A Clinical Study to Evaluate the Effect of the Connected Inhaler System (CIS) on Adherence to Maintenance Therapy in Poorly Controlled Asthmatic Subjects

Study Overview
=================
Brief Summary
-----------------
GlaxoSmithKline (GSK) in collaboration with Propeller Health has developed a sensor, which can clip on to the ELLIPTA® dry powder inhaler (DPI) and monitor the time and date that the ELLIPTA DPI cover is fully opened and closed. Additionally, a sensor will be attached to the rescue medication metered dose inhaler (MDI). The data from both sensors will be fed back to the subject via an application (app) on smart phone and will be reviewed by the subject's health care professional (HCP) via an online dashboard. The sensors, app, dashboard and systems to provide data comprise the CIS. This study will be the first to evaluate the effect of CIS on adherence to maintenance therapy in subjects with uncontrolled asthma. This is an open-label, randomized, parallel group study in asthmatic subjects currently on a fixed dose inhaled corticosteroid (ICS)/long-acting beta 2 agonist (LABA) maintenance therapy. Eligible subjects will receive RELVAR®/BREO® maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI with sensors attached to both inhalers during the run-in period, which may last for up to 3 months. Eligible subjects will then be randomized into five treatment arms depending on whether the data, from RELVAR/BREO ELLIPTA or RELVAR/BREO ELLIPTA and salbutamol MDI, is fed back to the subject or subject and HCP, or not at all. The treatment period for the study is approximately 6 months and there will be a follow-up period one week post last visit. The total duration of a subject in the study will be approximately 9 months. RELVAR, BREO and ELLIPTA are registered trademarks of GlaxoSmithKline group of companies.

Official Title
-----------------
An Open Label, Randomised, Parallel Group Clinical Study to Evaluate the Effect of the Connected Inhaler System (CIS) on Adherence to Relvar/Breo ELLIPTA Therapy, in Asthmatic Subjects With Poor Control

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: RELVAR/BREO
* Drug: Salbutamol
* Device: Smart phone app
* Device: HCP Dashboard
* Device: Sensors


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects aged 18 years or older, at the time of signing the informed consent. Subjects with documented physician diagnosis of asthma as their primary respiratory disease. ACT score <20 at screening visit. Non-smokers (never smoked or not smoking for >6 months with <10 pack years history (Pack years = [cigarettes per day smoked/20] multiplied by number of years smoked). Male or female subjects will be included. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: (i) Not a woman of childbearing potential (WOCBP). (ii) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 5 days] after the last dose of study treatment. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and protocol. Subject understands and is willing, able, and likely to comply with study procedures and restrictions. Subject must be able to read in a language supported by the smart phone app in their region. Subject must have been on maintenance therapy (Fixed dose combination ICS/LABA) for 3 months, cannot have changed dose in the month prior to screening and be able to change to an equivalent dose of RELVAR/BREO for the duration of the study. Other background asthma medication such as anti-leukotrienes and oral corticosteroids are permitted provided the dose has been stable for 1 month prior to screening. Subject must be able to change to Salbutamol/Albuterol MDI rescue for the duration of the study and judged capable of withholding albuterol/salbutamol for at least 6 hours prior to study visits. Subject must have their own Android or iPhone operating system (IOS) smart phone and a data package suitable for the installation and running of the app and sending and receiving data. Data used by the CIS is approximately 1 megabyte (MB) per month as a maximum; this is less data than a 1 minute video streamed from YouTube (2MB). Subjects must be willing and able to download the app on their personal smart phone and keep it turned on for the duration of the study. This will also require Bluetooth to be turned on for duration of the study. Subjects will also have to turn on mobile data for the app for the duration of study; unless travelling and when extra data roaming costs could be incurred. Inclusion criteria for randomization: ACT score <20 at randomization visit (visit 2). Exclusion Criteria: Subjects with a known or suspected alcohol or drug abuse which in the opinion of the investigator could interfere with the subject's proper completion of the protocol requirement. History of life threatening asthma: Defined as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures within the last 6 months. A lower respiratory tract infection within 7 days of the screening visit. Concurrent diagnosis of chronic obstructive pulmonary disease (COPD) or other respiratory disorders including active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases. History of hypersensitivity/intolerance to any components of the study inhalers (example, lactose, magnesium stearate). In addition, subjects with a history of severe milk protein allergy that, in the opinion of the study physician, contraindicates