2016N286379_03 CONFIDENTIAL GlaxoSmithKline group of companies 204710

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TITLE PAGE

Division: Worldwide Development Information Type: Worldwide Epidemiology Study Protocol

Title: A Multinational, Single Arm, Observational Study to Evaluate the Real-world Effectiveness and Pattern of Use of Mepolizumab in Patients with Severe Eosinophilic Asthma (204710; the REALITI-A study).

Short Title: Compound Number:

REAL world effectiveness of mepolizumab In paTIent care – Asthma (REALITI-A)

SB-240563

Development Phase IV

Effective Date: 06-NOV-2017

Subject: Real World Effectiveness

Author(s):

.

Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

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MARKETING AUTHORISATION HOLDER(S)

Marketing authorisation holder(s) (MAHs)

GlaxoSmithKline Research & Development Limited, 980 Great West Road, Brentford, Middlesex, TW8 9GS, UK

MAH contact person Global Regulatory Affairs Lead, Respiratory Therapeutic Group, Global Regulatory Affairs, GlaxoSmithKline Research

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TABLE OF CONTENTS

PAGE

1. LIST OF ABBREVIATIONS ...................................................................................... 5

2. RESPONSIBLE PARTIES ........................................................................................ 7

3. ABSTRACT ............................................................................................................ 12

4. AMENDMENTS AND UPDATES ............................................................................ 14

5. MILESTONES ........................................................................................................ 15

6. RATIONALE AND BACKGROUND ........................................................................ 15 6.1. Background ................................................................................................ 15 6.2. Rationale .................................................................................................... 16

7. RESEARCH QUESTION AND OBJECTIVE(S) ...................................................... 17

8. RESEARCH METHODS ......................................................................................... 19 8.1. Study Design .............................................................................................. 19

8.1.1. Use of Interactive Digital Media ................................................... 22 8.2. Study Population and Setting ...................................................................... 24 8.3. Variables..................................................................................................... 25

8.3.1. Exposure definitions .................................................................... 25 8.3.2. Outcome definitions ..................................................................... 26

8.3.2.1. Summary of Patient Characteristics ............................ 26 8.3.2.2. Primary outcome: Clinically Significant Asthma

exacerbations ............................................................. 26 8.3.2.3. Secondary outcomes .................................................. 27 8.3.2.4. Other outcomes .......................................................... 30 8.3.2.5. Exploratory Outcomes ................................................ 32 8.3.2.6. Confounders and effect modifiers ............................... 33

8.4. Data sources .............................................................................................. 33 8.5. Study size ................................................................................................... 33 8.6. Sample size assumptions ........................................................................... 33 8.7. Sample Size Sensitivity ............................................................................... 33 8.8. Sample size review ..................................................................................... 37 8.9. Data management ...................................................................................... 37 8.10. Data analysis .............................................................................................. 37

8.10.1. Analysis populations .................................................................... 37 8.10.2. Protocol Deviations ...................................................................... 37 8.10.3. Summary of patient characteristics .............................................. 38 8.10.4. Interim analysis ............................................................................ 38 8.10.5. Primary analysis .......................................................................... 38 8.10.6. Secondary analyses .................................................................... 39 8.10.7. Other analyses ............................................................................ 41 8.10.8. Exploratory analyses ................................................................... 41 8.10.9. Country Based Analyses .............................................................. 41

8.11. Quality control and Quality Assurance ........................................................ 41 8.12. Limitations of the research methods ........................................................... 41

8.12.1. Study closure/uninterpretability of results ..................................... 42

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9. PROTECTION OF HUMAN SUBJECTS ................................................................ 42 9.1. Ethical approval and subject consent .......................................................... 42 9.2. Subject confidentiality ................................................................................. 43

10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS .......................................................................................................... 43 10.1. Medical Device Incidents (Including Malfunctions) ...................................... 44

10.1.1. Medical Device Incident Definition ............................................... 44 10.1.2. Detecting and Reporting Medical Device Incidents ...................... 45 10.1.3. Documenting Medical Device Incidents ....................................... 46 10.1.4. Follow-up of Medical Device Incidents ......................................... 46 10.1.5. Regulatory Reporting Requirements for Medical Device

Incidents ...................................................................................... 46

11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .............................................................................................................. 48

12. REFERENCES ....................................................................................................... 49

13. APPENDICES ........................................................................................................ 51 13.1. Appendix 1 Time and Events Table ............................................................ 51 13.2. Appendix 2: Protocol Changes .................................................................... 54

13.2.1. Amendment 01 ............................................................................ 54 13.2.2. Amendment 02 ............................................................................ 56 13.2.3. Amendment 03 ............................................................................ 58

