relationship between device errors and outcomes. Sixteen studies were identified (12 in patients with asthma, one in patients with COPD, and three in both asthma and COPD) with varying study designs, endpoints, and patient populations. Most of the studies reported that inhalation errors were associated with worse disease outcomes in patients with asthma or COPD. Patients who had a reduction in errors over time had improved outcomes. These findings suggest that time invested by healthcare professionals is vital to improving inhalation technique in asthma and COPD patients to improve health outcomes.

Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial.

Importance: Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD. Objective: To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD. Design, Setting, and Participants: The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites. Interventions: Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787). Main Outcomes and Measures: The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period. Results: Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%). Conclusions and Relevance: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations. Trial Registration: isrctn.org Identifier: ISRCTN27066620.

Evaluation of inhaler technique and achievement and maintenance of mastery of budesonide/formoterol Spiromax® compared with budesonide/formoterol Turbuhaler® in adult patients with asthma: the Easy Low Instruction Over Time (ELIOT) study.

BACKGROUND: Incorrect inhaler technique is a common cause of poor asthma control. This two-phase pragmatic study evaluated inhaler technique mastery and maintenance of mastery with DuoResp® (budesonide-formoterol [BF]) Spiromax® compared with Symbicort® (BF) Turbuhaler® in patients with asthma who were receiving inhaled corticosteroids/long-acting ß2-agonists. METHODS: In the initial cross-sectional phase, patients were randomized to a 6-step training protocol with empty Spiromax and Turbuhaler devices. Patients initially demonstrating ≥1 error with their current device, and then achieving mastery with both Spiromax and Turbuhaler (absence of healthcare professional [HCP]-observed errors), were eligible for the longitudinal phase. In the longitudinal phase, patients were randomized to BF Spiromax or BF Turbuhaler. Co-primary endpoints were the proportions of patients achieving device mastery after three training steps and maintaining device mastery (defined as the absence of HCP-observed errors after 12 weeks of use). Secondary endpoints included device preference, handling error frequency, asthma control, and safety. Exploratory endpoints included assessment of device mastery by an independent external expert reviewing video recordings of a subset of patients. RESULTS: Four hundred ninety-three patients participated in the cross-sectional phase, and 395 patients in the longitudinal phase. In the cross-sectional phase, more patients achieved device mastery after three training steps with Spiromax (94%) versus Turbuhaler (87%) (odds ratio [OR] 3.77 [95% confidence interval (CI) 2.05-6.95], p < 0.001). Longitudinal phase data indicated that the odds of maintaining inhaler mastery at 12 weeks were not statistically significantly different (OR 1.26 [95% CI 0.80-1.98], p = 0.316). Asthma control improved in both groups with no significant difference between groups (OR 0.11 [95% CI -0.09-0.30]). An exploratory analysis indicated that the odds of maintaining independent expert-verified device mastery were significantly higher for patients using Spiromax versus Turbuhaler (OR 2.11 [95% CI 1.25-3.54]). CONCLUSIONS: In the cross-sectional phase, a significantly greater proportion of patients using Spiromax versus Turbuhaler achieved device mastery; in the longitudinal phase, the proportion of patients maintaining device mastery with Spiromax versus Turbuhaler was similar. An exploratory independent expert-verified analysis found Spiromax was associated with higher levels of device mastery after 12 weeks. Asthma control was improved by treatment with both BF Spiromax and BF Turbuhaler. TRIAL REGISTRATION: EudraCT 2013-004630-14 (registration date 23 January 2014); NCT02570425 .

Relationship of Inhaled Corticosteroid Adherence to Asthma Exacerbations in Patients with Moderate-to-Severe Asthma.

