Device use errors with soft mist inhalers: A global systematic literature review and meta-analysis.

Inhaled bronchodilators are the cornerstone of treatment for chronic obstructive pulmonary disease (COPD). Soft mist inhalers (SMIs) are devices that deliver bronchodilators. Although correct device use is paramount to successful medication delivery, patient errors are common. This global systematic literature review and meta-analysis examined device use errors with SMIs among patients with obstructive lung diseases. PubMed, EMBASE, PsycINFO, Cochrane, and Google Scholar were searched to identify studies published between 2010 and 2019 that met the following inclusion criteria: (a) English language; (b) a diagnosis of COPD, bronchitis, or emphysema; and (c) reported device use errors among adults receiving long-acting bronchodilator treatment with Respimat® SMI (i.e. Spiriva®, Stiolto®, Spiolto®, and Striverdi®). Descriptive statistics examined sociodemographics, clinical characteristics, and device use errors. Meta-analysis techniques were employed with random-effects models to generate pooled mean effect sizes and 95% confidence intervals (CIs) for overall and step-by-step errors. The I2 statistic measured heterogeneity. Twelve studies (n = 1288 patients) were included in this meta-analysis. Eighty-eight percent of patients had COPD, and most had moderate/very severe airflow limitation (Global Initiative for Chronic Obstructive Lung Disease spirometric stages II to IV). Aggregate results revealed that 58.9% (95% CI: 42.4-75.5; I2 = 92.8%) of patients made ≥1 device use errors. Among 11 studies with step-by-step data, the most common errors were failure to (1) exhale completely and away from the device (47.8% (95% CI: 33.6-62.0)); (2) hold breath for up to 10 seconds (30.6% (95% CI: 17.5-43.7)); (3) take a slow, deep breath while pressing the dose release button (27.9% (95% CI: 14.5-41.2)); (4) hold the inhaler upright (22.6% (95% CI: 6.2-39.0)); and (5) turn the base toward the arrows until it clicked (17.6% (95% CI: 3.0-32.2)). Device use errors occurred in about 6 of 10 patients who used SMIs. An individualized approach to inhalation device selection and ongoing training and monitoring of device use are important in optimizing bronchodilator treatment.

The Respimat® Soft Mist Inhaler: Implications of Drug Delivery Characteristics for Patients.

Successful treatment for respiratory diseases relies on effective delivery of medication to the lungs using an inhalation device. Different inhalers have distinct characteristics affecting drug administration and patient adherence, which can impact clinical outcomes. We report on the development of the Respimat® soft mist inhaler (SMI) and compare key attributes with metered-dose inhalers (MDIs) and dry powder inhalers (DPIs). The Respimat SMI, a pocket-sized device generating a single-breath, inhalable aerosol, was designed to enhance drug delivery to the lungs, reduce the requirements for patient coordination and inspiratory effort, and improve the patients' experience and ease of use. The drug deposition profile with Respimat SMI is favorable compared with MDIs and DPIs, with higher drug deposition to the lung and peripheral airways. The slow velocity and long spray duration of the Respimat SMI aerosol also aid patient coordination. Clinical equivalence has been demonstrated for maintenance treatment of chronic obstructive pulmonary disease using once-daily tiotropium between Respimat SMI (5 µg) and HandiHaler DPI (18 µg). In comparative studies, patients preferred Respimat SMI to MDIs and DPIs; they reported that Respimat SMI was easy to use and felt the inhaled dose was delivered. The Respimat SMI, designed to generate a slow-moving and fine mist, is easy to use and effectively delivers drug treatment to the lungs. The patient-centered design of Respimat SMI improved patient satisfaction, and may help to promote long-term adherence and improve clinical outcomes with asthma and chronic obstructive pulmonary disease.

Improving usability and maintaining performance: human-factor and aerosol-performance studies evaluating the new reusable Respimat inhaler.