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1. LIST OF ABBREVIATIONS

ACQ Asthma Control Questionnaire ACT Asthma Control Test AE Adverse Event Anti-IgE Anti-Immunoglobulin E APG As per Local Guidelines APL As per Label app Application ASE All Subjects Enrolled AT As Treated ATS American Thoracic Society eCRF Electronic Case Report Form ED Emergency Department ERS European Respiratory Society ETT Exposed to Treatment FeNO Fractional nitric oxide concentration in exhaled breath FEV1 Forced expiratory volume in 1 second FVC Forced Vital Capacity GINA Global Initiative for Asthma GSK GlaxoSmithKline HCPs Healthcare Providers ICF Informed Consent Form ICH International Conference on Harmonization ICS Inhaled Corticosteroids IEC Independent Ethics Committee IgE Immunoglobulin E IgG Immunoglobulin G IL-5 Interleukin-5 IL-5 Interleukin-5 IMI Innovative Medicine Initiative IV Intravenous L Litre LABA Long-Acting Beta2-Agonists LAMA Long-acting muscarinic antagonist LTRA Leukotriene receptor antagonist MAH Marketing authorisation holder mg Milligrams MPR Medication Possession Ratio OCS Oral Corticosteroids PDC Proportion of Days Covered PDE4 phosphodiesterase type 4 PRO Patient Reported Outcome RAP Reporting and Analysis Plan RCTs Randomised Controlled Trials SABA Short-acting beta2-agonist

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SABD Short-acting bronchodilator SAE Serious Adverse Event Th2 Type 2 T helper cells WPAI Work Productivity and Activity Impairment Questionnaire yr Year

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

NUCALA Cinqair Xolair

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2. RESPONSIBLE PARTIES

Sponsor

The Marketing Authorisation Holder (MAH) will serve as the sponsor of this study. It is

the responsibility of the MAH to ensure proper monitoring of the study and compliance

with all applicable regulatory guidelines and laws.

Primary contact:

Global Regulatory Affairs Lead

Respiratory Therapeutic Group

Global Regulatory Affairs

GlaxoSmithKline Research & Development Ltd.

Study Conduct

The Study sponsor has contracted with PPD to conduct the study.

PPD contact:

Sr. Project Manager Medical Affairs Research Operations

Andrew Roddam

Digitally signed by Andrew Roddam DN: cn=Andrew Roddam, o=GSK, ou=RWE, email=andrew.w.roddam@gsk.com, c=GB Date: 2017.11.06 09:45:48 Z

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SPONSOR INFORMATION PAGE

Sponsor Legal Registered Address:

GlaxoSmithKline Research & Development Limited 980 Great West Road Brentford Middlesex, TW8 9GS UK

Sponsor Contact Address

GlaxoSmithKline Research & Development Limited Iron Bridge Road Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK Telephone: +44 (0)208 990 9000

In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate Company (or designee). If applicable, the details of the alternative Sponsor and contact person in the territory will be provided to the relevant regulatory authority as part of the clinical trial application.

Sponsor Medical Monitor Contact Information:

Primary Medical monitor: , MD, FCCP (Medical Director, Pharmacovigilance PPD)

Email: Phone

Secondary Medical monitor MD, PhD (Medical Director, Respiratory Franchise, GSK)

Email: Tel: Mobile:

Sponsor Serious Adverse Events (SAE) Contact Information: Medical monitors as above.

Regulatory Agency Identifying Number(s): N/A

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INVESTIGATOR PROTOCOL AGREEMENT PAGE

• I confirm agreement to conduct the study in compliance with the protocol.

• I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study.

• I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study.

Investigator Name: _____________________________

Investigator Signature Date

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3. ABSTRACT

Title

A Multinational, Single Arm, Observational Study to Evaluate the Real-world Effectiveness and Pattern of Use of Mepolizumab in Patients with Severe Eosinophilic Asthma (204710).

Rationale and Background

Although the majority of asthma patients can be controlled with standard maintenance therapies, there is still a substantial portion of patients whose asthma is uncontrolled resulting in a significant public health problem [Demoly, 2012; Colice, 2012].

Some of these patients with uncontrolled asthma may be difficult to treat due to inadequate or inappropriate treatment, persistent problems with adherence or co-morbidities. However, there is a subset of patients who remain uncontrolled despite optimised medical condition.

Mepolizumab (NUCALA™) has recently been launched for severe eosinophilic asthma. The aim of this study is to evaluate effectiveness of NUCALA and to describe the use of NUCALA in real world clinical practice to provide a more complete understanding of the value of NUCALA for patients with severe eosinophilic asthma.

