Aradigm Corporation Research Articles

The Sputum Microbiome Is Associated with Lung Inflammation, Exacerbations and Mortality in Patients with Bronchiectasis

Introduction: Infection is a key component of the pathophysiology of bronchiectasis. Characterisation of the microbiome offers a higher degree of sensitivity and resolution than traditional culture to evaluate the importance of infection in determining the risk of exacerbation and long-term outcomes, including mortality, in bronchiectasis. Methods: Sputum samples from 281 patients with bronchiectasis included in a longitudinal cohort of patients from two hospitals in the East of Scotland underwent 16S rRNA amplicon sequencing. Sputum supernatant was used to measure neutrophil elastase activity by immunoassay. Patients were enrolled from 2012-2015 and followed up until January 2019 for long term outcomes. Repeat sputum samples were obtained at exacerbation and stable visits during follow-up. Dominant genera was assigned based on a previously published method. Microbiome characteristics were compared to measures of clinical disease severity and long term outcomes. Results: In both stable bronchiectasis and during exacerbations, a microbiome dominated by Proteobacteria and Firmicutes was observed. Beta diversity analysis indicated that patients' microbiomes were relatively stable over time and showed less variation than that observed between patients. During disease stability, reduced Shannon-Wiener Diversity Index was associated with higher bronchiectasis severity (P<0.0001), more exacerbations (P=0.03) and more severe exacerbations requiring hospitalisations (P=0.02). Patients in whom the dominant genera was Pseudomonas were at increased risk of mortality (Hazard ratio 3.12, 95% CI 1.32-7.38, P=0.009) and had more frequent exacerbations (Incident rate ratio 3.11 95% CI 1.56-6.20, P=0.001) during follow-up. Changes in the microbiome at exacerbation were heterogeneous but exacerbations associated with an increase in pathogenic Proteobacteria from baseline were associated with an increase in sputum neutrophil elastase activity (r=0.30, P=0.0002) suggesting a subset of neutrophilic-bacterial exacerbations accounting for 41.5% of events. Conclusion: A reduction in microbiome diversity, particularly associated with Pseudomonas or Proteobacteria dominance is associated with greater disease severity, increased frequency and severity of exacerbations, and a higher risk of mortality. Funding Statement: Funded by the GSK/British Lung Foundation Chair of Respiratory Research and European Respiratory Society through the EMBARC2 consortium. EMBARC2 is supported by project partners Chiesi, Grifols, Insmed, Novartis and Zambon. Declaration of Interests: JDC reports research grants and personal fees from Glaxosmithkline, Boehringer-Ingelheim, Astrazeneca, Pfizer, Bayer Healthcare, Grifols, Napp, Aradigm Corporation and Insmed. All other authors declare no conflicts of interest Ethics Approval Statement: Patients gave written informed consent and the study was approved by the East of Scotland Research Ethics committee (12/ES/0059).

Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials

In patients with non-cystic fibrosis bronchiectasis, lung infection with Pseudomonas aeruginosa is associated with frequent pulmonary exacerbations and admission to hospital for treatment, reduced quality of life, and increased mortality. Although inhaled antibiotics are conditionally recommended for long-term management of non-cystic fibrosis bronchiectasis with frequent exacerbations, there is no approved therapy. We investigated the safety and efficacy of inhaled liposomal ciprofloxacin (ARD-3150) in two phase 3 trials. ORBIT-3 and ORBIT-4 were international, randomised, double-blind, placebo-controlled, phase 3 trials run concurrently in similar geographical regions. Eligible patients had non-cystic fibrosis bronchiectasis, had had at least two pulmonary exacerbations treated with antibiotics in the previous 12 months, and had a history of chronic P aeruginosa lung infection. Patients were randomly assigned (2:1) to receive either ARD-3150 or placebo. ARD-3150 (3 mL liposome encapsulated ciprofloxacin 135 mg and 3 mL free ciprofloxacin 54 mg) or 6 mL placebo (3 mL dilute empty liposomes mixed with 3 mL of saline) was self-administered once daily for six 56-day treatment cycles, for 48 weeks. The primary endpoint was time to first pulmonary exacerbation from the date of randomisation to week 48. We did primary and secondary efficacy, safety, and microbiology analyses on the full analysis population, which comprised all randomised patients who received at least one dose of study drug. ORBIT-3 and ORBIT-4 are registered with ClinicalTrials.gov, numbers NCT01515007 and NCT02104245, respectively. Between March 31, 2014, and Aug 19, 2015, we screened 514 patients in ORBIT-3 and 533 patients in ORBIT-4. The full analysis populations consisted of 278 patients in ORBIT-3 (183 patients received at least one dose of ARD-3150 and 95 received placebo) and 304 patients in ORBIT-4 (206 patients received at least one dose of ARD-3150 and 98 received placebo). In ORBIT-4, the median time to first pulmonary exacerbation was 230 days in the ARD-3150 group compared with 158 days in the placebo group, a statistically significant difference of 72 days (hazard ratio [HR] 0·72 [95% CI 0·53-0·97], p=0·032). In ORBIT-3, the median time to first pulmonary exacerbation was 214 days in the ARD-3150 group and 136 days in the placebo group, a non-statistically significant difference of 78 days (HR 0·99 [95% CI 0·71-1·38], p=0·97). In a pooled analysis of data from both ORBIT-3 and ORBIT-4, the median time to first pulmonary exacerbation was 222 days in the ARD-3150 group and 157 days in the placebo group, a non-statistically significant difference of 65 days (0·82 [0·65-1·02], p=0·074). The numbers of adverse events and serious adverse events were similar in both groups in ORBIT-3 and ORBIT-4. In patients with non-cystic fibrosis bronchiectasis and chronic P aeruginosa lung infection requiring antibiotic therapy in the preceding year, ARD-3150 led to a significantly longer median time to first pulmonary exacerbation compared with placebo in ORBIT-4, but not in ORBIT-3 or the pooled analysis. Inconsistency between the trials suggests further research is needed into the heterogeneity of non-cystic fibrosis bronchiectasis and optimal outcome measures for inhaled antibiotics. Aradigm Corporation.

1330. Diagnosis and Management of NTM Lung Disease: Effect of Online Educational Interventions on Infectious Disease Specialist Knowledge

BackgroundDiagnosis and management of nontuberculous mycobacterial (NTM) lung disease is challenging for clinicians due to its rarity and the need for complicated, multidrug antibiotic regimens. The objective of this study was to determine whether online educational interventions can effectively address knowledge gaps among ID specialists regarding diagnosis and treatment of patients with NTM lung disease.MethodsTwo educational interventions, consisting of a text-based activity with interactive questions, and a video-based discussion between two experts, were developed and made available online. Educational impact of each intervention was assessed using a 3-question repeated pairs pre-/post-assessment study design. Data from a sampling of learners were collected from September 11, 2017 through January 17, 2018. Statistical analyses included a paired (within-physician) two-tailed t-test and McNemar’s χ2 statistic, with Cramer’s V to determine the overall effect of each intervention.ResultsOverall, a total of 1,273 ID specialist learners participated in the two activities from launch through April 30, 2018. Analysis demonstrated a significant improvement (P < 0.05) in overall knowledge with considerable educational impact (V = 0.195 and 0.259). Improvements in specific areas included (figure). Despite gains in knowledge, additional gaps were also identified: (1) Regarding treatment of M. abscessus lung disease, 18% were unable to discern between guideline recommended therapies for M. abscessus and MAC complex NTM, and an additional 14% would treat with a less aggressive, noncurative regimen (n = 211), and (2) regarding treatment of fibrocavitary MAC complex NTM; nearly one-third (31%) would treat a using a thrice-weekly regimen, despite an indication for a daily regimen (n = 114).ConclusionParticipation in interactive text-based as well as video-based activities improved the ability of ID specialists to make evidence-based decisions in the care of NTM lung disease. The findings also uncovered educational needs that warrant further education in selecting appropriate therapeutic regimens particularly in cases where aggressive therapy is indicated. Disclosures E. Jackson, Medscape: Employee, Salary. P. Chatterjee, Medscape: Employee, Salary. S. Smith, BioFire Diagnostics: Independent Medical Education, Educational grant. K. Badal, Medscape: Employee, Salary. D. E. Griffith, Aradigm Corporation: Advisor/consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium. Bayer Healthcare Pharmaceuticals: Advisor/consultant, Consulting fee. Grifols: Advisor/consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium. Insmed Incorporated: Advisor/consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Grant recipient and Speaker honorarium.

