Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04132778 |
| Other study ID # |
v.10 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
October 14, 2019 |
| Est. completion date |
December 1, 2024 |
Study information
| Verified date |
February 2023 |
| Source |
Karolinska Institutet |
| Contact |
Björn Nordlund, PhD |
| Phone |
+46703234414 |
| Email |
bjorn.nordlund[@]ki.se |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Asthma self-management is dependent on support and education. To facilitate self-management
have we developed and CE-mark a novel digital self-management system called Asthmatuner
(Medituner AB, Sweden).The primary aim of this program is to evaluate if self-management with
Asthmatuner improves asthma control more than traditional self-management. RCT with two arms,
Asthmatuner or traditional asthma management, during at least 6 months. Thereafter, the study
continues to be observational from 6- 12 months. Eligible patients with doctor's diagnosed
asthma that are managed within the municipality of Tiohundra and Astrid Lindgren Children's
Hospital will be invited to participate. Approximately 800 patients, adults and
schoolchildren of the age of 6 years will be recruited.Outcomes: Asthma Control Test, number
of exacerbations, unplanned healthcare visits, Medicine Adherence Report Scale and lung
function.
Description:
The ultimate goal for all patients is to achieve asthma control. There are various tools for
evaluating a patient's asthma control, one is to use validated questionnaires e.g. Asthma
Control Test (ACT) (1), another is to evaluate symptoms in patient history based on
recommended characteristics from the Global Initiative for Asthma (GINA) (2). These
characteristics emphasize optimal asthma control as no symptoms, undisturbed sleep, no severe
exacerbations, no emergency visits, normal lung function and no limitations in daily
activities.
The characteristics defining asthma control according to GINA guidelines are widely used as
the golden standard for both clinical research and for asthma care (3, 4). Based on a
patient's number of characteristics, GINA classifies asthma as controlled, partly controlled
or uncontrolled (5). The GINA guidelines include two domains for assessment, the first is the
evaluation of symptoms and the second is physician´s evaluation of patient's future risk for
exacerbations. Indicators of increased health cost of asthma like e.g. health care
utilization, medication and lost school/work days are associated with uncontrolled asthma
(6). In addition, studies have shown that patients with lower socio-economic status are
associated with more impaired asthma control (7-9), and further attention is needed to assist
patients with impaired asthma control through new approaches and better management
strategies.
Poor adherence to asthma management and simple practical tools for diagnosing asthma can lead
to under- and over-diagnosis of asthma in primary health care (10, 11). In most cases,
including in the EU, asthma patients visit their doctors less than once a year, giving
healthcare providers only a snapshot of the patient's condition (12, 13). New approaches are
needed to improve adherence in asthma care.
Patient education in self-management using self-monitoring of lung function and symptoms,
coupled with adjustable treatment plan appear to be effective compared with other forms of
asthma self-management according to a Cochrane review (14). National asthma programmes
focusing on management and improving asthma care has proved to reduce the morbidity of asthma
and its impact on individuals as well as on the society (15). Patient education in
self-management improves health and the quality of life for people with asthma, as well as
reducing health care costs (14). However, in spite of this convincing evidence on how to
treat and manage asthma, there is worldwide significant discrepancy between real life
practice and guidelines of asthma management (16, 17).
Clinical decision support systems for self-management Significant worldwide discrepancy
exists between real life asthma practice and guidelines of management (16, 17).
Self-management based on self-monitoring of lung function and symptoms, coupled with
adjustable treatment plan appear to be effective compared with other forms of asthma
self-management according to a Cochrane review (14). Furthermore, electronic medical records
are largely implemented in asthma care, and it is feasible to enable health care providers to
monitor and support patient's self-management with computer decision support systems (CDSS).