Objective(s)

Primary objective:

• To compare the rates of clinically significant asthma exacerbations in the pre-exposure and the 12-month post-exposure period with NUCALA treatment. A clinically significant asthma exacerbation is defined as deterioration in asthma requiring (1) use of systemic corticosteroids and/or (2) emergency department (ED) visit and/or hospital admission.

Secondary objectives:

• Determine patterns of NUCALA usage including adherence/persistence, duration of therapy, discontinuation and reasons for discontinuation.

• To compare the rates of clinically significant asthma exacerbations in the pre-exposure and the 24-month post-exposure period with NUCALA.

• Determine and compare the rate of asthma exacerbations requiring an ED visit or hospitalisation in the pre-exposure and the 12-month and 24-month post-exposure period with NUCALA.

• Determine and compare the rate of asthma exacerbations requiring hospitalisation in the pre-exposure and the 12-month and 24-month post-exposure period with NUCALA.

• Describe change from baseline in Oral Corticosteroids (OCS) dose during the post-exposure period among participants on maintenance OCS.

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• Describe asthma related healthcare resource utilization including count of hospital admissions, ED visits, visits to healthcare providers (HCPs), and prescription medication utilisation for asthma.

• Determine and compare the level of asthma control as measured by an ACQ-5 at baseline and the 12- and 24-month post-exposure periods.

• Characterise and compare patterns of work status, productivity and absenteeism at baseline and the 12 and 24-month post-exposure periods as measured by WPAI

Study Design

This is a prospective, self-controlled cohort study conducted to collect observational data from participants with a clinical diagnosis of severe eosinophilic asthma. To reflect the real world nature of the study, all eligible participants who have a physician decision to initiate NUCALA treatment, and are consented for the study, will be observed. The assignment of a patient to a particular therapeutic strategy is not decided in advance by the study protocol, but is determined by the usual practice of medicine, and the decision to prescribe a particular drug is clearly dissociated from the decision to include the patient in the study. No visits should be scheduled for this study. Data will be collected at the patient’s usual healthcare visit.

Data Sources

Data will be collected by entry into an electronic Case Report Form (eCRF). In addition to this in some countries, which have suitable electronic health record systems (EHRs) or claims data , this will be supplemented with data directly from EHRs. The method of data collection for the primary outcome will be standardised across countries.

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Supplementary exploratory data based on participant’s experience with NUCALA will be collected using interactive digital media, including a smartphone application (app) and a wearable activity monitor.

4. AMENDMENTS AND UPDATES

GlaxoSmithKline Document Number

Date Version

2016N286379_00 2016-JUN-08 Original

2016N286379_01 2016-SEPT-09 Amendment No. 1

The purpose of the amendment is to include wording mandated by Spanish regulatory authorities and to clarify the observational nature of the study. Defined study visits have been removed and wording added to strengthen the request for data collection at usual asthma healthcare visits. Additionally, questionnaires may now be offered to participants for completion at the time of enrolment and at an asthma healthcare visit unrelated to NUCALA administration. Other protocol updates include reference to the collection of sputum cell counts and reference to the use of administrative claims data (included for clarity). The Time and Events Table has been updated to reflect these changes. Details of US specific enrolment activities have also been added.

This amendment was completed prior to IRB and ethics approval.

2016N286379_02 2016-NOV-08 Amendment No. 2

The purpose of this amendment is to remove wording relating to collection of supplementary exploratory data based on participant’s experience with NUCALA using interactive digital media including an application for mobile devices and a wearable activity monitor. The correction of various typographical errors has also been performed. This amendment was completed prior to IRB and ethics approval.

2016N286379_03 2017-NOV-06 Amendment No. 3

The following substantive changes have been made:

• Addition of REALITI-A as study name and corresponding short title • Inclusion of supplementary exploratory outcomes based on participants’

experience with NUCALA collected using an interactive study specific smartphone app and a wearable activity monitor. Associated updates to Data Management and subjection confidentiality have been added.

• Inclusion of a Participant Study Experience Questionnaire to assess participant satisfaction with their study experience and the digital media components.

• Clarification that ACQ-5 and WPAI questionnaires should not be offered at future assessments if they have not been completed at either enrolment or index.

• Analysis populations have been updated to reduce complexity and are limited to populations that are defined at index. Sub-groups will be described in the RAP.

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• Additional section on Protocol Deviations added. • Inclusion of the potential for additional interim analyses to be performed to meet

individual country evidence requirements. • AE and SAE definitions added and timelines for reporting of non-serious AEs

explicitly attributed to any GSK product have been clarified . • Instructions on the identification and reporting of Medical Device Incidents

(including malfunctions) have been added in relation to the inclusion of the activity monitor in the study.