PURPOSE: The Respimat is a handheld, propellant-free, soft-mist inhaler. Observations by patients and physicians prompted development of an improved second-generation Respimat inhaler. Human-factor studies assessing the usability of the new inhaler and in vitro assessment of aerosol performance are important to demonstrate functionality of the updated inhaler. METHODS: Studies were performed to assess any possible impact of the reusable Respimat inhaler design on aerosol performance (delivered dose [DD] and fine-particle dose [FPD]) and iteratively assess and improve usability of the new design. The tiotropium-olodaterol inhalation solution for Respimat was used as a model. The DD and FPD of the reusable Respimat inhaler (across multiple cartridges) and the disposable Respimat inhaler were determined by laser diffraction and with an alternative Andersen cascade impactor. Usability was measured across three studies involving health care professionals and patients with diagnoses of COPD, asthma, or combined disease (with and without experience with the Respimat inhaler). These studies measured performance of handling tasks and collected subjective feedback directly related to the inhaler's new or altered features, which fed into optimization of the inhaler. RESULTS: DDs of tiotropium and olodaterol were stable up to 15 cartridges and consistently within the upper and lower limits of the disposable Respimat inhaler. The FPD was also found to be batch-consistent over the cartridges and comparable with the reference. The usability of the reusable Respimat inhaler compared with the disposable inhaler was improved in terms of assembly and daily use. Cartridge exchange was rated as intuitive and easy to very easy. CONCLUSION: The new reusable Respimat is a medical inhaler developed with enhanced features that meets health care professionals' and patients' needs. Drug delivery across multiple cartridges is not affected by the design. Compared with the original disposable inhaler, the usability of the reusable inhaler has been improved, and cartridge exchange was rated as easy to perform. The reusable Respimat provides greater convenience for patients vs the disposable inhaler, with reduced environmental impact.

Maximizing participant retention in a phase 2B HIV prevention trial in Kampala, Uganda: The MTN-003 (VOICE) Study.

BACKGROUND: The success of longitudinal trials depends greatly on using effective strategies to retain participants and ensure internal validity, maintain sufficient statistical power, and provide for the generalizability of study results. OBJECTIVE: This paper describes the challenges and specific strategies used to retain participants in a Phase 2B safety and effectiveness study of daily oral and vaginal tenofovir formulations for the prevention of HIV-1 infection in the MTN-003 (VOICE) trial in Kampala, Uganda. METHODS: Once enrolled, participants were seen every 28 days at the research site and their study product was re-filled. Challenges to retention included a mobile population, non-disclosure of study participation to spouse/family, and economic constraints. Strategies used to maintain high participation rates included the use of detailed locator information, a participant tracking database, regular HIV/STI testing, and the formation of close bonds between staff and subjects. RESULTS: We enrolled 322 women out of the 637 screened. The overall retention rate was 95% over a 3 year follow up period. Only 179 (3%) out of the 6124 expected visits were missed throughout study implementation. Reasons for missed visits included: participants thinking that they did not need frequent visits due to their HIV negative status, time constraints due to commercial sex work, and migration for better employment. CONCLUSIONS: With the implementation of multi-faceted comprehensive follow-up and retention strategies, we achieved very high retention rates in the MTN-003 study. This paper provides a blueprint for effective participant retention strategies for other longitudinal HIV prevention studies in resource-limited settings in Sub-Saharan Africa.

The effects of respiratory inhaled drugs on the prevention of acute mountain sickness.

BACKGROUND: Acute mountain sickness (AMS) is common in high-altitude travelers, and may lead to life-threatening high-altitude cerebral edema (HACE) or high-altitude pulmonary edema (HAPE). The inhaled drugs have a much lower peak serum concentrations and a shorter half-life period than oral drugs, which give them a special character, greater local effects in the lung. Meanwhile, short-term administration of inhaled drugs results in almost no adverse reactions. METHODS: We chose inhaled ipratropium bromide/salbutamol sulfate (combivent, COM), budesonide (pulmicortrespules, BUD), and salbutamol sulfate (ventolin, VEN) in our study to investigate their prophylactic efficacy against AMS. Since COM is a compound drug of ipratropium bromide and salbutamol sulfate, to verify which part of COM plays a role in the prevention of AMS, we also tested VEN in our experiment. RESULTS: In our study, Lake Louise scores (LLS) in the COM (1.14 ±â€Š0.89 vs 1.91 ±â€Š1.23, P < .05) and BUD (1.35 ±â€Š0.94 vs 1.91 ±â€Š1.23, P < .05) groups were both significantly lower than the placebo group at 72 hours. There were no significant differences in LLS scores among the 4 groups at 120 hours. The incidence of AMS in the COM group was significantly reduced at 72 hours (16.7% in COM group vs 43.4% in placebo group, P < .05) after exposure to high-altitude. There were no significant differences in AMS incidences at 120 hours among the 4 groups. CONCLUSION: The prophylactic use of COM could prevent AMS in young Chinese male at 72 hours after high-altitude exposure. BUD also could reduce LLS but not prevent AMS at 72 hours. Ipratropium bromide maybe the effective drug in COM work on the prevention of AMS alone.