Therefore, we target to improve incomplete asthma management by develop and CE-mark the novel
digital self-management system Asthmatuner (Medituner AB, Sweden). The system consists of a
patient smartphone application and a portable wireless spirometer for measuring lung
function, and a healthcare provider user interface to prescribe treatment plan and assess
patient data. The app provides patients with a daily treatment recommendation linked to
patient's current status of asthma (controlled, partly- or uncontrolled asthma) (2). Recently
in 2018, Asthmatuner significantly reduced asthma symptoms in children and adolescents
compared to traditional management in a randomised controlled cross-over trial (18).
Prevention of exacerbations and symptoms is major health care challenge. Combining data from
a variety of sources, including risk factors and real-time biological and environmental data
has the potential to improve the prediction of asthma attacks in individuals. Quantifying
time-serial measures of lung function contain unexpected amounts of information that can be
linked to occurrence of symptoms and exacerbations (19). Thus, our hypothesis is that
Asthmatuner constitutes a unique data source that offers identification of longitudinal
fluctuating patterns of lung function that can be used to develop algorithms capable of
predicting airway obstruction and generating early individual-specific action plan.
Individual action plan could contain phenotype specific information about step-up treatment,
reminders on how to use and inhaler medication and avoiding specific factors that may trigger
or worsen asthma symptoms, as well as contact details for healthcare providers (20). In
addition, Asthmatuner has the potential to strengthen quality in primary health care at
reduced cost (21), by identify patients with poor asthma control and therefore most needed
for clinical follow-up or video online visit. Therefore, the municipality of Tiohundra (22),
with a population of more 56000 people, has decided to assess the effect and benefit of using
Asthmatuner in a randomised controlled trial (RCT).
The primary aim of this program is to evaluate if self-management with Asthmatuner improves
asthma control more than traditional self-management.
Secondary aims are to:
- Evaluate if Asthmatuner can reduce the number of planned or unplanned health care visits
compared with traditional asthma care
- Investigate if Asthmatuner improves adherence to intake of control medication and
health-related quality of life (HR-QoL) more than traditional traditional asthma care
- Assess if Asthmatuner can reduced the number of exacerbations and missed work/school
days due to asthma compared with traditional asthma care
- Characterise specific phenotypes based on biodata and time-serial measurements of lung
function in relation to occurrence of symptoms and exacerbation in patients using
Asthmatuner. The goal is to develop mathematical algorithms generating action plan for
prevention of exacerbation. Moreover, the data collected with Asthmatuner and the daily
treatment recommendations generated with this system will be used to train a deep
(artificial) neural network towards an optimization of the ACT scores (i.e., the level
of asthma control) attained.
- Perform a qualitative study with the third and final aim to explore patients' and
caregivers' experience of using Asthmatuner
MATERIAL AND METHODS Design RCT with two arms, Asthmatuner or traditional asthma management,
during at least 6 months. Thereafter, the study continues to be observational from 6- 12
months, offering all willing participants to use Asthmatuner. In addition, a complementary
qualitative study of patients' and caregivers' experiences of the introduction and use of
Asthmatuner and its impact on work processes and communication.
Primary outcomes at baseline, 3- and 6 months study period
- Mean score validated Asthma Control Test (ACT) Secondary outcomes by 6 months study
period
- Number of exacerbations requiring oral corticosteroids or health care utilisation
- Unplanned health care visits due to asthma
- Mean score of Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ)
- Mean score of Medicine Adherence Report Scale
- Fluctuation in time-serial measurements (forced expiratory volume in one second FEV1
(L)) with use of Asthmatuner, linked to information about exacerbations and daily or
nocturnal symptoms or treatment with bronchodilator
- Cost benefit with Asthmatuner compared with traditional health care visits based on
costs for planned/unplanned visits, exacerbations, and effect on ACT
- Patient and caregiver satisfaction with Asthmatuner. using survey and interviews after
completed study participation.
The qualitative study will focus on patients' experiences (eg patient satisfaction,
empowerment, communication with healthcare professionals and perceived quality of care) as
well as the caregivers' experiences (eg work processes, perceived stress, impact on
communication and perceived quality of care).
Subjects Primary care Eligible patients with doctor's diagnosed asthma that are managed at
any health care centre within the municipality of Tiohundra will be invited to participate.