participation will also be excluded. Historical or current evidence of clinically significant or rapidly progressing or unstable cardiovascular, neurological, cardiovascular, neurological, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the analysis if the disease/condition exacerbated during the study. Subjects who have ever received treatment with biological based therapy example, omalizumab, mepolizumab, for asthma. Subjects who have received an investigational drug and/or medical device within 30 days of entry into this study (Screening), or within five drug half-lives of the investigational drug, whichever is longer. A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, sub-investigator, study coordinator, employee of the participating investigator, or any family member of a Propeller Health employee.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible subjects will receive RELVAR/BREO maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI. Clip-on sensors will be attached to both inhalers which will provide data on maintenance therapy and rescue medication use to the subjects and their HCP. Subjects will be randomized into five treatment arms in a ratio of 1:1:1:1:1 depending on whether the data, from RELVAR/BREO ELLIPTA or RELVAR/BREO ELLIPTA and salbutamol MDI, is fed back to the subject or subject and HCP, or not at all.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Data on Maintenance use supplied to Subject and HCP<br>Eligible subjects will receive RELVAR/BREO maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI with sensors attached to both inhalers. Information from sensor attached to RELVAR/BREO ELLIPTA will be fed back to the subject via an app on smart phone and to the subject's HCP via an online dashboard. | Drug: RELVAR/BREO<br>* RELVAR/BREO will be available at doses of 100/25 micrograms (µg) and 200/25 µg to be administered via ELLIPTA DPI. Subjects will be administered one inhalation of RELVAR/BREO once daily.<br>Drug: Salbutamol<br>* Salbutamol will be available at a dose of 100 µg to be administered via MDI. Subjects will be administered salbutamol as and when required.<br>Device: Smart phone app<br>* Subjects will be required to download an app associated with sensor on their smartphone. The sensors attached to the inhalers will be connected to the smartphone via Bluetooth.<br>Device: HCP Dashboard<br>* The information from sensors will be reviewed by the HCP via an online dashboard.<br>Device: Sensors<br>* Clip-on sensors will be fitted to electronically record the actuation data.<br>|
| Experimental: Data on Maintenance use supplied to Subject<br>Eligible subjects will receive RELVAR/BREO maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI with sensors attached to both inhalers. Information from sensor attached to RELVAR/BREO ELLIPTA will be fed back to the subject via an app on smart phone. | Drug: RELVAR/BREO<br>* RELVAR/BREO will be available at doses of 100/25 micrograms (µg) and 200/25 µg to be administered via ELLIPTA DPI. Subjects will be administered one inhalation of RELVAR/BREO once daily.<br>Drug: Salbutamol<br>* Salbutamol will be available at a dose of 100 µg to be administered via MDI. Subjects will be administered salbutamol as and when required.<br>Device: Smart phone app<br>* Subjects will be required to download an app associated with sensor on their smartphone. The sensors attached to the inhalers will be connected to the smartphone via Bluetooth.<br>Device: Sensors<br>* Clip-on sensors will be fitted to electronically record the actuation data.<br>|
| Experimental: Data on Maintenance and Rescue use supplied to Subject and HCP<br>Eligible subjects will receive RELVAR/BREO maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI with sensors attached to both inhalers. Information from sensors attached to RELVAR/BREO ELLIPTA and salbutamol MDI will be fed back to both subject and HCP. The data will be fed back to the subject through an app and to HCP through an online dashboard. | Drug: RELVAR/BREO<br>* RELVAR/BREO will be available at doses of 100/25 micrograms (µg) and 200/25 µg to be administered via ELLIPTA DPI. Subjects will be administered one inhalation of RELVAR/BREO once daily.<br>Drug: Salbutamol<br>* Salbutamol will be available at a dose of 100 µg to be administered via MDI. Subjects will be administered salbutamol as and when required.<br>Device: Smart phone app<br>* Subjects will be required to download an app associated with sensor on their smartphone. The sensors attached to the inhalers will be connected to the smartphone via Bluetooth.<br>Device: HCP Dashboard<br>* The information from sensors will be reviewed by the HCP via an online dashboard.<br>Device: Sensors<br>* Clip-on sensors will be fitted to electronically record the actuation data.<br>|
| Experimental: Data on Maintenance and Rescue use supplied to Subject<br>Eligible subjects will receive RELVAR/BREO maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI with sensors attached to both inhalers. Information from sensors attached to RELVAR/BREO ELLIPTA and salbutamol MDI will be fed back to subject through an app. | Drug: RELVAR/BREO<br>* RELVAR/BREO will be available at doses of 100/25 micrograms (µg) and 200/25 µg to be administered via ELLIPTA DPI. Subjects will be administered one inhalation of RELVAR/BREO once daily.<br>Drug: Salbutamol<br>* Salbutamol will be available at a dose of 100 µg to be administered via MDI. Subjects will be administered salbutamol as and when required.<br>Device: Smart phone app<br>* Subjects will be required to download an app associated with sensor on their smartphone. The sensors attached to the inhalers will be connected to the smartphone via Bluetooth.<br>Device: Sensors<br>* Clip-on sensors will be fitted to electronically record the actuation data.<br>|