In vitro and clinical characterization of the valved holding chamber AeroChamber Plus® Flow-Vu® for administrating tiotropium Respimat® in 1-5-year-old children with persistent asthmatic symptoms.

BACKGROUND: When characterizing inhalation products, a comprehensive assessment including in vitro, pharmacokinetic (PK), and clinical data is required. We conducted a characterization of tiotropium Respimat® when administered with AeroChamber Plus® Flow-Vu® anti-static valved holding chamber (test VHC) with face mask in 1-5-year-olds with persistent asthmatic symptoms. METHODS: In vitro tiotropium dose and particle size distribution delivered into a cascade impactor were evaluated under fixed paediatric and adult flow rates between actuation and samplings. The tiotropium mass likely to reach children's lungs was assessed by tidal breathing simulations and an ADAM-III Child Model. PK exposure to tiotropium in preschool children with persistent asthmatic symptoms (using test VHC) was compared with pooled data from nine Phase 2/3 trials in older children, adolescents, and adults with symptomatic persistent asthma not using test VHC. RESULTS: At fixed inspiratory flow rates, emitted mass and fine particle dose decreased under lower flow conditions; dose reduction was observed when Respimat® was administered by test VHC at paediatric flow rates. In <5-year-old children, such a dose reduction is appropriate. In terms of dose per kg/body weight, in vitro-delivered dosing in children was comparable with adults. Transmission and aerosol holding properties of Respimat® when administered with test VHC were fully sufficient for aerosol delivery to patients. At zero delay, particles <5 µm (most relevant fraction) exhibited a transfer efficacy of ≥60%. The half-time was>10 s, allowing multiple breaths. Standardized tidal inhalation resulted in an emitted mass from the test VHC of approximately one-third of labelled dose, independent of coordination and face mask use, indicating predictable tiotropium administration by test VHC with Respimat®. Tiotropium exposure in 1-5-year-old patients using the test VHC, when adjusted by height or body surface, was comparable with that in older age groups without VHCs; no overexposure was observed. Adverse events were less frequent with tiotropium (2.5 µg, n = 20 [55.6%]; 5 µg, n = 18 [58.1%]) than placebo (n = 25 [73.5%]). CONCLUSIONS: Our findings provide good initial evidence to suggest that tiotropium Respimat® may be administered with AeroChamber Plus® Flow-Vu® VHC in 1-5-year-old patients with persistent asthmatic symptoms. To confirm the clinical efficacy and safety in these patients, additional trials are required. CLINICAL TRIALS REGISTRY NUMBER: The trial was registered under NCT01634113 at http://www.clinicaltrials.gov.

Size distribution of salbutamol/ipratropium aerosols produced by different nebulizers in the absence and presence of heat and humidification.

BACKGROUND: Few studies have evaluated the size distribution of inhaled and exhaled aerosolized drugs, or the effect of heated humidification on particle size and lung deposition. The present study evaluated these aspects of bronchodilator (salbutamol/ipratropium) delivery using a lung model in the absence and presence of heat and humidification. METHODS: We positioned filters to collect and measure the initial drug, inhaled drug, and exhaled drug. Particle size distribution was evaluated using an 8-stage Marple personal cascade impactor with 0.2-µm polycarbonate filters. RESULTS: A greater inhaled drug mass was delivered using a vibrating mesh nebulizer (VMN) than by using a small volume nebulizer (SVN), when heated humidifiers were not employed. When heated and humidified medical gas was used, there was no significant difference between the inhaled drug mass delivered by the VMN and that delivered by the SVN. A significantly greater mass of inhaled 1.55-µm drug particles was produced by the VMN than with the SVN, under heated and humidified conditions. However, the mass median aerodynamic diameters (MMADs) of the aerosolized drug produced by the SVN and VMN did not differ significantly under the same conditions. CONCLUSIONS: The VMN produced more fine particles of salbutamol/ipratropium, and the drug particle size clearly increased in the presence of heat and humidification.

