We conducted a parallel-group randomized controlled trial in patients with moderate or severe asthma at 10 university hospitals in Spain. Patients were recruited from 2013 to 2014. Patients were randomized to an SMS group or a control group; follow-up was for 6 months.

The eligibility criteria for participants were (1) aged 18 to 85 years, (2) asthma diagnosed according to the Global Initiative for Asthma (GINA) criteria [41], (3) all patients treated with maintenance therapy according GINA guidelines, (4) currently own cell phone, (5) not currently being treated with systemic corticosteroids or biologic drugs, (6) not currently participating in another research study.

Exclusion criteria were (1) inability to use inhaler devices [30]; (2) other associated chronic respiratory disease (eg, chronic obstructive pulmonary disease); (3) previous participation in a study using SMS-related asthma reminders (4) asthma exacerbation within 3 months of inclusion in the study (defined by oral corticosteroid use, emergency department visit, or hospitalization); (5) previous treatment with budesonide/formoterol as maintenance and reliever therapy; (6) other uncontrolled severe medical conditions.

The SMS group received psychologist-developed motivational messages every 3 days for 6 months in addition to usual care recommendations according to GINA guidelines [41]. SMS messages were not reminders to take a dose of medication. The control group was treated with general care recommendations alone according to GINA guidelines [41]. Four study visits were required (1 for enrollment and 3 for follow-up) in both groups. Outcome data were collected at the clinic by study staff in V0, V1 (1 month later), V3 (3 months later), and V6 (6 months later—end of study).

Demographic data, ACT, lung function (spirometry), FeNO levels, and exacerbation history in the previous year were collected at the enrollment visit (V0). ACT, lung function, FeNO levels, and exacerbation history were also collected at V1, V3, and V6.

The primary outcome was adherence to inhaled medication. SmartTrack devices were used to quantify adherence to control medication. The secondary outcomes were asthma control measured by the ACT, spirometry parameters (FEV1, forced vital capacity, and FEV1/forced vital capacity ratio), FeNO levels, number of asthma exacerbations, visits to the emergency department, and hospital admissions due to asthma.

The sample size was calculated according to an adherence rate to inhaled asthma therapy between 30% and 70% [9]. On the assumption of the maximal uncertainty of 50% and considering a clinically relevant difference of 25%, with a type I error of .05, a power of 80%, and a 20% loss, 73 patients per arm were needed (total 146 patients).

We generated the 2 comparison groups using simple randomization with an equal allocation ratio by referring to a table of random numbers. A mathematician, also in charge of randomization of the SMS sending, generated the sequences of random allocation, who enrolled participants, and who assigned participants to interventions and SMS sending.

Blinding of patients was not possible. To avoid bias and with ethics approval, physicians were not notified about the SmartTrack recording function or SMS intervention until the study ended.

Categorical variables were expressed as frequencies and percentages and continuous variables as means and standard deviations. The chi-square or Fisher exact test were used for the analysis of categorical variables, and the Student t test or Mann-Whitney U test were used for the comparison of quantitative variables according to the standard or nonnormal distribution of variables. Tests were 2-tailed. Statistical significance was set at P<.05. Statistical analyses were performed using the SPSS Statistics version 20.0 (IBM Corp).

The clinical research ethics committees of the participating centers approved the study. All participants provided written informed consent. The study was classified by the Spanish Agency of Medicines and Medical Devices as a noninterventional imposed postauthorization safety study, and for this reason we were not required to register the clinical trial.

Of patients recruited, 63.8% (97/152) were women. At the first data collection time point, the mean age was 48.9 (SD 16.7) years, and the mean duration of asthma was 16.5 (SD 13) years. A total of 6.6% (10/152) of patients were current smokers. Most patients were well controlled at enrollment, with a mean ACT score of 20.2 (SD 4.5) points. The mean FEV1 before the bronchodilation test was 79% (SD 17.9%) predicted, the mean FEV1 after bronchodilation test was 82.5% (SD 16.2%) predicted, and the mean FeNO level was 37.9 (SD 35.9) ppb. A total of 13.2% (20/152) of patients reported one or more exacerbations during the last 12 months, 15.8% (24/152) reported an episode of asthma-related urgent health care utilization and prednisone use in the previous year, and 5.9% (9/152) required admission to hospital.