Approximately 400 patients, adults and schoolchildren of the age of 6 years will be included.
Subjects with untreated or treated comorbidity with major effect on the state of asthma will
not be included.
Paediatric cohort The study population will be extended to 400 schoolchildren with asthma to
ensuring sufficient number of participants and time-serial measurements of lung function.
Children and adolescents 6-18 years, at Astrid Lindgren Children's Hospital in Stockholm
(Karolinska University Hospital) will be invited to attend during the year 2019-2020.
Sample Size The sample size for the trial will be estimated based on our pilot study showing
that Asthmatuner improves asthma control with 3.72 ACT points compared to traditional
management 2.35 points (mean standard deviation 3.45). Assuming a dropout rate up to 10%,
including 200 eligible subjects for Asthmatuner and equal number in the control group would
be clinical relevant, worthwhile and feasible to attain 80% power at 5% significant level.
Intervention - Asthmatuner Patients download the app from AppStore or Google Play and create
a user account. The healthcare provider must also have access to patients' Asthmatuner
accounts so the doctor or asthma nurse can ensure the treatment plan is up to date. The
patient will then be able to see the treatment plan and which inhaler they should use
displayed on the screen of the smartphone. The smartphone application has been designed to
minimize the time needed to generate an individual treatment recommendation. Once the user
profile has been created, the wireless spirometer is paired with the smartphone and the
physician creates and uploads a treatment plan based on an automated recommendation, which is
generated in seconds.
The user interface is intuitively structured into four sections: 1) Lung function, 2)
Symptoms, 3) Treatment, and 4) Trends view.
To get an up-to-date treatment recommendation the patient follows the instructions on the
screen under the Lung function section to generate an FEV1 (Forced Expiratory Volume) value
using the connected spirometer from MIR (Medical International Research, Italy). The
interface shows if the value was correctly generated and how it relates to patient's personal
best value. Four symptom questions - in accordance with the GINA - are presented and the
patient answers yes or no. Once the symptom questions have been saved, the patient is
automatically transferred to the "treatment section" where the current treatment
recommendation is presented based on lung function and symptoms. The trend feature shows the
patient/provider a historical overview of lung function, symptoms and treatment.
Control group - Traditional asthma management Traditional self-management is defined as all
other types of non-digital asthma management. This could be treatment plan written on paper
or by oral communication to patient/caregiver on asthma treatment.
Registers Complementary information about unplanned visits and health care utilisation both
in-patient care and out-patient care in Sweden will be collected from the medical record Take
Care or the National Quality Register for Asthma and COPD "Luftvägsregistret". The study will
be registered at ClinicalTrials.gov.
Asthma control test Asthma symptoms during the last 4 weeks will be assessed using Childhood
asthma control test (C-ACT) in children 6-11 years and ACT patients aged > 12 years. The
questionnaire is validated and regular used in clinical practice (23). Well-controlled asthma
is defined as score > 20 points and uncontrolled asthma score of < 19.
Health survey Health survey including socio-demographics, medical history about asthma,
comorbidities and symptoms, as well as ACT will be filled out by patient/caregiver at
inclusion.
Electronic questionnaires Questionnaires will be sent out electronically by use of KI-survey,
collecting information on ACT, symptoms, exacerbations, unplanned health care
visits/consultations due asthma, loss of work and school days due to asthma at 3 and 6
months.
Health-related quality of life (HR-QoL) HR-QoL will be applied at baseline, 3- and 6 months
using the validated Swedish translated the Mini-AQLQ in patients from 12 years of age (24).
The MARS questionnaire Self-reported medication adherence will be measured with validated
five-item MARS, developed to assess adherence with asthma medication (25). 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 (25).
Lung function testing Lung function will be measured at each study visit, analysing FEV1,
forced vital capacity (FVC), FEV1/FVC and forced expiratory flow after 25-75% of vital
capacity (FEF25-75). At visit 1 is a reversibility test performed after intake short-acting
beta-2 agonist.