| Active Comparator: No data supplied to Subject or HCP<br>Eligible subjects will receive RELVAR/BREO maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI with sensors attached to both inhalers. Subjects will be provided with a home hub through which their data will be uploaded during the study but the subjects and their HCP will not be able to view the data. | Drug: RELVAR/BREO<br>* RELVAR/BREO will be available at doses of 100/25 micrograms (µg) and 200/25 µg to be administered via ELLIPTA DPI. Subjects will be administered one inhalation of RELVAR/BREO once daily.<br>Drug: Salbutamol<br>* Salbutamol will be available at a dose of 100 µg to be administered via MDI. Subjects will be administered salbutamol as and when required.<br>Device: Sensors<br>* Clip-on sensors will be fitted to electronically record the actuation data.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of ELLIPTA Doses Taken (Daily Adherence) Between Month 4 and Month 6 as Determined by the Maintenance Sensor for Arms; (Cohort 1: Data on Maintenance Use Supplied to Participant and HCP andCohort 5: no Data Supplied to Participant or HCP) | Daily adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA, within a 24-hour period, starting at 12.00 anti-meridiem (a.m.) each day of the treatment period. The percentage of ELLIPTA doses taken were determined by the clip-on sensor attached to ELLIPTA, which records the time and date when the ELLIPTA cover was opened and closed. Analysis was carried out by Analysis of Covariance (ANCOVA) model. Least Square mean percentage of ELLIPTA doses taken (daily adherence) between Months 4 and 6 was determined by the maintenance sensor daily adherence over the last three months of the study period (between months 4 to 6). The daily adherence to ELLIPTA maintenance therapy when both the participant and the HCP were supplied with data from the maintenance sensor (Cohort 1) versus no data supplied to the participant or HCP (Cohort 5) is summarized. | Month 4 to Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of ELLIPTA Doses Taken (Daily Adherence) Between Month 4 and Month 6 as Determined by the Maintenance Sensor | Daily adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA, within a 24-hour period, starting at 12.00 a.m. each day of the treatment period. The percentage of ELLIPTA doses taken were determined by the clip-on sensor attached to ELLIPTA, which records the time and date when the ELLIPTA cover was opened and closed. Least Square mean percentage of ELLIPTA doses taken (daily adherence) between Months 4 and 6 was determined by the maintenance sensor daily adherence over the last three months of the study period (between months 4 to 6). The effect on daily adherence to maintenance therapy when maintenance data was only supplied to participants (Cohort 2), rescue and maintenance data were supplied to participant and HCP (Cohort 3), and rescue and maintenance data only supplied to participant (Cohort 4) versus no data supplied to the participant or HCP (Cohort 5) is summarized. | Month 4 to Month 6 | 
| Percentage of ELLIPTA Doses Taken (Daily Adherence) Between Month 1 and Month 3 as Determined by the Maintenance Sensor | Daily adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA, within a 24-hour period, starting at 12.00 a.m. each day of the treatment period. The percentage of ELLIPTA doses taken were determined by the clip-on sensor attached to ELLIPTA, which records the time and date when the ELLIPTA cover was opened and closed. Least Square mean percentage of ELLIPTA doses taken (daily adherence) between Months 1 and 3 was determined by the maintenance sensor daily adherence. The effect on daily adherence to maintenance therapy when maintenance data was supplied to both the participant and the HCP (Cohort 1), maintenance data was only supplied to participants (Cohort 2), rescue and maintenance data were supplied to participant and HCP (Cohort 3), and rescue and maintenance data only supplied to participant (Cohort 4) versus no data supplied to the participant or HCP (Cohort 5) is summarized. | Month 1 to Month 3 | 
| Percentage of ELLIPTA Doses Taken (Daily Adherence) Between Month 1 and Month 6 as Determined by the Maintenance Sensor | Daily adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA, within a 24-hour period, starting at 12.00 a.m. each day of the treatment period. The percentage of ELLIPTA doses taken were determined by the clip-on sensor attached to ELLIPTA, which records the time and date when the ELLIPTA cover was opened and closed. Least Square mean percentage of ELLIPTA doses taken (daily adherence) between Months 1 and 6 was determined by the maintenance sensor daily adherence. The effect on daily adherence to maintenance therapy when maintenance data was supplied to both the participant and the HCP (Cohort 1), maintenance data was only supplied to participants (Cohort 2), rescue and maintenance data were supplied to participant and HCP (Cohort 3), and rescue and maintenance data only supplied to participant (Cohort 4) versus no data supplied to the participant or HCP (Cohort 5) is summarized. | Month 1 to Month 6 | 