805. Amikacin Liposome Inhalation Suspension (ALIS) Add-on Therapy for Refractory Mycobacterium avium Complex (MAC) Lung Disease: Effect of In Vitro Amikacin Susceptibility on Sputum Culture Conversion

BackgroundALIS (590 mg amikacin base) is liposome-encapsulated amikacin for inhalation, which delivers amikacin directly to the lung and limits systemic exposure. In the CONVERT phase 3 trial, significantly more adults with treatment-refractory MAC lung disease receiving ALIS plus guideline-based therapy (GBT) vs. GBT alone achieved sputum culture conversion by month 6 (29.0% vs. 8.9%, P < 0.0001). Amikacin treatment failure has previously been reported in patients with amikacin minimum inhibitory concentrations (MIC) >64 µg/mL. We analyzed the impact of amikacin MIC on culture conversion during treatment with add-on ALIS.MethodsIn CONVERT, patients were randomly assigned (2:1) to receive once daily ALIS+GBT (n = 224) or GBT alone (n = 112). Patients with amikacin-resistant MAC isolates (MICs >64 μg/mL by broth microdilution) were excluded prior to randomization. The primary endpoint was culture conversion, defined as 3 consecutive monthly MAC-negative sputum cultures by month 6. Amikacin MICs were correlated with culture conversion rates.ResultsAmikacin MIC distributions at baseline (day 1) were similar in both groups (Figure 1). Conversion rates in the ALIS+GBT arm were 28.6–34.5% for MAC with amikacin MICs of 8–64 µg/mL (Figure 2). Overall, 28 patients developed post-screening amikacin MIC >64 µg/mL, 4/112 in the GBT alone arm (post-baseline), and 24/224 in the ALIS+GBT arm (1 at baseline and 23 post-baseline after adding ALIS). Most of these (18/24) had MAC isolates with persistent amikacin MIC >64 µg/mL. Only 1/24 patients in the ALIS+GBT arm with amikacin MIC >64 µg/mL achieved culture conversion. No patient with both macrolide resistance and persistent amikacin MIC >64 µg/mL (8/24) converted.ConclusionIn the ALIS+GBT arm of CONVERT, culture conversion rates were similar for amikacin MICs ranging from 8–64 µg/mL at baseline. Amikacin MIC >64 µg/mL emerged in 10.3% of patients after initiation of add-on ALIS treatment, and 3.6% in the GBT alone arm. Emergent amikacin MIC >64 µg/mL was associated with failure to convert, particularly with concurrent macrolide resistance. Determining amikacin susceptibility at both treatment initiation and during treatment may have utility for guiding treatment decisions. Disclosures B. A. Brown-Elliott, Insmed: Investigator, Research support. G. Eagle, Insmed Incorporated: Employee, Salary. R. J. Wallace, Insmed: Investigator, Research support. J. Van Ingen, Insmed: Investigator, Research support. L. J. Pennings, Insmed: Investigator, Research support. B. Berry, Insmed: Investigator, Research support. S. Pandey, Insmed: Investigator, Research support. C. Coulter, Insmed: Investigator, Research support. M. Syrmis, Insmed: Investigator, Research support. K. L. Winthrop, Insmed Incorporated: Consultant and Scientific Advisor, Consulting fee and Research grant. D. E. Griffith, Aradigm Corporation: Advisor/consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium. Bayer Healthcare Pharmaceuticals: Advisor/consultant, Consulting fee. Grifols: Advisor/consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium. Insmed Incorporated: Advisor/consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Grant recipient and Speaker honorarium.

Two Randomised Controlled Trials of Inhaled Liposomal Ciprofloxacin (ARD-3150) in Patients with Non-Cystic Fibrosis Bronchiectasis and Chronic Lung Infection with Pseudomonas Aeruginosa