Follow-up visits Frequency of follow-up visits and management are recommended according to
Swedish National Board of Health and Welfare, Table 3.
Statistical analysis Statistical analysis will be carried out analysing proportion of
subjects maintaining asthma control or improving their asthma control according to ACT and
GINA between management groups, as well as the numeric change in ACT scores from baseline to
study end.
Methods of computational methodology
The fluctuation-based clustering (FBC) method consists of identifying clusters of patients
with similar patterns of lung function fluctuation by comparing each patient's empirical
distribution of daily lung function measurements recorded over a predetermined window of
observation. The FBC method has been described in detail elsewhere (26). In brief, this
approach consists of the following steps:
1. Quantification of similarity in lung function fluctuation between individuals; and
2. Grouping of individuals into clusters such that similarity between members of the same
cluster is strong and between different clusters is weak.
Furthermore, the FBC method includes a data-driven process for determining the tolerable
amount of missing measurements. It starts with the selection of a highly compliant subset of
patients (i.e. with a high number of performed lung function measurements, normally with at
least as many measurements as the 60th percentile of the overall distribution of the number
of lung function measurements from the entire analysis population), the so-called gold
standard. Then, within the gold standard, to quantify similarities in lung function
fluctuation between individuals, the distribution of normalised lung function values of a
given patient is compared with the distributions of all other patients in the gold standard.
This pairwise comparison is done using the earth mover's distance. A low value of earth
mover's distance indicates high similarity in lung function fluctuation between two
individuals. Patients are then grouped into clusters, such that the similarity between
members of the same clusters is strong while that between different clusters is weak, using
Ward's minimum-variance hierarchical clustering method. Following this, a cluster stability
analysis is performed to assess the stability of the clusters upon random data point removal.
The outcome of this stability analysis enables us to establish the minimum number of lung
function measurements required to ensure the clusters' stability. Those patients who
performed the minimum number of lung function measurements required but were not part of the
gold standard are now added to the gold standard. Finally, the cluster analysis procedure is
repeated with this extended gold standard to obtain the final clusters.
Monitoring plan Before the beginning of the investigation, the Sponsor will appoint an
independent monitor. Monitoring will be performed before, during the study and after the
study is completed in accordance with the ISO 141 55 GCP (Good Clinical Practice) standard.
Study conductance, source data, device accountability, adherence to the study protocol, Good
Clinical Practice, and regulatory requirements will be monitored in approximately 30-50% of
all included subjects.
Data to be monitored at site are e.g.
- Patient information and Informed Consent. That patient included in the study has signed
an Informed Consent and that no study procedures have begun before the date of the
consent.
- That inclusion and exclusion criteria are met for the included patients that are
monitored
- That all types of adverse events and serious adverse events, device related or not, as
well as, those that might have led to SAE shall be reported.
- Check that CRF data are entered in those subjects that are monitored
- Other CRF data will be source data verified against patient records according to a
detailed Monitoring Plan (that will contain details regarding the overall monitoring)
signed by the Sponsor prior to the start of the study. At least 20% of the patients will
have data in the CRFs 100% source data verified.
The monitor and possible authorities must be given direct access to source documents
(original documents, data and records). Direct access includes permission to examine,
analyse, verify and reproduce any record(s) and report(s) that are important to the
evaluation of the clinical investigation. In order to be able to do that, a written consent
from each patient should be obtained. Also a secrecy agreement between the monitor and the
person responsible for patient records at the study site will be signed.
Data management Procedures for data management will be implemented in collaboration with KTA
and conducted according to standards of GCP. Due to work load and the nature of the
intervention, neither health care personnel nor participants can be blinded to allocation. An
employee outside the research team will feed data into the computer in separate datasheets so
that the researchers can analyse data without having access to information about the
allocation.
Database cleaning and issuing data queries will be traceable and transparent with logs and
data is stored at Karolinska Institutet, department of Women's and Children's Health. Audit
will be performed once by certified CRO to assure quality, and to verify the monitoring
process and data as appropriate.