A failure with the randomization program unbalanced the number of patients in both arms. During the study period, 57 patients were assigned to the intervention group, and 95 to the control group. At follow-up, 11 patients were excluded because of the total failure of the electronic monitoring device. The final analysis included 53 patients in the intervention group and 88 in the control group. The flowchart of the study population is shown in Figure 2. Demographic and baseline characteristics were similar between groups, apart from a lower proportion of men and university education in the SMS group (Table 1).

In this study, motivational SMS was not associated with an improvement in adherence to inhaled medication. We also found no significant differences in secondary variables, asthma control, lung function, exhaled nitric oxide levels, or exacerbations due to asthma.

Education strategies are useful to improve adherence to asthma therapy [10]. Few studies have examined the effect of SMS reminders on adherence to asthma treatment. Strandbygaard et al [46] conducted a 12-week study with 26 asthma patients randomized to the SMS group (n=12) or control group (n=14). The SMS group received this message daily: “Remember to take your asthma medication morning and evening. From the Respiratory Unit.” A medicine dose-count for Diskus inhaler was used to assess adherence. The mean adherence rate increased in the SMS group and decreased in controls, with a difference in mean adherence rate between the 2 groups after 12 weeks of 17.8% (95% CI 3.2%-32.3%; P=.02). Changes in adherence in the SMS group, however, were not associated with clinical or functional improvement. Few patients were included in this study, and adherence may have been overestimated due to the possibility to take actions before the medical visit.

In another study, Charles et al [47] used the audiovisual reminder function on the Smartinhaler metered-dose inhaler device. After 12 weeks, the absolute difference in the median percentage of medication taken between the intervention (n=55) and control (n=55) groups was 18% (95% CI 10%-26%; P<.001). But, again, no improvements in clinical or lung functions were observed.

In a 6-month cluster-randomized study, Foster et al [35] assessed the effect of inhaler reminders plus adherence feedback (n=21) versus usual care or personalized discussion with the general practitioners (n=22) in the primary care setting. Reminders were associated with improvements in adherence (73% [SD 26%] vs 46% [SD 28%] of prescribed daily doses, P<.001) as well as with an improvement in the ACT but without differences between the study groups.

In a recent systematic review of interventions aimed at improving adherence to inhaled corticosteroids for asthma, 11 studies assessing electronic trackers or reminders versus control were analyzed [10]. Electronic trackers or reminders led to better adherence of 19 percentage points (95% CI 14.47-25.26; 6 studies; moderate-quality evidence), but a clear benefit on clinical outcomes was not found.

In our study, a simple intervention based on motivational SMS sent every 3 days for 6 months was not adequate to improve adherence. Different reasons may account for this adverse finding. First, the messages sent were motivational; they were not reminders for taking medication. Second, the pattern of nonadherence behavior (eg, erratic, deliberate, unwitting) [21] was not evaluated nor were patients stratified according to a nonadherent model. Third, asthma was well controlled at baseline as shown by high ACT scores and lung function parameters; the magnitude of improvement depends to a large extent on the degree of control of the disease before the intervention.

An interesting finding of this study, in which all patients had twice-daily medication schedules, is that adherence rates were higher in the morning than in the evening. It is possible that in patients on single-dose inhaled medication regimens, SMS could have had a more significant impact on adherence.

Although the Smartinhaler is accurate in recording and retaining actuation data [48,49], potential malfunction during real-life use by patients is possible. In our study, failure of communication technology occurred in all centers without differences between the study groups; in these cases, however, analyses were performed using backup files. Only 91% (SD 59.9%) of the Smartinhalers worked fine and collected information until the study ended.

In our study, patients were recruited in specialized asthma units established in different hospitals throughout Spain for the management of patients with severe and difficult-to-control asthma [50]. Therefore, it is possible that this particular circumstance may account for the adequate adherence at baseline and proper control of asthma before enrollment and at the end of the study.

In summary, in this prospective randomized clinical study, reinforcement of adherence to inhaled asthma medication using motivational SMS via cell phones was not capable of improving adherence. Mobile health interventions are increasingly popular for implementing on a large scale in different chronic health conditions [51-53], but further research into these issues is needed. Despite the negative results that may be justified because of the study’s limitations as described above, the study’s results are not conclusive. However, an interesting fact that can be seen in both groups is that morning adherence to the inhaler is much higher than afternoon adherence. These data should be verified in a new well-designed clinical trial that could reinforce the use of ultralong action treatments, which only need to be taken once a day, in order to improve the adherence and control of asthma.