Background: In patients with non-cystic fibrosis bronchiectasis (NCFB), lung infection with Pseudomonas aeruginosa is associated with severe disease, frequent pulmonary exacerbations (PEs) and hospitalisations, reduced quality of life, and higher mortality. Although inhaled antibiotics are conditionally recommended for long-term management of NCFB with frequent exacerbations, there is no approved therapy. The safety and efficacy of inhaled, liposomal ciprofloxacin (ARD-3150) was investigated in two phase III trials. Methods: ORBIT-3 (NCT01515007) and ORBIT-4 (NCT02104245) were randomised (2:1), double-blind, placebo-controlled trials in patients with NCFB and P. aeruginosa lung infection with at least two PEs requiring antibiotics in the prior year. Inhaled ARD-3150 or placebo was self-administered once daily for six cycles of 28 days on-treatment/28 days off-treatment, for 48 weeks. Findings: In ORBIT-3, 183 patients received ARD-3150 and 95 received placebo; in ORBIT-4 206 patients received ARD-3150 and 98 received placebo. Median time to first PE (primary endpoint) was significantly delayed in ORBIT-4 only (treatment effect hazard ratio [HR with 95% confidence interval (CI)] 0·72 [0·53-0·97], p=0·032; ORBIT-3 HR 0·99 [0·71-1·38], p=0·974; pooled analysis HR 0·82 [0·65-1·02], p=0·074). Frequency of PEs was not significantly reduced in ORBIT-3; however, the frequency of all severities of PEs was significantly reduced in ORBIT-4 and the pooled analysis. Sputum density of P. aeruginosa was significantly reduced with ARD-3150 at end of on-treatment periods in both trials. The safety and tolerability of ARD-3150 was similar to placebo. Interpretation: ARD-3150 may provide benefit to patients with NCFB with chronic P. aeruginosa lung infections and frequent exacerbations. Funding: Aradigm Corporation. Declaration of Interest: CSH reports personal fees from Aradigm Corporation, personal fees from Grifols, during the conduct of the study; and reports personal fees from Chiesi, personal fees from Gilead, personal fees from GlaxoSmithKline, personal fees and grants from Insmed, personal fees and grants from Teva, personal fees and grants from Vertex, personal fees from Zambon, outside of the submitted work. DB reports personal fees from Aradigm Corporation, during the conduct of the study. JDC reports personal fees with Aradigm Corporation, grants from AstraZeneca, personal fees and grants from Bayer Healthcare, personal fees and grants from BoehringerIngelheim, personal fees and grants from GlaxoSmithKline, personal fees and grants from Grifols, Ethical Approval: The trial protocols were approved at each site by an ethics committee or institutional review board. Patients provided written informed consent at enrolment.

Development of Liposomal Ciprofloxacin to Treat Lung Infections.

Except for management of Pseudomonas aeruginosa (PA) in cystic fibrosis, there are no approved inhaled antibiotic treatments for any other diseases or for infections from other pathogenic microorganisms such as tuberculosis, non-tuberculous mycobacteria, fungal infections or potential inhaled biowarfare agents including Francisella tularensis, Yersinia pestis and Coxiella burnetii (which cause pneumonic tularemia, plague and Q fever, respectively). Delivery of an antibiotic formulation via the inhalation route has the potential to provide high concentrations at the site of infection with reduced systemic exposure to limit side effects. A liposomal formulation may improve tolerability, increase compliance by reducing the dosing frequency, and enhance penetration of biofilms and treatment of intracellular infections. Two liposomal ciprofloxacin formulations (Lipoquin® and Pulmaquin®) that are in development by Aradigm Corporation are described here.

New anti-infective strategies for treatment of tularemia

New anti-infective strategies for treatment of tularemia

The potential of liposome-encapsulated ciprofloxacin as a tularemia therapy.

Liposome-encapsulation has been suggested as method to improve the efficacy of ciprofloxacin against the intracellular pathogen, Francisella tularensis. Early work with a prototype formulation, evaluated for use against the F. tularensis live vaccine strain, showed that a single dose of liposomal ciprofloxacin given by the intranasal or inhalational route could provide protection in a mouse model of pneumonic tularemia. Liposomal ciprofloxacin offered better protection than ciprofloxacin given by the same routes. Liposomal ciprofloxacin has been further developed by Aradigm Corporation for Pseudomonas aeruginosa infections in patients with cystic fibrosis and non-cystic fibrosis bronchiectasis. This advanced development formulation is safe, effective and well tolerated in human clinical trials. Further evaluation of the advanced liposomal ciprofloxacin formulation against the highly virulent F. tularensis Schu S4 strain has shown that aerosolized CFI (Ciprofloxacin encapsulated in liposomes for inhalation) provides significantly better protection than oral ciprofloxacin. Thus, liposomal ciprofloxacin is a promising treatment for tularemia and further research with the aim of enabling licensure under the animal rule is warranted.

