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Empowering pharmacists in asthma management through interactive SMS (EmPhAsIS): study protocol for a… De Vera, Mary A; Sadatsafavi, Mohsen; Tsao, Nicole W; Lynd, Larry D; Lester, Richard; Gastonguay, Louise; Galo, Jessica; FitzGerald, J M; Brasher, Penelope; Marra, Carlo A Dec 13, 2014

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STUDY PROTOCOL Open AccessEmpowering pharmacists in asthma managementthe availability of effective treatments, there is a tremendous potential to reduce the burden of asthma throughTRIALSDe Vera et al. Trials 2014, 15:488http://www.trialsjournal.com/content/15/1/488Wesbrook Mall, Vancouver V6T 1Z3, CanadaFull list of author information is available at the end of the articleimproving adherence. This is the first study of an intervention based on mobile communication technology involvingcommunity pharmacists in asthma management.Trial registration: ClinicalTrials.gov identifier: NCT02170883; date of registration: 19 June 2014.Keywords: Asthma, Medication adherence, Inhaled corticosteroids, Cluster randomized controlled trial,Community pharmacy, Pharmacy practice research* Correspondence: mdevera@mail.ubc.ca†Equal contributors1Faculty of Pharmaceutical Sciences, University of British Columbia, 2405through interactive SMS (EmPhAsIS): studyprotocol for a randomized controlled trialMary A De Vera1*†, Mohsen Sadatsafavi2,3†, Nicole W Tsao1, Larry D Lynd1, Richard Lester2, Louise Gastonguay1,Jessica Galo1, J Mark FitzGerald2, Penelope Brasher3 and Carlo A Marra1,4AbstractBackground: Medication regimens for asthma are particularly vulnerable to adherence problems because of therequirement for long-term use and periods of symptom remission experienced by patients. Pharmacists are suitedto impact medication adherence given their training, skills, and frequent contact with patients. The Empoweringpharmacists in asthma management through interactive SMS (EmPhAsIS) trial involves an intervention leveragingmobile health (mHealth) technology to support community pharmacy practice with the hypothesis of improvedmedication adherence in asthma.Methods/Design: This study is a pragmatic pharmacy-based, cluster, randomized controlled trial with 12 monthsof intervention delivery and follow-up. Pharmacies (the clusters) will be randomized at a 1:1 ratio to provideintervention or usual care. The EmPhAsIS intervention consists of patient asthma education, short message service(SMS)-based monthly assessment of adherence, and follow-up of non-adherent individuals by community pharmacists.There are no inclusion or exclusion criteria for pharmacies. Patients are eligible if they: are 14 years of age or older, fill aprescription for inhaled corticosteroid (either monotherapy or in a combination inhaler with long-acting beta-agonists),have been diagnosed with asthma, possess a mobile phone with SMS capabilities, and have no communicationdifficulties such as inability to communicate in English, or significant impairment in vision, hearing, or speech. Theprimary outcome is adherence to inhaled corticosteroids ascertained by the medication possession ratio, the ratio ofthe days of medication supplied to days in a given time interval. This study will also evaluate secondary outcomesincluding: asthma control, asthma-related quality of life, asthma-related hospital admissions, and use of relievermedications during the follow-up period. A nested economic evaluation using a probabilistic decision-analyticmodel will be used to perform a cost-effectiveness analysis from the societal perspective of the interventioncompared with usual care over a 10-year time horizon.Discussion: Considering the prevalence of asthma, the extent of the non-adherence problem in this disease, and© 2014 De Vera et al.; licensee BioMed CentraCommons Attribution License (http://creativecreproduction in any medium, provided the orDedication waiver (http://creativecommons.orunless otherwise stated.l. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andiginal work is properly credited. The Creative Commons Public Domaing/publicdomain/zero/1.0/) applies to the data made available in this article,De Vera et al. Trials 2014, 15:488 Page 2 of 10http://www.trialsjournal.com/content/15/1/488BackgroundAsthma is a chronic inflammatory disease of the airwayswhich is characterized by recurrent, but reversible, epi-sodes of shortness of breath, chest tightness, coughing,and wheezing [1]. The global prevalence of asthma isestimated at 300 million [2,3] and the condition affectsindividuals of all ages [4]. In 2010, more than 2.4 millionCanadians aged 12 years or older reported that they havebeen diagnosed as having asthma [5]. The ultimate goalof asthma management is to bring the disease underclinical control [6]. Compared to controlled asthma, un-controlled asthma is associated with increased medicalcosts, reduced quality of life, and loss of productivity [7].Pharmacotherapy remains the cornerstone of asthmamanagement. All modern guidelines recommend dailyuse of controller medications regardless of the level ofasthma impairment (with the exception of very mild andintermittent asthma) [6,8]. Currently, inhaled corticoste-roids (ICS) are widely accepted as the primary controllertherapy for asthma [6]. Yet despite recommendations,there is a disappointingly low level of adherence to asthmacontroller therapies [9]. The average rate of adherenceto inhaled corticosteroids for asthma is reported to bebetween 22 and 63% [10-16]. Medication regimens forasthma are particularly vulnerable to adherence problemsbecause of the requirement for long-term use and the longperiods of symptom remission experienced by patients[17]. The relationship between adherence to controllertherapies and short- and long-term adverse asthma-related outcomes is well established [18,19]. Landmarkstudies in the 1990s showed that regular treatment withICS is associated with up to an 80% reduction in the riskof death, as well as severe asthma exacerbations requiringhospitalization [20-23].Pharmacists are ideally suited to impact medicationadherence given their training, skills, and frequent con-tact with patients; up to eight times more often thandoctors [24]. A few studies have evaluated community-pharmacist-based interventions in the management ofasthma. A Spanish cluster randomized controlled trial(RCT), in which patients in the intervention group sched-uled three to six visits to their pharmacist over six monthsof follow-up, reported that adherence was improved by40.3% in the intervention group compared with the controlgroup [25]. Similarly, an Australian cluster RCT with 50pharmacies (396 patients), involving an ongoing cycle ofassessment, goal setting, monitoring, and review bypharmacists, showed that compared with usual care, theintervention resulted in improved adherence to controllermedication (odds ratio for adherence: 1.89) [26]. A clusterRCT of community pharmacists in British Columbia (BC)also showed promising results of an ‘enhanced care proto-col’, with pharmacists responsible for assessing a patient’sreadiness to change, tailoring asthma education to thatreadiness, monitoring compliance, and collaborating withphysicians to achieve asthma prescribing guidelines [27].Mobile phones are globally the most pervasive andaccessible form of two-way communication technology[28]. The use of mobile phones in public health practice(mobile health, mHealth) [29] offers opportunities to en-hance patient care and impact medication adherenceacross many diseases. Previous studies have consideredtext messages to be a behavior change communicationmodality [30]; a process of any intervention with indi-viduals to develop communication strategies to promotepositive behaviors [31]. In a multisite randomized clinicaltrial of HIV-infected adults initiating antiretroviral therapy(ART) in three clinics in Kenya, patients were randomizedat a 1:1 ratio to receive weekly short message service(SMS) intervention coupled with clinic nurse follow-up, orstandard care. The primary outcome (adherence to ART)was reported in 168 of 273 patients receiving the SMSintervention compared with 132 of 265 in the controlgroup (relative risk (RR) for non-adherence: 0.81; 95% CI:0.69 to 0.94; P = 0.006) [32].To overcome the epidemic of low adherence, our health-care system requires innovative models of care that fullyharness the knowledge, skills, availability, and enthusiasmof healthcare providers, and facilitate communicationacross the chain of healthcare delivery [33]. In a criticalreview of the literature on adherence interventions inasthma, Bender et al. concluded that research is encour-aged into innovative interventions that are brief, easilyimplemented, and can be tailored to individual patientsand diverse clinical settings [33]. Previous