Paper case report forms (CRF) will be completed for each included patient in combination with
standardized health questionnaires at baseline, together with validated ACT at 3- and 6 or
later after study inclusion. Investigators will ensure completion and review of the CRF.
Investigators have personal responsibility for the accuracy and authenticity of all clinical
and other data that are entered into the CRF. Subjects included in the study will be
desidentified on the CRFs and subsequent reporting. A Subject Identification List, with cross
reference between the subjects identification number in the study and the subjects personal
data, will be kept looked away with the study documentation at the study centre. Monitors
will do on site monitoring to review the data in the CRFs versus source data and issue
queries to the Investigator to correct and clean data before CRF is sent to be entered into
the a database, stored and kept by the Sponsor. The study database will be reviewed and
cleaned prior to locking the study database and analysing the data, and a Clean File Report
will be issued. During the course of the study the investigational team, and the monitor will
have access to the study material, which will be kept in a locked place. Retention period for
data storage is 10 years. All study documentation will be saved as paper copies and
electronic files after the study has been published and reported. Participating investigators
/ Sponsor will be responsible for data collection, data processing and report writing.
Adverse events, adverse device effect and device deficiencies
DEFINITIONS of categories of adverse events from ISO/FDIS 14155:
Adverse Device Effect (ADE) is an adverse event related to the use of Asthmatuner:
NOTE 1- This includes any adverse event resulting from insufficiencies or inadequacies in the
instructions for use, the deployment, the implantation, the installation, the operation, or
any malfunction of the investigational medical device.
NOTE 2- This includes any event that is a result of a use error or intentional misuse.
Adverse Event (AE) is any untoward medical occurrence, unintended disease or injury or any
untoward clinical signs (including an abnormal laboratory finding) in subjects, users or
other persons whether or not related to the investigational medical device:
NOTE 1: This includes events related to the investigational device or the comparator.
NOTE 2: This includes events related to the procedures involved (any procedure in the
clinical investigation plan).
NOTE 3: For users or other persons this is restricted to events related to the
investigational medical device.
Device deficiency is inadequacy of a medical device related to its identity, quality,
durability, reliability, safety or performance, such as malfunction, misuse or use error and
inadequate labeling. Investigational medical device Asthmatuner will in this clinical
investigation be assessed for safety or performance.
Serious Adverse Device Effect (SADE) is adverse device effect that has resulted in any of the
consequences characteristic of a serious adverse event.
Serious Adverse Event (SAE) is an adverse event that:
1. led to a death,
2. led to a serious deterioration in health that either:
1. resulted in a life-threatening illness or injury, or
2. resulted in a permanent impairment of a body structure or a body function, or
3. required in-patient hospitalization or prolongation of existing hospitalization, or
4. resulted in medical or surgical intervention to prevent life threatening illness or
injury or permanent impairment to a body structure or a body function.
3. led to fetal distress, fetal death or a congenital abnormality or birth defect.
NOTE 1: This includes device deficiencies that might have led to a serious adverse event if
a) suitable action had not been taken or b) intervention had not been made or c) if
circumstances had been less fortunate. These are handled under the SAE reporting system.
NOTE 2: A planned hospitalization for pre-existing condition, or a procedure required by the
Clinical Investigation Plan, without a serious deterioration in health, is not considered to
be a serious adverse event.
Unanticipated Serious Adverse Device Effect is serious adverse device effect which by its
nature, incidence, severity or outcome has not been identified in the current version of the
risk analysis report.
NOTE: Anticipated: an effect which by its nature, incidence, severity or outcome has been
previously identified in the risk analysis report
Reportable events according 90/385/EEC and 93/42EEC. The following events are considered
reportable events based on definitions above:
- any SAE
- any Device Defieciency that might have led to a SAE if a) suitable action had not been
taken or b) intervention had not been made or c) if circumstances had been less
fortunate
- new findings/updates in relation to already reported events
Report by whom: Reportable events have to be reported by the sponsor of the clinical
investigation, which could be the manufacturer, the authorized representative or another
person or entity.