New Approaches to Diabetes Disease Control, Insulin Delivery, and Monitoring

Some of the most dangerous outcomes of either form of diabetes are those related to long-term complications, including kidney damage, or diabetic nephropathy. Over time, small blood vessels inside the kidneys can become damaged and reduce the body’s ability to filter toxins from the blood. Damaged kidneys leak a protein, albumin, into the urine. Detection of even small albumin levels, microalbuminuria, is one of the earliest signs of kidney problems, and also one that is not always noticeable in the earliest stages of the disease. Left untreated, the damage worsens until the kidneys fail, a condition called end-stage renal disease (ESRD). Because of the serious long-term consequences of kidney damage, in mid-November, 2004 the International Society of Nephrology urged national health bodies around the world to proactively implement albuminuria screening with the goal of preventing further kidney function deterioration in diabetics and others with kidney disease. Currently, the American Diabetes Association recommends that people diagnosed with type 2 diabetes be tested for microalbuminuria at the time they are diagnosed and every year thereafter. Those with type 1 diabetes should be tested 5 years after diagnosis and every year thereafter. About 21% and 28% of people with type 1 and 2 diabetes, respectively, have detectable levels of microalbuminaria by age 15.New York, NY-based AusAm Biotechnologies, founded in 2000, has developed a new type of diagnostic test to better detect extremely low levels of albuminuria. The FDA approved the company’s Accumin diagnostic test in August 2003 as the first test to measure total intact urinary albumin. The technology is based on the work of Wayne Comper, Ph.D., DSc, of Monash University, Australia. “The problem with conventional tests for urine albumin is that they can miss intact albumin that does not react with the antibodies used in making these tests. As a result, conventional urine testing is subject to a potentially large false negative rate for microalbuminuria,” says Mr. James McCullough, AusAm’s CEO. “It was derived from raising antibodies to serum albumin. Dr. Comper recognized that as the serum albumin passes through the kidney and out through the urine, it can undergo a slight conformational change rendering it unreactive to conventional serum-derived albumin antibodies. In other words, intact albumin that is invisible to conventional antibodies—which is in all the major manufacturers’ platforms and dipsticks—ends up unrecognized in the urine.” In the clinical tests that Dr. Comper and colleagues performed, conventional tests generated a 33% false negative rate for microalbuminuria when they were compared with Accumin.“In May 2004, we published that we can detect microalbuminuria up to 12 years earlier than radioimmunoassay, which is the most sensitive of the conventional urine tests,” says McCullough, “But on average, it is really about 3 years earlier.” The key, claims McCullough, is that the antibody used in the test was raised to urine albumin. “After doing 2D electrophoresis and HPLC, we discovered this whole population of intact albumin which was unrecognizable by the conventional antibodies in all the major immunoassays around the world,” says McCullough.The test is done in combination with a test for creatinine, a protein excreted by the muscles. The results are reported as a ratio of microalbumin/creatinine. “If you are above 30 mg of albumin per gram of creatinine, you are said to be microalbuminuria positive,” explains McCullough. “We can pick up as low as 3–4 mg albumin per gram of creatinine.”“We are platform agnostic,” says McCullough. “The FDA-approved Accumin quantitative test is currently done with chromatography. But we are in the process now of working with several analyzer companies to place the technology in high-throughput immunochemical devices.” In 2005, AusAm hopes to roll out a dipstick version of the technology to bring it even closer to the point of care.

United States Court of Appeals for the Federal Circuit: Eli Lilly and Company v. Aradigm Corporation (03-1336, -1337)

United States Court of Appeals for the Federal Circuit: Eli Lilly and Company v. Aradigm Corporation (03-1336, -1337)

Insulin inhalation: NN 1998.

