Asthmatuner a Self-management App for Asthma: A Randomized Controlled Multicentre Trial

1. Background Clinical gaps hamper proper asthma management, and leads to delayed or undiagnosed disease, poor adherence to treatment, inadequate self-care abilities, inadequate understanding of disease severity, poor patient education, inadequate measurement of lung function, and inconsistent evaluation of symptoms. To improve the patient's ability to self-manage and to overcome clinical gaps, evidence emphasizes clinics to offer comprehensive patient education. The national Finish asthma programme (1994-2004) focused on applying effective strategies of asthma management, as a result, patient's self-management was improved, and cost-effective through limited demands on the health-care and social security system.

Novel applications embodied in smartphones are straightforward alternative to facilitate health care and support patients with hands-on guidance for self-management of asthma. Asthmatuner is a smartphone app that enables evaluation of lung function and symptoms. The app provides patients with a daily treatment plan adjusted for symptoms and lung function. Additionally, information is accessible and can be assessed by health care providers through a back-end system. Future versions of Asthmatuner will be enabled through patient's own medical record. Self-management apps with hands-on guidance for self-management of asthma present a promising future for closing clinical gaps, but the overall benefits of using the service in the treatment of asthma need comprehensive evaluation that answers scientific questions and end-user opinions.

1. Aims The primary aim is to evaluate Asthmatuner and the clinical effect on patients´ self-reported asthma control test (scores of ACT/C-ACT).

The secondary aim is to evaluate the effect on patients´ and HR-QoL and medical adherence.

Primary outcomes The primary outcome will be scores of ACT/C-ACT and Paediatric asthma quality of life questionnaire (PAQLQ) or Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ).

Secondary outcomes The secondary outcomes are scores of Medicine adherence report scale (MARS) and costs of prescribed dose and type of control medication and total amount of direct and indirect costs for patient/caregiver.

1. Material and methods Study design: Multicenter randomized controlled physician blinded crossover trial, where study participants were randomized to start with AsthmaTuner or conventional treatment, and a washout period between treatments, Figure 1. Primary outcome of asthma control test (ACT) or Childhood Asthma Control Test (C-ACT) were measured two times in each treatment period, at baseline and at follow-up visit, equal or more than 8 weeks after treatment started. The participating centers were recommended to comply with Swedish national treatment and management of asthma, which closely resemble with Global Initiative for Asthma (GINA). A study nurse at each site performed the randomization by open a sealed envelope indicating the start of either AsthmaTuner or conventional treatment. The physician was blinded for the order of given treatments when one paper personalized treatment plan and one individual treatment plan for AsthmaTuner were arranged to each patient according to levels of controlled, partly controlled and uncontrolled asthma. The regional board of Ethical Committee in Stockholm (number: 2015/1527-31/1 and 2016/1546-32) and Swedish Medical Products Agency (number 5.1-2016-19829) both approved the study. The study was registered at ClinicalTrial.gov

Intervention: Asthmatuner is a CE-marked cloud-based system with healthcare interface and a downloaded patient app (Android or iOS). The intended use of Asthmatuner is to automate and facilitate self-management of asthma, by letting patient register symptoms and to measure forced expiratory volume in one second (FEV1) with a Bluetooth spirometer (MIR, SmartOne). The patient receives an immediate feedback on asthma control and treatment recommendation with an image of the correct inhaler to use and the dose. Asthma control is defined based on to GINA and a summary of lung function; liter to percentage of personalized best FEV1 using cutoff equal or less than 80%, and asthma symptoms last week in terms of; need for recue medication more than twice, daytime symptoms, nocturnal symptoms/awakenings and limitation of activities. Furthermore, Asthmatuner offers patient and asthma care provider a longitudinal data view of prescribed treatments, lung function and experienced symptoms.

Study subjects, children from 6 years and adults, with doctor's diagnosis of asthma and ACT or C-ACT score below 20 points, were included in the region of Stockholm, Sweden. The study was conducted in the primary health care sector and in asthma clinics specialised for children and adolescents in Stockholm. Patients were included at Liljeholmen Health Care Centre, Sophiahemmet Health Care Centre, and Astrid Lindgren Children's Hospital (Lung- and Allergy Department in Solna and Children and Adolescents Health Care Department in Huddinge) during the years of 2016-2018. Exclusion criteria were other ongoing comorbidity impairing the asthma control, participation in other drug trial, and a patient or all caregiver(s) (in case the patient is a child) incapable to read Swedish.

Data collection

Questionnaires:

• A health questionnaire completed at the first visit will provide information regarding asthma medical history, health utilization, annual income and employment status.
• ACT will be used to assess asthma control in patients 12 years or older, and C-ACT in children of age 6 to 11 years. A mean score equal or below 19 indicates uncontrolled asthma. Scores above 19 defines asthma to be controlled in both tests.
• HR-QoL will be applied in patients from 6 to 11 years of age using the validated Swedish translated Paediatric Asthma Quality of Life Questionnaire (PAQLQ), and the mini Asthma Quality of Life Questionnaire (mini-AQLQ) in patients from 12 years of age.
• Self-reported medication adherence will be measured with five-item MARS, developed to assess adherence with asthma medication. The MARS comprises statements about medication use behaviors. The patient is asked to answer each behavior with a score between 1-5 based on of following alternatives; "always", "often", "sometimes", "rarely" or "never". A mean MARS score will then be calculated, and a score of 4.5 or greater indicates good adherence.
• Time consume, utility and satisfaction using Asthmatuner will be asked patient/caregiver, nurses and physicians in relation to applied management.