| Percentage of Rescue Free Days Between Month 4 and Month 6 as Determined by the Rescue Medication Sensor | Data for rescue medication use was collected by the clip-on sensor for salbutamol MDI which records time and date when the MDI was actuated. Percentage of rescue free days were determined by the rescue sensor records of date, time and number of inhaler actuations. Least Square mean percentage of rescue free days between Months 4 and 6 when maintenance data was supplied to both the participant and the HCP (Cohort 1); maintenance data was only supplied to participants (Cohort 2); rescue and maintenance data were supplied to participant and HCP (Cohort 3) and rescue and maintenance data only supplied to participant (Cohort 4) versus no data supplied to the participant or HCP (Cohort 5) is summarized. | Month 4 to Month 6 | 
| Number of Doses of Rescue Medication Use Between Month 4 and Month 6 as Determined by the Rescue Medication Sensor | Data for rescue medication use was collected by the clip-on sensor for salbutamol MDI which records time and date when the MDI was actuated. Total rescue use was determined by the rescue sensor records of date, time and number of inhaler actuations. The mean number of doses of rescue medicines between Months 4 and 6 when maintenance data was supplied to both the participant and the HCP (Cohort 1); maintenance data was only supplied to participants (Cohort 2); rescue and maintenance data were supplied to participant and HCP (Cohort 3) and rescue and maintenance data only supplied to participant (Cohort 4) versus no data supplied to the participant or HCP (Cohort 5) is summarized. | Month 4 to Month 6 | 
| Change From Baseline in Asthma Control Test (ACT) Total Score | The ACT is a validated self-completed questionnaire utilizing 5 questions to assess asthma control on a 5-point categorical scale ranging from 1 (not controlled at all) to 5 (completely controlled). Total score is calculated as the sum of the scores from the 5 questions and can range from 5 to 25, with higher scores indicating better control. An ACT total score of 5 to 19 suggests that the participant's asthma is unlikely to be well controlled, whilst a score of 20 to 25 suggests that the participant's asthma is likely to be well controlled. Baseline value was the latest assessment prior to randomization (Day 1, pre-dose). Change from Baseline was calculated as post-dose visit value minus the Baseline value. | Baseline and Month 6 | 
| Percentage of Participants Attaining Asthma Control (Percentage of Participants With an ACT Total Score >=20) at Month 6 | Percentage of participants attaining asthma control was defined as participants with an ACT total score >=20 at Month 6. The ACT is a validated self-completed questionnaire utilizing 5 questions to assess asthma control on a 5-point categorical scale ranging from 1 (not controlled at all) to 5 (completely controlled). Total score is calculated as the sum of the scores from the 5 questions and can range from 5 to 25, with higher scores indicating better control. An ACT total score of 5 to 19 suggests that the participant's asthma is unlikely to be well controlled, whilst a score of 20 to 25 suggests that the participant's asthma is likely to be well controlled. Percentage of participants who attained asthma control at Month 6 is presented. | Month 6 | 
| Percentage of Participants With an Increase From Baseline >=3 in ACT Total Score at Month 6 | The ACT is a validated self-completed questionnaire utilizing 5 questions to assess asthma control on a 5-point categorical scale ranging from 1 (not controlled at all) to 5 (completely controlled). Total score is calculated as the sum of the scores from the 5 questions and can range from 5 to 25, with higher scores indicating better control. An ACT total score of 5 to 19 suggests that the participant's asthma is unlikely to be well controlled, whilst a score of 20 to 25 suggests that the participant's asthma is likely to be well controlled. Baseline value was the latest assessment prior to randomization (Day 1, pre-dose). Percentage of participants with an increase from Baseline >=3 in ACT total score at Month 6 is presented. | Baseline and Month 6 | 
| Percentage of Participants Who Have Either an ACT Total Score of >=20 and/or an Increase From Baseline >=3 in ACT Total Score at Month 6 | The ACT is a validated self-completed questionnaire utilizing 5 questions to assess asthma control on a 5-point categorical scale ranging from 1 (not controlled at all) to 5 (completely controlled). Total score is calculated as the sum of the scores from the 5 questions and can range from 5 to 25, with higher scores indicating better control. Baseline value was the latest assessment prior to randomization (Day 1, pre-dose). Percentage of participants who had either an ACT total score of >=20 and/or an increase from Baseline >=3 in ACT total score at Month 6 is presented. | Baseline and Month 6 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Connected Inhaler System, Metered Dose Inhaler, ELLIPTA, RELVAR/BREO, Dry Powder Inhaler, Salbutamol, Asthma