studies haveevaluated communication technologies in asthma care[34,35], but none of these studies have involved phar-macists. On the other hand, pharmacist-based studieson improving the management of asthma have hithertoused interventions whose real-world feasibility and cost-effectiveness have not been evaluated. Altogether, weperceive a role for mHealth to support community phar-macy practice and provide a means for an accessible andcost-effective method of communication between asthmapatients, with the ultimate goal of facilitating patient en-gagement in their disease management, thereby improvingadherence and outcomes [35].Methods/DesignStudy designThis trial, known as ‘Empowering pharmacists in asthmamanagement through interactive SMS’ (EmPhAsIS), will beimplemented from 2015 to 2018 in BC, Canada. It is apragmatic, cluster RCT trial of a community-pharmacist-initiated, mHealth-supported, adherence intervention(EmPhAsIS intervention) for asthma, with 12 monthsof participant (pharmacies and patients) recruitment and12 months of follow-up over which the intervention willDe Vera et al. Trials 2014, 15:488 Page 3 of 10http://www.trialsjournal.com/content/15/1/488also be delivered. Community pharmacies in the prov-ince of BC define the clusters based on three reasons.First, patient-level randomization would require eachstudy pharmacist to provide either the intervention orusual care to different patients of the same pharmacyand can lead to contamination. Second, pharmacist-level randomization would require the pharmacist to beboth the participant recruiters and randomization unitswhich could lead to selection bias concerns (for example,pharmacists randomized to the intervention group prefer-entially recruiting patients whom they know are at higherrisk of medication non-adherence). Third, given that mostpharmacists in community pharmacies are scheduled on ashift-work basis and provide overlapping care to all pa-tients of the pharmacy, the risk of contamination cannotbe practically controlled in this environment. To eliminatesuch randomization problems, it was therefore pragmatic-ally decided to randomize clusters at an organizationallevel and make these services available on a per phar-macy basis. This trial has been approved by the Universityof British Columbia Clinical Research Ethics Board (ap-proval number: H14-01451).ObjectivesOur primary objective is to compare adherence to ICSbetween asthma patients attending pharmacies assignedto provide the EmPhAsIS intervention to usual care.Our secondary objective is to evaluate the impact of theEmPhAsIS intervention on asthma control, asthma-relatedquality of life, asthma-related hospital admissions, and useof reliever medications during the follow-up period. Ourthird objective is to evaluate the cost-effectiveness of theEmPhAsIS intervention from a societal perspective over a10-year time horizon.ParticipantsPharmaciesPharmacies will be recruited from an existing databaseof community pharmacies we have partnered with, ofwhich pharmacists have indicated interest in collaboratingwith us. Pharmacies (the clusters) will be randomized in a1:1 ratio to intervention or usual care. All recruited phar-macies will receive pamphlets that will describe the studyprotocol and the Global Initiative for Asthma (GINA)’sPocket Guide for Asthma [36]. All pharmacists will attendan online workshop (webinar) during which they will betrained on the study protocol and provided educationon asthma and medication adherence as part of thestudy. Pharmacists will also attend separate webinars(intervention webinar and usual care webinar) and willreceive written study manuals specific to whether theyhave been assigned to the EmPhAsIS intervention orusual care group. There are no inclusion or exclusioncriteria for pharmacies.PatientsPatients eligible for this study are individuals who fill a(incident or prevalent) prescription for ICS (either mono-therapy or in a combination inhaler with long-acting beta-agonists) who answer affirmatively to the question ‘Haveyou ever been diagnosed by a doctor as having asthma?’