Table 2.

Studies of digital inhalers reporting clinical outcomes

Author (year) Design Setting	Study population Study group(s) Duration	Digital device Drug(s)	Patient and clinician interfaces with EMD and apps	Primary endpoint(s)
Alshabani (2018) [47] (Abstract only) Prospective open-label	COPD patients at high risk of adverse events from COPD (n = 20) 6 months	Propeller (albuterol pMDI)	EMD with clinician dashboard Poor compliance by excess SABA or daily controller use prompted clinician response	All-cause HCU with EMD + dashboard compared to prior year
Alshabani (2020) [48] Retrospective pre- and post- analysis, open-label	COPD patients with high health care utilization (n = 39) 12 months	Propeller (digital inhalers for both controller and albuterol pMDI)	EMD with patient dashboard Patients alerted when adherence to controller was suboptimal or rescue inhaler use increased	All-cause and COPD HCU compared with year prior to enrolment in study
Barrett (2017) [40] Prospective, observational Community project	People with asthma > 4 years old (n = 95) 13 months	Propeller Albuterol pMDI	Smartphone app to aid patient self-management No clinician dashboard	SABA use compared to 30 day baseline ACT and c-ACT compared to 30 day baseline
Chan (2015) [35] RCT Children with asthma presenting to ED	Children with asthma aged 6–15 years on ICS with recent exacerbation requiring ED (n = 220) EMD + BF vs. usual care 6 months	Adherium SmartTrack® ICS pMDI Albuterol pMDI	Patient adherence reminders by device	School absenteeism (co-primary) Medication adherence (co-primary)
Foster (2014) [37] RCT 6 months	Adults with mod/severe asthma based on ACT (n = 143) EMD + BF + clinician/patient adherence discussions vs. EMD + BF vs. Clinician/patient adherence discussion only vs. Usual care 6 months	Adherium SmartTrack® ICS/LABA (Accuhaler®) Albuterol pMDI	Patient inhaler reminders with clinician dashboard prompting patient contact with suboptimal inhaler adherence	ACT Mini-AQLQ Anxiety/depression scale
Gregoriano (2019) [49] Single-blind RCT Pulmonary clinic	Adult asthma and COPD with exacerbation in last year (n = 149) 6 months	Adherium Hailie® sensor (formerly SmartInhaler) Albuterol pMDI Controllers DPI	EMD with clinician dashboard + BF (patient inhaler alerts, clinician assessments) vs. Passive EMD	Time to first exacerbation
Kaye(2020) [42] (Abstract only) Prospective, observational	COPD (n = 1000) 6 months	Propeller Albuterol pMDI	EMD with patient dashboard	CAT at 6 months compared to baseline Albuterol use
Lin (2020) [50] Open-label study Inner city school	Asthma 10–17 years old (n = 21) Inner city school-based intervention 6 months	Propeller Health Albuterol pMDI and controllers	Monthly clinic visits Clinician and patient dashboards Behavioral interventions to improve adherence	Composite Asthma Severity Index (CASI)
Merchant (2016) [38] RCT, parallel arms Allergy clinic	Children and adults with asthma > 5 years old (n = 495) EMD + BF vs. Usual care 12 months	Propeller Albuterol pMDI	Clinician access to dashboard Personalized feedback to patient via mobile phone app	SABA-free days
Merchant (2018) [51] Prospective, open-label Allergy clinic	Adults with asthma (n = 224) (n = 76 on controller medication) 12 months	Propeller Albuterol pMDI Various controllers	Clinician access to web-based dashboard Patient feedback from software on personal device	ED visits Hospitalizations Combined ED visits and hospitalizations
Moore (2020) [43] (Abstract only) Open-label, parallel-group RCT	Adults with uncontrolled asthma (ACT < 20) on fixed-dose ICS/LABA maintenance therapy (n = 437) 6 months	Ellipta sensor Fluticasone furoate/vilanterol Ellipta DPI Albuterol pMDI	One of five connected inhaler systems with different levels of data feedback from sensors: (1) Maintenance use to participants and health care professionals (HCPs) (N = 87); (2) Maintenance use to participants (N = 88); (3) Maintenance and rescue use to participants and HCPs (N = 88); (4) Maintenance and rescue use to participants (N = 88); (5) No feedback (control) (N = 86)	Mean adherence to maintenance treatment at 4–6 months
Morton (2017) [46] Open-label RCT	Pediatric asthma 6–16 years old (n = 77) Intervention group (EMD with controller reminders and review of adherence at clinic visits) 1 year	Adherium Hailie® sensors for pMDI and for turbuhaler (formerly Smartinhaler®, SmartTurbo®) ICS pMDI and ICS DPI SABA pMDI	Passive recording of EMD use Adherence reviewed at clinic visits with health care provider	Asthma Control Questionnaire