Quantifying the importance of inhaler attributes corresponding to items in the patient satisfaction and preference questionnaire in patients using Combivent Respimat.

BACKGROUND: Physicians consider ease of use, satisfaction, and preferences when prescribing an inhaler device. These factors may impact appropriate usage and compliance. METHODS: The objectives were to quantify the relative importance of inhaler attributes in patients currently using Combivent Respimat by eliciting preferences for performance and convenience attributes assessed by items in the Patient Satisfaction and Preference Questionnaire (PASAPQ). Using a pharmacy database, 19,964 adults in the United States who filled ≥2 Combivent Respimat prescriptions were identified. Of those, 8150 patients were randomly selected to receive invitation letters. The online cross-sectional survey included the PASAPQ and best-worst scaling (BWS) questions. The PASAPQ measures satisfaction with medication attributes across two domains: performance and convenience. BWS questions asked participants to select the most and least important device attributes. A descriptive statistics analysis of the PASAPQ and a random-parameters logit model of BWS responses were conducted. RESULTS: The survey was completed by 503 participants. Most were female (57.3%), white (88.5%), and 51-70 years old (67.6%). Approximately 47% reported a chronic obstructive pulmonary disease diagnosis, 21.9% asthma, 8.2% other lung disease, and 23.1% more than one lung disease. PASAPQ scores indicated that the majority were satisfied or very satisfied; up to 20% reported being dissatisfied with Combivent Respimat. The three most important inhaler attributes were Feeling that your medicine gets into your lungs, Inhaler works reliably, and Inhaler makes inhaling your medicine easy. The most important attributes corresponded to six of seven items in the PASAPQ performance domain. CONCLUSIONS: Most participants reported satisfaction with Combivent Respimat. Performance attributes were more important than convenience attributes.

A Tablet-Based Multimedia Education Tool Improves Provider and Subject Knowledge of Inhaler Use Techniques.

BACKGROUND: Although inhaled medications are effective therapies for COPD, many patients and providers use them incorrectly. METHODS: We recruited providers who prescribe inhalers or teach inhaler technique and assessed their use of metered-dose inhalers (MDIs), various dry powder inhalers (DPIs), and Respimat using predefined checklists. Then they watched tablet-based multimedia educational videos that demonstrated correct inhaler technique by a clinical pharmacist with teach-back from a patient and were re-evaluated. We also recruited patients with COPD and assessed their use of their prescribed inhalers and then retested them after 3-6 months. Baseline and follow-up respiratory symptoms were measured by the COPD Assessment Test. RESULTS: Fifty-eight providers and 50 subjects participated. For all providers, correct inhaler technique (reported as percentage correct steps) increased after the videos: MDI without a spacer (72% vs 97%) MDI with a spacer (72% vs 96%), formoterol DPI (50% vs 94%), mometasone DPI (43% vs 95%), tiotropium DPI (73% vs 99%), and Respimat (32% vs 93%) (before vs after, P < .001 for all comparisons). Subjects also improved their inhaler use technique after viewing the educational videos: MDI without a spacer (69% vs 92%), MDI with a spacer (73% vs 95%), and tiotropium DPI (83% vs 96%) (before vs after, P < .001 for all comparisons). The beneficial effect of this educational intervention declined slightly for subjects but was durably improved after several months. COPD Assessment Test scores did not demonstrate any change in respiratory symptoms. CONCLUSIONS: A tablet-based inhaler education tool improved inhaler technique for both providers and subjects. Although this intervention did show durable efficacy for improving inhaler use by patients, it did not reduce their respiratory symptoms.

The Respimat Soft Mist Inhaler, a Novel Inhaled Drug Delivery Device.

Summary The Respimat SMI offers a novel delivery mechanism for the management of primarily COPD, but asthma as well. Presently, four different medications, as monotherapy or a combination of two active ingredients, are available using the Respimat SMI technology. Multiple studies have demonstrated safety and efficacy of these drugs when delivered via Respimat SMI. Patients tend to prefer the Respimat SMI over traditional inhaler devices, as it overcomes some of the disadvantages posed by traditional delivery devices.

TIOtropium Safety and Performance In Respimat® (TIOSPIRTM ): Analysis of Asian cohort of COPD patients.