.In line with the principles of pragmatic trials, our inclu-sion criteria are not overly restrictive so that the studysample remains representative of the target population.These inclusion criteria are similar to recent pragmatictrials in asthma [37] and are the following: 1) aged 14 yearsor older; 2) possessing a cellphone with the ability to sendand receive text messages; 3) residing in BC, and planningto reside in BC for the next 12 months; 4) having beenregistered with the medical services plan (MSP, the pro-vincial insurer of medically-required services) in the past12 months, and planning to remain registered for the next12 months; 5) not participating in another interventionalstudy; 6) no communication difficulties, such as inabilityto communicate in English, or significant impairment invision, hearing, or speech; and 7) consenting to participatein the study. Written informed consent will obtained fromeligible patients before enrollment into the study.We will utilize recruitment strategies used in our priorpharmacy practice studies [38-40], including posters andshelf-talkers. We will also advertise the study throughvarious communication channels available to our researchteam, including the study website and social media. Wewill also implement strategies for targeting recruitment,including working closely with participating pharmacies toestablish recruitment targets that are appropriate for thecommunity they service. Furthermore, we will also im-plement regular monitoring of recruitment, includingcommunication (for example, site visits, telephone calls,and/or emails) to discuss challenges and progress as wellas offer ongoing support.RandomizationAssignment of pharmacies to provide the EmPhAsIS in-tervention or usual care will be done in a 1:1 ratio withrandomly permuted blocks in sizes of four and six. Acomputer-generated list will be used to ensure balance inthe distribution of intervention and usual care groups atany point in the trial while minimizing the risk that re-search staff may be able to predict group assignment. Clus-ters will be allocated to intervention or usual care group byone designated research staff member using the computer-generated list. It will not be possible for participating phar-macies to be blinded to which group they are assigned.However, while the trial will be managed by a coordinatorwho will also be unblinded, team members responsible fordata collection (an interviewer who will collect patient-reported data at 0, 6, and 12 months) and analyses (statis-tical analyst) will be blinded to group allocation.De Vera et al. Trials 2014, 15:488 Page 4 of 10http://www.trialsjournal.com/content/15/1/488Study groupsIntervention (EmPhAsIS) groupPatients attending pharmacies assigned to the interventiongroup will receive the EmPhAsIS intervention whichconsists of three main pillars: a) patient education, b)SMS-based monthly assessment of adherence to control-ler therapies, and c) follow-up of non-adherent individualsby community pharmacists.a) Patient education: the education component willinvolve the pharmacist discussing patients’ individualtreatments, information on the chronic, episodic natureof asthma and the importance of continuous controllertherapy, with emphasis on medication adherence.b) SMS-based monthly assessment of adherence tocontroller therapies: The principal component of theintervention is monthly text messages, delivered overthe 12 month follow-up period, by which patients areasked to provide their level of agreement with the state-ment ‘I follow my asthma medication plan’. Responsesrange on a Likert scale (1: Agreeing completely, 2:Agreeing mostly, 3: Agreeing somewhat, 4: Disagreeingsomewhat, 5: Disagreeing mostly, and 6: Disagreeingcompletely). Individuals will be asked to respond bytyping back a number (between one and six) corre-sponding to the response items. This question andthe set of responses are the first item in the AdultAsthma Adherence Questionnaire™ (AAAQ) [41]. TheAAAQ is a five-item questionnaire developed specificallyas a screening diagnostic tool for adherence by careproviders, as well as for identifying potential adherencebarriers [42]. The first question is a general adherencemonitoring question, and questions two to five deter-mine specific barriers to adherence among individualswith low adherence (forgetting, no need, adverse effects,and costs). The AAAQ has been shown to have a highdegree of construct validity and has proven to be astrong predictor of adherence, as measured throughadministrative health data [42]. There are alternativeadherence questionnaires [43,44], but they do not havethe predictive power of the AAAQ [44], or consist oftoo many questions and thus are cumbersome to admi-nister [43]. In addition, the AAAQ is particularly suitedto the EmPhAsIS intervention given the separation ofthe adherence-monitoring question (question one) fromthose determining specific barriers to adherence (ques-tions two to five). The transmission and receipt of textmessages will be centralized and automated using theUniversity of British Columbia (UBC) designed WelTelsystem. WelTel is an SMS support and engagementplatform that will be administered at our researchcentre and accessed online by pharmacists throughthe study website. Centralizing text message transmis-sions minimizes the burden on pharmacists who willnot have to send messages themselves, and reducesthe delays and potential errors in the evaluation ofresponses.c) Follow-up of non-adherent individuals by commu-nity pharmacists: If the response to item one of AAAQ,received through SMS, is anything other than one(Agreeing completely), then this would indicate anadherence problem and the individual will be asked therest of the adherence-barriers questions of the AAAQ(questions two to five) via SMS. Based on the responses,WelTel will generate an AAAQ adherence report thatidentifies potential adherence barrier(s) (such as cost orfear of side effects) to help facilitate and guide the phar-macist’s follow-up telephone call with the patient. Apharmacist will then follow-up with the individual withinthe next 24 hours. During the telephone follow-up, thepharmacist will administer the Asthma Control Test(ACT, a five-item validated and widely used questionnaireassessing asthma control) [41]. In separate training pro-vided to pharmacists in the EmPhAsIS intervention group,webinars will provide step-by-step instruction on use ofthe WelTel platform as well as administration of the ACTover the telephone. Patient responses to the ACT itemswill be entered into a survey system that will automaticallyscore the questionnaire in order to facilitate this step forthe pharmacist. Based on the individual’s response to theACT, the outcome of this phone interview may be coun-selling and education to address adherence problems, or areferral to the patient’s physician (if the individual receivesa score of 19 or lower in the ACT, which may indicate thepresence of uncontrolled asthma). For patients where theadherence problem is unintentional, the pharmacist willprovide phone-based counselling and support, for ex-ample by clarifying instructions, offering suggestions onincorporating medication taking with the patient’s dailyroutine, and offering adherence tools such as calendars.For patients where the adherence problem is intentional,the pharmacist can provide education on the risks andbenefits of treatment and non-treatment, evaluate adverseeffects, and consider medication coverage options (or theuse of alternative formulations). Figure 1 illustrates SMStransmission for pillars two and three of the EmPhAsISintervention along with scenarios for instances of non-responses to the monthly SMS message. Pharmacistswill log telephone calls, including response and non-responses, and in instances of non-responses, at least twofollow-up attempts will be made.Usual care (control) groupPatients attending pharmacies assigned to the controlgroup will receive usual care. However, it is imperativethat the study can distinguish between the impact of theintervention itself and the training that pharmacists andpatients receive upon recruitment into the study. In-deed, previous adherence-intervention studies have beensseervDe Vera et al. Trials 2014, 15:488 Page 5 of 10http://www.trialsjournal.com/content/15/1/488Figure 1 Schematic of transmission of short message service (SMS) apatients by community pharmacist (pillar three) of the EmPhAsIS intControl Test.criticized because the individuals in the interventiongroup were more likely to receive an evidence-based edu-cation [33]. As such, patients in the control group willreceive the patient education component of the EmPhAsISintervention (pillar one).Data collection and study follow-upThe design of the trial and the schematic of data collec-tion and outcomes are illustrated in Figure 2. Pharma-cists will screen for eligibility, obtain informed consent,and enroll patients at their pharmacy. Upon patientenrollment, pharmacists will securely fax the individual’scontact information to the study research coordinator.Prospective data will be collected by telephone interviewby an interviewer at