BACKGROUND: Patients with asthma and elevated blood eosinophils are at increased risk of severe exacerbations. Management of these patients should consider nonadherence to inhaled corticosteroid (ICS) therapy as a factor for increased exacerbation risk. OBJECTIVE: The objective of this study was to investigate whether poor adherence to ICS therapy explains the occurrence of asthma exacerbations in patients with elevated blood eosinophil levels. METHODS: This historical cohort study identified patients within the Optimum Patient Care Research Database, aged 18 years or more, at Global Initiative for Asthma step 3 or 4, with 2 or more ICS prescriptions during the year before the clinical review. Patient characteristics and adherence (based on prescription refills and patient self-report) for ICS therapy were analyzed for those with elevated (>400 cells/µL) or normal (≤400 cells/µL) blood eosinophils. RESULTS: We studied 7195 patients (66% female, mean age 60 years) with median eosinophil count of 200 cells/µL and found 81% to be not fully adherent to ICS therapy. A total of 1031 patients (14%) had elevated blood eosinophil counts (58% female, mean age 60 years), 83% of whom were not fully adherent to ICS. An increased proportion of adherent patients in the elevated blood eosinophil group had 2 or more exacerbations (14.0% vs 7.2%; P = .003) and uncontrolled asthma (73% vs 60.8%; P = .004) as compared with non-fully adherent patients. CONCLUSIONS: Approximately 1 in 7 patients had elevated eosinophils. Adherence to ICS therapy was not associated with decreased exacerbations for these patients. Additional therapy should be considered for these patients, such as biologics, which have been previously shown to improve control in severe uncontrolled eosinophilic asthma.

Study of the Emitted Dose After Two Separate Inhalations at Different Inhalation Flow Rates and Volumes and an Assessment of Aerodynamic Characteristics of Indacaterol Onbrez Breezhaler® 150 and 300 µg.

Onbrez Breezhaler® is a low-resistance capsule-based device that was developed to deliver indacaterol maleate. The study was designed to investigate the effects of both maximum flow rate (MIF) and inhalation volume (Vin) on the dose emission of indacaterol 150 and 300 µg dose strengths after one and two inhalations using dose unit sampling apparatus (DUSA) as well as to study the aerodynamic characteristics of indacaterol Breezhaler® using the Andersen cascade impactor (ACI) at a different set of MIF and Vin. Indacaterol 150 and 300 µg contain equal amounts of lactose per carrier. However, 150 µg has the smallest carrier size. The particle size distribution (PSD) of indacaterol DPI formulations 150 and 300 µg showed that the density of fine particles increased with the increase of the primary pressure. For both strengths (150 µg and 300 µg), ED1 increased and ED2 decreased when the inhalation flow rate and inhaled volume increased. The reduction in ED1 and subsequent increase in ED2 was such that when the Vin is greater than 1 L, then 60 L/min could be regarded as the minimum MIF. The Breezhaler was effective in producing respirable particles with an MMAD ≤5 µm irrespective of the inhalation flow rate, but the mass fraction of particles with an aerodynamic diameter <3 µm is more pronounced between 60 and 90 L/min. The dose emission of indacaterol was comparable for both dose strengths 150 and 300 µg. These in vitro results suggest that a minimum MIF of 60 L/min is required during routine use of Onbrez Breezhaler®, and confirm the good practice to make two separate inhalations from the same dose.

Inhaler technique mastery and maintenance in healthcare professionals trained on different devices.

OBJECTIVE: Healthcare professionals (HCPs) are required to assess and train patients in the correct use of inhalers but are often unable to demonstrate correct technique themselves. We sought to assess the level of training required for HCPs to master and maintain device mastery when using two different dry powder inhalers (DPIs). METHODS: We conducted a randomized, un-blinded, crossover study in undergraduate HCPs who undertook a six-step training procedure (intuitive use, patient information leaflet, instructional video, individual tuition from expert, then two repeats of individual tuition) for the use of Turbuhaler® (an established device) and Spiromax® (a newer device, reportedly easier to use). Device mastery (absence of errors) was evaluated by expert assessors at each training step. Maintenance of mastery was assessed 4 ± 1 week (visit 2) and 8 ± 2 weeks (visit 3) after initial training (visit 1). RESULTS: Of 516 eligible participants, 113 (22%) demonstrated device mastery prior to training on Spiromax® compared with 20 (4%) on Turbuhaler® (p < 0.001). The median number of training steps required to achieve mastery was 2 (interquartile range [IQR] 2-4) for Spiromax® and 3 (IQR 2-4) for Turbuhaler® (p < 0.001). A higher number of participants maintained mastery with Spiromax® compared with Turbuhaler®, at visits 2 and 3 (64% vs 41% and 79% vs 65%, respectively; p < 0.001). CONCLUSIONS: There are significant differences in the nature and extent of training required to achieve and maintain mastery for Spiromax® and Turbuhaler® devices. The implications on clinical practice, device education delivery, and patient outcomes require further evaluation.