BACKGROUND AND OBJECTIVE: The TIOtropium Safety and Performance In Respimat (TIOSPIR) trial showed similar safety and exacerbation efficacy profiles for tiotropium Respimat and HandiHaler in patients with COPD. The TIOSPIR results for patients in Asia are presented here. METHODS: TIOSPIR evaluated once-daily tiotropium Respimat 5 and 2.5 µg with HandiHaler 18 µg in patients with COPD. Primary endpoints included time to death and time to first COPD exacerbation. Safety and exacerbation efficacy profiles were determined for the Asian region, and for Asia (all treatment arms pooled) versus the rest of the world (RoW). RESULTS: In Asia (n = 2356), time to death was similar for Respimat 5 and 2.5 µg versus HandiHaler 18 µg (hazard ratio (HR) (95% CI): 0.96 (0.67, 1.38) and 1.23 (0.87, 1.73)). Risk of COPD exacerbation was similar for Respimat 5 µg, but increased for 2.5 µg versus HandiHaler 18 µg (HR (95% CI): 0.99 (0.85, 1.15) and 1.17 (1.00, 1.35)). Time to death in Asia and RoW was similar (HR (95% CI): 1.15 (0.99, 1.35)). Time to first COPD exacerbation was longer (HR (95% CI): 0.84 (0.78, 0.89)) and exacerbation rates were lower in Asia, but severe exacerbations were more frequent than in the RoW. Risk of major adverse cardiovascular events was similar for both regions. CONCLUSION: Similar safety and exacerbation efficacy profiles were observed for tiotropium Respimat 5 µg and HandiHaler 18 µg in patients with COPD from Asia, analogous to the global analysis. Asian patients had lower risk of, and fewer exacerbations overall, but a higher proportion of severe exacerbations than in the RoW.

Randomised, double-blind, placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat® in patients with moderate to severe persistent asthma.

BACKGROUND: A Phase II, multicentre, randomised, double-blind, placebo-controlled, crossover trial comparing the 24-h forced expiratory volume in 1 s (FEV1) time profile after 3 weeks' treatment with once-daily (QD) or twice-daily (BID) olodaterol (at the same total daily dose) versus placebo delivered via Respimat® in patients with moderate to severe asthma. METHODS: Patients were randomised to different sequences of olodaterol with 2-week washout, either as a total daily dose of 5 µg (5 µg QD [AM] or 2.5 µg BID) or placebo, or 10 µg (10 µg QD [AM] or 5 µg BID) or placebo. Primary end point was FEV1 area under the curve from 0 to 24 h (AUC0-24) response (defined as change from study baseline FEV1) after 3 weeks. Key secondary end points were FEV1 AUC0-12 and AUC12-24 responses. RESULTS: Two hundred and six patients received treatment. All olodaterol treatments demonstrated statistically significant improvements in FEV1 AUC0-24 response at 3 weeks versus placebo (p < 0.0001); adjusted mean treatment difference versus placebo was 0.191 L for olodaterol 2.5 µg BID (95 % confidence interval [CI] 0.152, 0.229), 0.150 L for 5 µg QD (95 % CI 0.111, 0.189), 0.228 L for 5 µg BID (95 % CI 0.190, 0.266) and 0.209 L for 10 µg QD (95 % CI 0.170, 0.247). These results were supported by the key secondary end points. Olodaterol 5 µg QD provided numerically lower mean values for 24-h bronchodilation than olodaterol 2.5 µg BID (p = 0.0465), with no statistically significant difference between treatment with olodaterol 10 µg QD and 5 µg BID. No relevant differences in morning and evening peak expiratory flow or Asthma Control Questionnaire scores at 3 weeks were observed between different doses and regimens. Adverse events were generally mild to moderate and comparable between groups. CONCLUSIONS: All doses and dose frequencies provided adequate 24-h bronchodilation superior to placebo. Based on the results of this study, it would be reasonable to include both posologies of 5 µg olodaterol daily (5 µg QD or 2.5 µg BID, both delivered in two puffs per dose from the Respimat® inhaler) in subsequent studies. Further studies are necessary to confirm the optimum dosing regimen in asthma. No safety concerns were identified. TRIAL REGISTRATION: ClinicalTrials.gov NCT01311661.