Mosnaim (2020) [36] RCT, single blinded Allergy clinic	Adults with uncontrolled asthma (n = 100) EMD + BF vs. Usual care with passive EMD 14 weeks	Propeller ICS and SABA pMDI	Yes	SABA-free days
O’Dwyer (2020) [39, 52] Randomized parallel study Community pharmacies and clinics	Adult asthma(n = 83) COPD (n = 55) Intervention group EMD + BF vs. Intervention group inhaler training only vs. Control group—usual care 6 months	INCA (Seretide® Accuhaler)	EMD + BF	ICS/LABA adherence (frequency of use and proper inhaler technique)
Sulaiman (2018)[41] RCT Pulmonary clinic	Adults with severe asthma with exacerbation in last year (n = 360) Control (Intensive education) vs. Intervention (Intensive education + BF from EMD) 3 months	INCA (Seretide®)		ICS/LABA adherence (frequency of user and inhaler technique)

Author (year) Design Setting	Secondary endpoint(s)	Primary outcome	Secondary outcome	Comments
Alshabani (2018) [47] (Abstract only) Prospective open-label		All-cause HCU (hosp + ED) lower with EMD + BF (p = 0.034) COPD-related hospitalization was also lower with EMD + BF (2.3 (2.2) vs. 3.9 (3.2) but not significant (p = 0.07), no CI provided		Prompted patient contact by clinicians
Alshabani (2020) [48] Retrospective pre- and post- analysis, open-label		Reduction in COPD-related HCU per year (2.2 [±2.3] vs. 3.4 [±3.2], p = 0.01). Reduction in all-cause HCU, but this was not statistically significant (3.4 [±2.6] vs. 4.7 [±4.1], p = 0.06), no CI provided		Average adherence was 44.4% (28.4%), with mean Charlson comorbidity index 5.6 (2.7)
Barrett (2017) [40] Prospective, observational Community project	––	39% ↓in SABA use in first 30 days (p < 0.001) Higher proportion with controlled asthma	Increase in percentage of symptom-free days from 77% during the baseline period to 86% after the first month (12% improvement)
Chan (2015) [35] RCT Children with asthma presenting to ED	Asthma morbidity score Child ACT FEV1 Exacerbations	Median medication adherence: 84% (10th percentile 54%, 90th percentile 96%) with EMD vs. 30% (8%, 68%) in control group (p < 0.0001) No difference in school absenteeism	Improved asthma score from baseline with EMD Improvement in asthma morbidity score (p = 0.008) and Childhood ACT (p < 0.0001) improved in EMD + BF Lower SABA use in EMD + BF (median % of days of SABA use = 9.5% [10th percentile 1.1%, 90th percentile 32.8%] in the intervention group vs. 17.4% [2.4%, 49.2%] in the control group; p = 0.002) No effect on FEV1	Adherence reduced over 6 months in both groups though difference between two groups remained statistically significant
Foster (2014) [37] RCT 6 months	ICS/LABA adherence FEV1	No difference in ACT among 4 groups (p = 0.14)	Adherence in EMD + BF + adherence discussion = 76% (95% CI: 65–86%), EMD + BF = 71% (95% CI: 61–81%); usual care = 46% (95% CI: 36–55%); discussion only group = 46% (95% CI: 32–60%) ↓ exacerbation rates with inhaler reminders (11% vs. 28%; p = 0.13) No difference in other PRO or FEV1 among 3 groups
Gregoriano (2019) [49] Single-blind RCT Pulmonary clinic	Exacerbation frequency Controller adherence SGRQ score	No effect on time to first exacerbation (HR 0.65, 95% CI: 0.21–2.07, p = 0.024)	Nonsignificant decrease in exacerbation frequency (RR = 0.61, CI: = 0.35–1.03, p = 0.07) Days adherent greater in intervention group (pMDI 82 ± 14% vs. 60 ± 30%, p  = 0.01) and DPI controllers (90 ± 10% vs. 80 ± 21%, p = 0.01) No effects on SGRQ	Exacerbations defined by acute worsening requiring contacting the clinician (not based on oral steroid use)
Kaye(2020) [42] (Abstract only) Prospective, observational		Albuterol use declined by 0.8 puffs/day (95% CI: −0.9 to −0.7; p < 0.001) compared to baseline CAT score decreased by 1.1 points (95% CI: −1.4 to −0.8; p < 0.001)		Albuterol use greater in non-adherent patients 46% of subjects met MCID for CAT (> 2 change)
Lin (2020) [50] Open-label study Inner city school	School absenteeism Exacerbations Medication adherence	No change in mean CASI from baseline; no CI provided	Decrease in school absenteeism (p = 0.003) Exacerbations decreased (p < 0001) Controller adherence increased by 8% during active intervention (months 1–5, p = 0.03), but returned to baseline by month 6 without behavioral interventions	81% with step-up in controller therapies