Aradigm Corporation has developed an inhaled form of insulin using its proprietary AERx drug delivery system. The system uses liquid insulin that is converted into an aerosol containing very small particles (1-3 micro in diameter), and an electronic device suitable for either the rapid transfer of molecules of insulin into the bloodstream or localised delivery within the lung. The AERx insulin Diabetes Management System (iDMS), AERx iDMS, instructs the user on breathing technique to achieve the best results. Aradigm Corporation and Novo Nordisk have signed an agreement to jointly develop a pulmonary delivery system for insulin [AERx iDMS, NN 1998]. Under the terms of the agreement, Novo Nordisk has exclusive rights for worldwide marketing of any products resulting from the development programme. Aradigm Corporation will initially manufacture the product covered by the agreement, and in return will receive a share of the overall gross profits from Novo Nordisk's sales. Novo Nordisk will cover all development costs incurred by Aradigm Corporation while both parties will co-fund final development of the AERx device. Both companies will explore the possibilities of the AERx platform to deliver other compounds for the regulation of blood glucose levels. Additionally, the agreement gives Novo Nordisk an option to develop the technology for delivery of agents outside the diabetes area. In April 2001, Aradigm Corporation received a milestone payment from Novo Nordisk related to the completion of certain clinical and product development stages of the AERx drug delivery system. Profil, a CRO in Germany, is cooperating with Aradigm and Novo Nordisk in the development of inhaled insulin. Aradigm and Novo Nordisk initiated a pivotal phase III study with inhaled insulin formulation in September 2002. This 24-month, 300-patient trial is evaluating inhaled insulin in comparison with insulin aspart. Both medications will be given three times daily before meals in addition to basal insulin administered once or twice daily. In 2003, the US FDA adopted new GMP guidelines requiring sterile production of inhalation products and their devices. Novo Nordisk, therefore, will need to repeat phase III studies following device optimisation. These studies may begin at the end of 2004 and will include efficacy studies for 6-12 months and safety studies for up to 2 years (Lehman Brothers, Equity research, 7 August 2003). A phase IIb, 12-week clinical trial in 107 patients with type 2 diabetes was completed in the US. This trial was designed to compare the safety and efficacy of pulmonary insulin delivered via AERx iDMS, with intensified treatment with subcutaneous insulin administered at mealtimes. The results of the study positively compared pulmonary insulin with intensified subcutaneous insulin. Aradigm Corporation has a total of 85 patents pertaining to its proprietary AERx drug delivery system. Among those granted patents, 18 patents cover pulmonary insulin formulation including the method of patient breathing technique during pulmonary delivery of insulin. This patent guides patients on how to breathe in certain defined ways to achieve an effective amount and reproducibility of blood levels of insulin.

Analgesic Efficacy of Inhaled Morphine in Patients after Bunionectomy Surgery

The AERx Pain Management System (Aradigm Corporation, Hayward, CA) is a novel pulmonary delivery system for the systemic administration of morphine. The authors compared the relative analgesic efficacy and safety of the AERx Pain Management System with those of placebo and intravenous morphine in an orthopedic postsurgical pain model. Eighty-nine male and female PS-1 to PS-3 patients underwent standardized bunionectomy surgery and received multiple doses of inhaled or intravenous placebo, inhaled morphine (one inhalation [2.2 mg] or three inhalations [6.6 mg]), or intravenous morphine (4 mg) in a blinded fashion. Open-label rescue morphine (2 mg) was also available as needed. Pain intensity, pain relief, and time to pain relief were measured after the first dose. Global evaluation, morphine consumption, vital signs, and adverse events were monitored for 8 h after treatment. Blinded study personnel performed all treatment administrations and pain assessments. Three inhalations of morphine and 4 mg intravenous morphine provided comparable single- and multiple-dose analgesia. One inhalation of morphine was statistically indistinguishable from placebo. Three inhalations of morphine and 4 mg intravenous morphine both consistently demonstrated significantly greater analgesic efficacy than did placebo and one inhalation of morphine. Comparable analgesic efficacy was demonstrated between a carefully matched dose of inhaled and intravenous morphine in a postsurgical pain model.

Accuracy of Three Electronic Monitors for Metered-Dose Inhalers

Prior studies indicate that some devices used to monitor metered-dose inhaler (MDI) use are not accurate. To assess the accuracy of the Doser CT (NEW-MED Corporation; Waltham, MA), the MDILog (Medtrac Technologies; Lakewood, CO), and the SmartMist (Aradigm Corporation; Hayward, CA) in a bench-top study. One, two, and four puffs of fluticasone propionate MDI (Flovent; GlaxoWellcome; Research Triangle Park, NC) were actuated twice daily for 30 days with two units of each device. The date and time of each actuation were recorded in a log and then compared with the output of the device. The percentage of doses recorded accurately was compared by analysis of variance. The SmartMist was 100% accurate, while both the Doser CT and MDILog devices occasionally recorded spurious actuations. The Doser CT also had missed actuations after the counter had prematurely reached zero secondary to the spurious recordings. The accuracy (mean plus minus SD) was 94.3 plus minus 2.9% for the Doser CT and 90.1 plus minus 6.9% for the MDILog (p = 0.21). The dose regimen actuated and duration of use did not significantly affect accuracy. All three devices are sufficiently accurate to monitor adherence in most clinical settings.