set time points as follows: 1) socio-demographic characteristics, such as age, education,income, BC provincial health number (baseline); 2) AsthmaControl Test and Asthma Quality of Life Questionnaire(AQLQ) (baseline, 6 months, and 12 months); and 3)changes in the enrollment of the individual with theprovincial healthcare system, changes in third-partyinsurance, as well as the frequency of receiving inhalermedications through samples. In addition to prospectivelycollected outcome data, we will also obtain data for ourstudy sample through BC PharmaNet (http://www.health.gov.bc.ca/pharmacare/pharmanet/netindex.html) [45] andPopulation Data BC (http://www.popdata.bc.ca) [46] Inssment of adherence (pillar two) and follow-up of non-adherentention. AAAQ: Adult Asthma Adherence Questionnaire; ACT: Asthmabrief, these are extensive data resources for appliedhealth services research with data holdings spanninginformation on all dispensed medications, includesdrug name (brand and generic), Canadian Drug Iden-tity Code, date dispensed, quantity dispensed, days of sup-ply (BC PharmaNet), outpatient services, hospitalseparations, and vital statistics (Population Data BC).OutcomesThe primary outcome is adherence to ICS ascertainedby the medication possession ratio (MPR), the ratioof the days of medication supplied over the one-yearfollow-up [47], which will be calculated using BCPharmaNet data. Secondary outcomes include: 1) asthmacontrol at the end of follow-up (measured by the AsthmaControl Test [41]; 2) asthma-related quality of life (mea-sured by using the AQLQ [48]); 3) asthma-related hospitaladmissions; and 4) use of reliever medications duringthe follow-up period (ascertained from the administrativehealth data).Sample size calculationSample size calculations for cluster RCTs must take intoaccount correlation among patients within clusters [49].We used the formula for calculating sample size, N, forcluster RCTs for comparison of means by Donner andDe Vera et al. Trials 2014, 15:488 Page 6 of 10http://www.trialsjournal.com/content/15/1/488Klar [50] inflated by the design effect (inflation factor,1 + (m – 1) ρ):N ¼ 2 Zα=2 þ Zβ=2 2σ2ð Þ 1 þ m − 1ð Þρ½ μ1 − μ2ð Þ2ð1Þwhere m is the average cluster size and ρ is the coeffi-cient of the intra-cluster correlation (ICC) or the ratio ofbetween-cluster variance to total variance, σ2 [49], μ isthe outcome (MPR), and Z indicates the normal Z-score.We drew from published ICC values based on adherenceoutcomes (0.0143 [51], 0.06 [52]), medication takingoutcomes (0.00994 [53], 0.08 [54]), and non-adherenceoutcomes in cluster RCTs of adherence interventions(0.02 [55], 0.05 [56]). We also drew from our prior clusterRCT in community pharmacies for information on thenumber of clusters in that study (32 overall, 14 interven-tion, 18 usual care) [38]. Based on these data, we appliedan ICC of 0.06 and calculated the number of patients thatwill be required to detect a 10% improvement in adher-ence rate - deemed clinically significant in prior studies[57] and also relevant from a cost-effectiveness perspectivebased on our previous research [58] - with a power of 80%and a significance level of 0.05, as 334. Accounting forapproximately 10% attrition, we determined a target of370 patients overall. The corresponding number of phar-macies (clusters) is 74 (37 randomized to intervention andFigure 2 EmPhAsIS trial design and schematic of data collection and37 to usual care). As such, we target recruitment at fivepatients per pharmacy.Statistical analysisGeneral analytical frameworkThe analysis of the association of the intervention withthe outcome will generally be based on regression analysis,and will be performed according to the intention-to-treatprinciple [59]. While randomization will in general causebalance in the distribution of covariates, regression-basedadjustment for covariates further strengthen the inference[60]. To accommodate the nested structure of the dataand variable follow-up times in a regression framework,generalized linear mixed models (GLMM) with appropri-ate distributions and link functions will be used. We willuse the GLIMMIX procedure in SAS (version 9.3, SASInstitute Inc., Cary, North Carolina, United States) to fitsuch models. All significance levels will be based on two-tailed P values at 0.05, except for post hoc exploratory andsecondary analyses, which will be adjusted for multiple-comparisons.CovariatesAll