Merchant (2016) [38] RCT, parallel arms Allergy clinic	ACT	↑SABA-free days in EMD + BF vs. usual care group +17% vs. +21%, p < 0.01); no CI provided	↑ in ACT with EMD + BF vs. control group (+6.2 vs. +4.6 p < 0.01)	Attrition 14.8% at 1 month and > 55% at 12 months
Merchant (2018) [51] Prospective, open-label Allergy clinic	SABA use ICS adherence	ED visits lower compared to baseline period (rate difference 6.3 [95% CI: 0.9–11.6], p = 0.04) Combined ED visits and hospitalizations lower (rate difference 7.6 [95% CI: 1.9–13.3]; p = 0.02)	SABA use ↓by 0.52 puffs/daily (95% CI: −0.69 to −0.34; p < 0.05) ↑ controller use 0.82 vs. 0.66 (0.16 [95% CI: 0.07–0.25]; p < 0.01)	↑Outpatient visits by 2.6 (95% CI: 2.2, 2.9) visits per patient-year (p < 0.01)
Moore (2020) [43] (Abstract only) Open-label, parallel-group RCT	SABA-free days ACT score	Mean (SD) adherence 82.2 (16.58)% in the “maintenance to participants and HCPs” arm and 70.8 (27.30)% in the control arm; difference of 12.0% (95% CI: 5.2–18.8%; p < 0.001) Adherence also significantly greater in other arms vs. control	Mean % SABA-free days (months 4–6) significantly greater in those who received data on rescue use vs. control ACT scores improved in all study arms—no significant differences between groups	Only measured inhaler use months 4–6
Morton (2017) [46] Open-label RCT	Adherence to ICS and use of SABA Acute care visits to office or ED FEV1 Pediatric Asthma QOL Questionnaire (PAQLQ) Guideline-based severity	No difference in Asthma Control Questionnaire (difference of the paired mean difference from baseline to 12 months =  −0.18 (95% CI: −0.76 to 0.38; p = 0.51)	Adherence improved in intervention group 70% vs. 49% (p = 0.001); no CI provided Fewer exacerbations in intervention group (controls 53% more likely to receive steroids—incident risk ratio = 1.53 [95% CI: 1.11–2.11]; p = 0.008) and hospitalizations (p < 0.001) No significant difference in SABA use, FEV1, or PAQLQ or asthma severity	Substantial number of devices damaged or lost by the children
Mosnaim (2020) [36] RCT, single blinded Allergy clinic	ICS adherence	↑ in SABA-free days = 19% (95% CI: 12–26%; p < 0.01) for EMD + BF vs. 6% (95% CI: −3 to 16; p = 0.18) in control group (passive EMD)	ICS adherence over 14 weeks = −2% (95% CI: −7 to 3%; p = 0.40) in EMD + BF vs. −17% (95% CI: −26 to −8%; p < 0.01) in control group	Exploratory outcomes of exacerbations and asthma control not different
O’Dwyer (2020) [39, 52] Randomized parallel study Community pharmacies and clinics	SGRQ Resp symptoms	↑Adherence 60.8% in EMD + BF + inhaler instruction vs. 44.2% in inhaler instruction only vs. 33.2% in usual care group (14% higher [95% CI: −1 to 30]; p = 0.07) in the BF group vs. demonstration group and 31% higher (95% CI: 13–48; p = 0.001) than in the control group)	SGRQ (−6.1; 95% CI: −9 to −0.4; p = 0.04) in EMD + BF group at 2 and 6 months Inhaler training group had improvement at 2 months, but not at 6 months	Pharmacies were unit of randomization Community pharmacists were trained and provided interventions
Sulaiman (2018)[41] RCT Pulmonary clinic	ACT AQLQ PEF	73% adherence (frequency of use, correct technique) in EMD + BF vs. 63% in control group (difference = 10%; 95% CI: 2.8–17.6%; p = 0.02)	PEF at 3 months, no statistically significant difference between groups ACT or AQLQ, no statistically significantly different between groups	27% of participants with severe asthma were refractory to current treatment despite being adherent and receiving intensive education

ACT Asthma Control Test, AQLQ Asthma Quality of Life Questionnaire, BF = biofeedback, CAT COPD Assessment Test, CI confidence interval, COPD chronic obstructive pulmonary disease, DPI dry powder inhaler, ED emergency department, EMD electronic monitoring device, FEV1 forced expiratory volume in 1 second, HCU health care utilization, ICS inhaled corticosteroids, LABA long-acting beta agonist, MCID minimal clinically important difference, PAQLQ  Pediatric Asthma Quality of Life Questionnaire, PEF peak expiratory flow, pMDI pressurized metered-dose inhaler, PRO patient-reported outcomes, RCT randomized controlled trial, SD standard deviation, SABA short-acting beta agonist, SGRQ St George's Respiratory Questionnaire