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

David B Price, Vicky Thomas, P N Richard Dekhuijzen, Sinthia Bosnic-Anticevich, Nicolas Roche, Federico Lavorini, Priyanka Raju, Daryl Freeman, Carole Nicholls, Iain R Small, Erika Sims, Guilherme Safioti, Janice Canvin, Henry Chrystyn, David B Price, Vicky Thomas, P N Richard Dekhuijzen, Sinthia Bosnic-Anticevich, Nicolas Roche, Federico Lavorini, Priyanka Raju, Daryl Freeman, Carole Nicholls, Iain R Small, Erika Sims, Guilherme Safioti, Janice Canvin, Henry Chrystyn

Abstract

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 β2-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 .

Keywords: Asthma; Budesonide/formoterol; Dry-powder inhaler; Inhaler mastery; Inhaler technique; Intuitive; Pragmatic clinical trial.

Conflict of interest statement

Ethics approval and consent to participate

The study was performed in accordance with the International Conference on Harmonization Good Clinical Practice Consolidated Guideline (E6). Written informed consent was signed and dated by patients before all study-related procedures. The trial was approved by the National Research Ethics Service Committee East Midlands – Northampton (13/EM/0468) and by the UK Medicines and Healthcare Products Regulatory Agency (EudraCT 2013–004630-14) and registered on Competing interests

David B. Price has board membership with Aerocrine, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Mundipharma, Napp, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme and Teva Pharmaceuticals; consultancy agreements with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Napp, Novartis, Pfizer, Teva Pharmaceuticals, and Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from Aerocrine, AKL Research and Development Ltd., AstraZeneca, Boehringer Ingelheim, British Lung Foundation, Chiesi, Mylan, Mundipharma, Napp, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service, and Zentiva (Sanofi Generics); payment for lectures/speaking engagements from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Merck, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, Skyepharma, and Teva Pharmaceuticals; payment for manuscript preparation from Mundipharma and Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma and Novartis; payment for travel/accommodation/meeting expenses from Aerocrine, AstraZeneca, Boehringer Ingelheim, Mundipharma, Napp, Novartis, and Teva Pharmaceuticals; funding for patient enrolment or completion of research from Chiesi, Novartis, Teva Pharmaceuticals, and Zentiva (Sanofi Generics); stock/stock options from AKL Research and Development Ltd. which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd. (Australia, and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd. (Singapore); and is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme, and Health Technology Assessment.

Vicky Thomas has no competing interests to declare.

Richard Dekhuijzen has received grants and personal fees from Chiesi, AstraZeneca, Teva, Mundipharma, and Boehringer Ingelheim; grants from GlaxoSmithKline; and personal fees from Sandoz and Zambon. All are unrelated to the present work.

Sinthia Bosnic-Anticevich has received sponsorship to carry out studies, together with Board Membership, consultant agreements and honoraria for presentation, from several pharmaceutical companies that market inhaled products. These include AstraZeneca, GlaxoSmithKline, Meda, Mundipharma, and Teva. Research sponsorship has also been received from grant awarding bodies (Australian Research Council, The Commonwealth of Australia Department of Health and the National Health and Medical Research Council).

Nicolas Roche reports grants and personal fees from BoehringerIngelheim, Novartis, and personal fees from Teva, GSK, AstraZeneca, Chiesi, Mundipharma, Cipla, Sanofi, Sandoz, 3 M, Pfizer, Zambon, outside the presented work.

Federico Lavorini received fees for lectures and advisory board meetings from Astra Zeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini International, TEVA, Zentiva.

Priyanka Raju is an employee of OPRI, which has conducted paid research in respiratory disease on behalf of the following organizations in the past 5 years: Aerocrine, AKL Research and Development Ltd., Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Orion, Takeda, Teva, Zentiva (a Sanofi company).

Daryl Freeman has received speaking honoraria, support for conferences or consultant agreements with AstraZeneca, Chiesi, Mundipharma, and Pfizer.

Carole Nicholls is an employee of OPRI, which has conducted paid research in respiratory disease on behalf of the following organizations in the past 5 years: Aerocrine, AKL Research and Development Ltd., Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Orion, Takeda, Teva, Zentiva (a Sanofi company).

Iain Small has no competing interests to declare.

Erika Sims was an employee of Research In Real Life at the time the study was conducted.

Guilherme Safioti is an employee of Teva Pharmaceuticals.

Janice Canvin was an employee of Teva Pharmaceuticals at the time the study was conducted.

Henry Chrystyn has received sponsorship to carry out studies, together with Board Membership, consultant agreements and honoraria for presentation, from several pharmaceutical companies that market inhaled products. These include Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Innovata Biomed, Meda, Napp Pharmaceuticals, Mundipharma, NorPharma, Novartis, Orion, Sanofi, Teva, Truddell Medical International, UCB and Zentiva. Research sponsorship has also been received from grant awarding bodies (EPSRC and MRC). He is the owner of Inhalation Consultancy Ltd. and a consultant to the Observational and Pragmatic Research Institute Pte Ltd., Singapore.

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Figures

Fig. 1
Fig. 1
Study design (a) and procedures (b). aRandomization into cross-over phase; bRandomization into longitudinal phase; patients meeting the inclusion criteria: step 3 or 4 asthma therapy as defined by BTS guidelines for persistent asthma, partially or poorly controlled asthma as defined by GINA, and ≥ 1 error on current device were included; cVideo review was used only with patients who provided consent; patients not providing consent were able to continue in the study. ACQ: Asthma Control Questionnaire; BTS: British Thoracic Society; GINA: Global Initiative for Asthma; HCP: healthcare professional; PASAPQ: Patient Satisfaction and Preference Questionnaire; RCT: randomized control trial
Fig. 2
Fig. 2
Patient disposition in the cross-sectional phase and the longitudinal phase. aEleven patients did not have device assessment because training devices were not available at the site. Withdrawals during the cross-sectional phase were not captured because of the study design. bOne patient was eligible for the longitudinal phase and was included in the ITT analysis; however, no device was available at the visit and the patient withdrew consent before treatment was allocated. cOnly patients who achieved device mastery on both devices could proceed to stage 2. dData were captured retrospectively. eOther reasons for study withdrawal during the longitudinal phase included the following: Visit 2 was not scheduled and patient inclusion/exclusion criteria were not met. Note: Numbers in parentheses are numbers of patients. Percentages are based on the number of patients randomly assigned device order in the cross-sectional phase (n = 493). BF: budesonide formoterol; FAS: full analysis set; ITT: intent-to-treat

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