Power analysis The power analysis is based on our previous analysis of ACT/C-ACT and HR-QoL scores in schoolchildren with uncontrolled severe asthma [21]. The scores for severe uncontrolled asthma were on average for ACT 17 (SD 3.3) and for PAQLQ 5.4 (SD 0.77). Thus, an estimated improvement of ACT from 17 to 19 (two points) or PAQLQ from 5.4 to 5.9 (0.5 points) requires 38-43 patients in each group (Asthmatuner vs. conventional management) to attain an 80 % power at 5% significance level.

Visit 1: Eligibility of participants will be checked. The patient will be given information about the study procedures and must sign the informed consent form. At the visit the following procedures will be conducted and documented:

• Demographic data
• Body height and weight
• Medical history about allergy and asthma will be obtained with health questionnaire
• Asthma control will be assessed with ACT or C-ACT
• HR-QoL; Mini-AQLQ or PAQLQ
• MARS questionnaire
• Lung function, dynamic spirometry including forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC, forced expiratory flow after 50% of vital capacity (FEF50)
• Randomization to; Asthmatuner - conventional self-management or conventional - Asthmatuner
• Prescribe and apply treatment plan (Asthmatuner or Conventional)
• Control of inhalation technique

At visit 2, the following procedures will be conducted and documented:

• ACT/C-ACT
• HR-QoL; Mini-AQLQ/PAQLQ
• MARS
• Lung function, dynamic spirometry (FVC, FEV1, FEV1/FVC and FEF50)
• Revise treatment plan if necessary (Asthmatuner or Conventional)
• Revision of adverse events.

At visit 3, the following procedures will be conducted and documented:

• ACT/C-ACT
• HR-QoL; Mini-AQLQ/PAQLQ
• MARS
• Lung function, dynamic spirometry (FVC, FEV1, FEV1/FVC and FEF50)
• Prescribe and apply treatment plan (Asthmatuner or Conventional)
• Control of inhalation technique
• Revision of adverse events.

At visit 4, the following procedures will be conducted and documented:

• ACT/C-ACT
• HR-QoL; Mini-AQLQ or PAQLQ
• MARS
• Lung function, dynamic spirometry including forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC, forced expiratory flow after 50% of vital capacity (FEF50)
• Revision of adverse events

4.5 Statistical analysis The study hypothesis will be tested by examining patients´ change from baseline in asthma control (ACT/C-ACT), HR-QoL (PAQLQ/Mini-AQLQ), and in MARS scores between asthma management groups. Results will be summarized between each group as mean scores and analysed by paired t-tests.

4.8 Withdrawal A patient should be withdrawn from the trial if, in the opinion of the investigator, it is medically necessary, or if it is the wish of the patient. In any circumstances the reasons for withdrawal should be documented in the Study termination report. Participants who discontinue from the study for any reason will be replaced.

4.9 Safety

An adverse event (AE) is any untoward medical occurrence in participants using or not using Asthmatuner. AE include the following:

• All suspect adverse reaction
• All reactions from medical overdose, abuse, withdrawal, sensitivity or toxicity
• Apparently unrelated illness, including the worsening of a preexisting illness
• Injury or accident
• Abnormalities in physiological testing or physical examination
• Laboratory abnormalities that require clinical intervention or further investigation unless they are associated with an already reported clinical event.

Preexisting conditions In this trial, a preexisting condition i.e. asthma, should not be reported as an adverse event unless the condition worsens or episodes increases (i.e. exacerbations) in the frequency during the adverse event reporting period.

Procedures Diagnostics and therapeutic non-invasive and invasive procedures, such as surgery, should not be reported as adverse events. However, the medical condition for which the procedure was performed should be reported if it meets the definition of an AE. The AE reporting period begins upon starting the use of Asthmatuner or conventional management (visit 1).

Each participant will be questioned about AE for each visit 2 and 3. All AE that occur in the trial should be reported to investigator and specified in the participants´ medical journal and in a separate AE form with following information:

• Type of AE
• Date and time of AE
• Association with Asthmatuner (No/Yes/Unknown)
• Gravity (Serious or Non-serious)
• Reporting time
• Follow-up (resolved or unresolved)

Gravity

Each AE is to be classified by the investigator as serious or non-serious. This classification of the gravity of the event determines the reporting procedure to be followed. An AE that meets one or more of the following criteria is classified as serious:

• Death
• Life-threatening
• Hospitalization
• Persistent or significant disability/incapacity
• Congenital anomaly/birth defect All serious AE should directly be reported to investigator.

5.0 Ethics The trial will be performed in accordance with the World Medical Assembly Helsinki recommendations guiding physicians in biomedical research involving human subjects [26]. It is the responsibility of the investigators to obtain approval of the trial from regional ethic committee´.

It is the responsibility of the investigators to give each patient prior to inclusion in the trial, full adequate information regarding the trial and the procedures. The patient must be informed about their right to withdraw from the trial at any time. Written patient information must be given to each patient before enrollment. In addition, it is the responsibility of the investigator to obtain signed informed consent from all participants.