the analyses will be adjusted for the following variables:age, sex, baseline level of asthma control, socioeconomicstatus (income and education), and coverage by any third-party insurance. We will also draw on administrative healthoutcomes. ICS: inhaled corticosteroids.records from the 12-month period before the study entryto measure other potential confounders such as comorbidconditions and general pattern of healthcare utilization(number of physician visits, hospitalization, and medicationdispensations).Analysis for objectivesTo evaluate the impact of the EmPhAsIS interventionon our primary outcome of one-year adherence as mea-sured by the MPR, we will use a random effects GLMM,assuming an approximate normal distribution and speci-fying an identity link function. The estimation will bebased on GLMM with a random-effects term for phar-macy and fixed-effects terms representing the interventionas well as covariates. The same analytical framework asabove will be used for secondary outcomes. The choiceof the distribution and link function will depend on thescale and type of the dependent variable. For asthmacontrol, a random-effects ordinal logistic regressionmodel (GLMM with binomial distribution and cumu-need for a rigorous economic evaluation of the program’scost and effectiveness outcomes extrapolated beyond thetime horizon of the RCT. Consequently, in line with othereconomic evaluations of asthma interventions [61], wechose a 10-year time horizon for this analysis. A prob-abilistic decision-analytic model will be used to performa cost-effectiveness analysis from the societal perspec-tive of the intervention compared with usual care. Thekey outcome of the cost-effectiveness analysis will bethe incremental cost-effectiveness ratio (ICER), withquality-adjusted life-years (QALY) as the effectivenessmeasure. The ICER is defined as the difference in arith-metic mean costs between the intervention and usualcare (Ci − Cu) divided by the difference in arithmeticmean effectiveness (QALYs) between the same groups(Ei − Eu).Co-investigators have already developed and calibrateda generic asthma Markov model that is capable of trans-lating adherence at any value of MPR (the primary out-come) into transition rates across levels of asthmaDe Vera et al. Trials 2014, 15:488 Page 7 of 10http://www.trialsjournal.com/content/15/1/488lative logit link function) will be performed. Normaldistribution and identity link function (equivalent of alinear mixed model) will be used to predict longitudinalchanges in AQLQ and ACT.Cost-effectiveness analysisThe ultimate figure of merit for the proposed interven-tion is whether the benefit of the program will justify theresources required for its implementation and operation.Once implemented, the intervention can provide long-term services; therefore, it is important to recognize theFigure 3 Schematic illustration of the asthma Markov model.control and exacerbation health states, and eventuallyinto costs and quality of life [62]. The core of the modelis based on the concept of asthma control, as defined byGINA [6], with weekly transition cycles (Figure 3). Wewill update this model to a Canadian context and adaptit to incorporate specific aspects of the EmPhAsIS in-tervention. Two key study-specific components that willinform the analysis which will be estimated from theRCT data are the operating resource use of the interven-tion, and change in adherence due to the intervention.The cost of the intervention will be assessed from theDe Vera et al. Trials 2014, 15:488 Page 8 of 10http://www.trialsjournal.com/content/15/1/488society’s perspective by collecting the number of SMStransactions, phone interviews, and pharmacy visits.We will also ensure careful documentation of the timespent by the pharmacist delivering the intervention(phone calls and in-person visits). Protocol-driven resour-ces (such as time spent to fill out the questionnaires) willbe excluded from this analysis.DiscussionIn a review of literature published between 1990 and2002 of adherence interventions in asthma, Bender et al.summarized the three key shortcomings of previousadherence intervention studies: reliance on inadequateadherence measures, inclusion of convenience samplesof well-motivated patients, and assessments of inter-vention outcomes artificially boosted by attrition of theleast adherent [33]. The design of the EmPhAsIS trialovercomes these key