Report to whom: Reportable events must be reported at the same time to all NCA where the
clinical investigation has commenced using the summary tabulation featured in the Appendix 4.
A list of clinical investigation contact points within the NCA's is published at the
Commission's homepage
(http://ec.europa.eu/growth/sectors/medical-devices/contacts/index_en.htm), access date:
2016-02-22
Reporting timelines
The sponsor must report to the NCAs where the clinical investigation has commenced:
- a SAE which indicates an imminent risk of death, serious injury, or serious illness and
that requires prompt remedial action for other patients/subjects, users or other persons
or a new finding to is: immediately, but not later than 2 calender days after awareness
by sponsor of a new reportable event or of new information in relation with an already
reported event.
- any other reportable events as described in section "Reportable events according
90/385/EEC and 93/42EEC" or a new finiding/update to it: immediately, but not later than
7 calendar days following the date of awareness by the sponsor of new reportable event
or of new information in relation with an already reported event.
Report by the investigator to the sponsor The sponsor will implement and maintain a system
consisting of email address and phone number to sponsor, to ensure that the reporting of the
reportable events will be provided by the investigator to the sponsor in acceptable timely
conditions, but not later than within 3 calendar days after the occurrence of the event.
Reporting form The reporting form template for the summary SAE tabulation is given in the
Appendix 4 of this document. The table gives a cumulative overview of the reportable events
per clinical investigation and will be updated and transmitted to participating NCAs each
time a new reportable event or a new finding to an already reported event is to be reported.
More detailed information has to be provided on request of an NCA.
The sponsor shall identify the new/updated information in the status column of the tabular
form featured in the Appendix 4 as:
a = added = new reportable event; m = modified = new finding/update to an already reported
event; u = unchanged. Changes in a line should be highlighted in bold and/or color in the
respective column. English is the recommended language for the reporting form. The report
should be sent by email.
Preexisting conditions and unanticipated adverse device effects 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. 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)
Contact details for reporting serious AE:
1. Björn Nordlund, RN and PhD, Department for Women's and Children's Health, Karolinska
Institutet. Phone: +46 703234414
2. Henrik Ljungberg, MD and PhD, Astrid Lindgren Children's Hospital, Lung-Allergy
Department and Department for Women's and Children's Health, Karolinska Institutet.
Phone: +46 706628642 QUALITATIVE STUDY - PROCEDURES Before the introduction of
Asthmatuner, caregivers will be interviewed focusing on their expectations. After at
least 6 months, caregivers and patients will be interviewed with regard to how they
experienced the use of Asthmatuner. All caregivers within Tiohundra's primary care that
work with asthma/COPD patients are asked about participation in the interview study. The
patient selection for the qualitative part is done among adult patients with asthma
diagnosis who are randomized to use Asthmatuner. They will have mixed disease history,
sex and age for maximum selection width.
For participation in the qualitative study, the participants will be informed that all
participation is voluntary and can be discontinued when and without any specific reason. The
participants who are patients will be asked at the primary care center in connection with the
planned visit, or be contacted via letter for participation in the interview. The responsible
doctor, nurse or researcher obtains informed written consent after the research subjects have
received sufficient time for consideration. When the caregivers are informed about the study,
participation in the qualitative study is offered. Information is then given that all
participation is voluntary and it can be interrupted at any time without specific reason and
the consent is then signed before the interview is carried out. Signed consent is saved in
study folder and a copy is submitted to the participant.
Sound recordings will be made during the interviews and transcribed afterwards. The
transcribed interviews will be provided with information on time, place and a serial number
for informants and researchers. No personal data is collected together with the interviews.
Archiving of interview data for the qualitative part takes place on digital medium according
to current security procedures that ensure that only authorized researchers have access to
the material. Recorded material will be unidentified and stored for 10 years as digital audio
files in our digital archive. Then the material will be destroyed.