shortcomings of the previous re-search. First, our objective assessment of adherence,made possible through the unique, data-rich environ-ment of BC, protects us from the biases that arise whenadherence is measured subjectively, and from the pro-hibitive costs and impracticalities of a direct measure ofadherence, such as the Medication Event MonitoringSystem [63]. Second, by applying liberal inclusion cri-teria and a follow-up plan that does not disrupt individ-uals’ health behavior, our study is a pragmatic trial witha high degree of external validity. Third, by assessingthe primary outcome variable (MPR) in a way that isnot affected by voluntary withdrawal from the study,we protect our results from the attrition of the leastadherent.The merit of an mHealth technology is not solely afunction of its clinical benefits. Large investments inmHealth may, by diverting resources, result in a shortfallin funding for basic infrastructure, equipment, and staff-ing elsewhere in the system [64]. Until mHealth inter-ventions are ‘fit for purpose’, healthcare professionals areunlikely to adopt them and this risks implementationfailure [64]. By focusing on a familiar and ubiquitouscommunication technology with low implementation andoperation costs, and low burden on the clients (patientsand pharmacists), we are confident of the successful up-take of our proposed intervention, provided that its meritsare demonstrated.Considering the prevalence of asthma, the extent of thenon-adherence problem in this disease, and the availabilityof effective treatments, there is a tremendous potential toreduce the burden of asthma through improving adher-ence. This is the first study of an intervention based onmobile communication technology involving communitypharmacists in asthma management. Our proposed in-tervention can also pave the way for the management ofother chronic diseases through facilitating patients’ accessto some of the most underutilized resources in the chainof healthcare delivery.Trial statusThe EmPhAsIS trial is not yet recruiting. Recruitment isexpected to begin January 2015.AbbreviationsAAAQ: Adult Asthma Adherence Questionnaire; ACT: Asthma Control Test;AQLQ: Asthma Quality of Life Questionnaire; BC: British Columbia;EmPhAsIS: Empowering pharmacists in asthma management throughinteractive SMS; GINA: Global Initiative for Asthma; GLM: Generalized linearmodels; ICC: Intra-class correlation; ICER: Incremental cost-effectiveness ratio;ICS: Inhaled corticosteroids; MPR: Medication possession ratio; MSP: Medicalservices plan; QALY: Quality-adjusted life-year; RCT: Randomized controlledtrial; SMS: Short messaging service; UBC: University of British Columbia.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsMDV designed the study and will lead all aspects as Principal Investigator.MS designed the study and will lead the economic evaluation of the study.NT participated in the design and coordination of the study. LL designed thestudy and will provide expertise in pharmaceutical outcomes research.RL designed the study and will lead the SMS component. LG and JGparticipated in the design and coordination of the study. JMF designed thestudy and will provide clinical expertise in asthma. PB designed the studyand will provide expertise in statistical analyses. CM designed the study andwill provide expertise in pharmacy practice research. All authors read andapproved the final manuscript.Authors’ informationMary A De Vera and Mohsen Sadatsafavi are co-principal investigators.AcknowledgementsThis study is funded by operating funds from the Canadian Institutes ofHealth Research (FRN 134033) and the College of Pharmacists of BritishColumbia, as well as infrastructure support from the Canadian Foundationfor Innovation (Project number 32724).Author details1Faculty of Pharmaceutical Sciences, University of British Columbia, 2405Wesbrook Mall, Vancouver V6T 1Z3, Canada. 2Faculty of Medicine, Universityof British Columbia, 317 - 2194 Health Sciences Mall, Vancouver, BC V6T 1Z3,Canada. 3Centre for Clinical Epidemiology and Evaluation, 7th Floor, 828West 10th Avenue Research Pavilion, Vancouver V5Z 1M9, Canada. 4Schoolof Pharmacy, Memorial University of Newfoundland, Health Sciences Centre300 Prince Philip Drive, St John’s A1B 3V6, Canada.Received: 13 August 2014 Accepted: 27 November 2014Published: 13 December 2014References1. 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