• The Time & Events table has been updated to include the offer of the smartphone app and the activity monitor, and the include of the Patient Study Experience Questionnaire. The opportunity has been taken to make additional updates to the Time & Events table to aid clarity.

Additional administrative and minor typographical/editorial changes have also been made and are not listed.

5. MILESTONES

Milestone Planned date Start of data collection 2016

Primary Effectiveness Outcome 2022 Final report of study results 2024

6. RATIONALE AND BACKGROUND

6.1. Background

Although the majority of asthma patients can be controlled with currently available medications, there is still a substantial proportion of patients whose asthma is uncontrolled resulting in a significant public health problem [Demoly, 2012; Colice, 2012]. Some of these patients with uncontrolled asthma may be difficult to treat due to inadequate or inappropriate treatment, persistent problems with adherence or co-morbidities. However, there is a subset of patients who remain uncontrolled despite optimised medical treatment.

The European Respiratory Society (ERS) and the American Thoracic Society (ATS), as part of a joint task force defined severe asthma as follows: asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy [Chung, 2014]. From the total asthma population, 5% to 10% are estimated to have severe asthma [Chung, 2014]. Patients with severe asthma have a greater need for medications and healthcare resource use. In addition, severe asthma patients are twice as likely to experience impairments in everyday life compared with patients with mild or moderate disease [Chen, 2008]. As such, morbidity and

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mortality in patients with severe asthma constitutes more than 50% of the total healthcare costs for asthma [Hartley, 2014].

Systemic corticosteroids are effective for controlling symptoms and reducing asthma exacerbations. However, the frequent, or regular, use of corticosteroids may be associated with serious detrimental short term effects such as an impact on mood state; effects of long term use may include osteoporosis and adrenal suppression particularly when used at high doses for prolonged period [Liu, 2013]. It is, therefore, clinically important to minimise the use of systemic corticosteroids.

Severe asthma is a heterogeneous condition, characterised by different clinical and physiological features [Wener, 2013]. Phenotyping of patients with severe asthma is increasingly important to enable the use of targeted therapies in addition to conventional therapies such as high-dose ICS and/or long-acting beta2 agonist (LABA) therapies. Asthma phenotypes were initially focused on clinical characteristics, but they are now evolving to link biology and inflammatory mechanisms. Inflammation in severe asthma can be categorised as eosinophilic or neutrophilic [Chung, 2014]. Patients with the eosinophilic phenotype have been shown to have greater airway remodelling and more frequent exacerbations [Wenzel, 2009; Bel, 2011]. The number of eosinophils tends to correlate with asthma severity and increased exacerbations [Romagnoli, 2002]. A strategy aimed specifically at eosinophilic inflammation may have particular benefit in patients with severe asthma and frequent exacerbations.

Eosinophilic inflammation is likely to have a Type 2 T helper cells (Th2) immune component; however, eosinophilic asthma may occur in allergic and non-allergic patients [Brusselle, 2013]. Eosinophil recruitment and activation is triggered by specific stimuli, most notably the interleukin-5 (IL-5) [Rosenberg, 2013]. Mepolizumab is a humanised, anti-IL5 antibody (immunoglobulin G (IgG) Kappa) that binds with high affinity to human IL-5 and blocks its binding to and activation of the IL-5 receptor present on eosinophils and basophils [Patterson, 2015].

The clinical utility of mepolizumab (NUCALA™) in patients with asthma has been demonstrated in randomised controlled trials (RCTs). When added to standard of care with high dose ICS and an additional controller, NUCALA treated patients with severe eosinophilic asthma, have shown significantly reduced rates of severe asthma exacerbations and have clinically meaningful improvement in health related quality of life when compared with patients on standard of care alone [Ortega, 2014]. In asthma patients with maintenance use of OCS, NUCALA reduced the need for OCS while maintaining asthma control [Bel, 2014].

6.2. Rationale

The high internal validity of RCTs has allowed the treatment effects of NUCALA to be reliably determined in patients with severe eosinophilic asthma. However, the strict inclusion and exclusion criteria which are necessary in RCTs produce data from a selected, homogeneous population which may not be representative of the wider population who may receive treatments in routine practice [Albert, 2013; Saturni, 2014]. The purpose of this ‘real-world’ study is to generate evidence which is complementary to

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that produced by RCTs. This study will assess the use of NUCALA in a more heterogeneous population, including patients with a broader spectrum of co-morbidities and concomitant medications than would typically be allowed in RCTs. Compared with data from RCTs, the data generated in this study will therefore be more representative of the effects of the medication in the context of real-world clinical practice.

Although it is recognised by clinicians that severe asthma is a heterogeneous syndrome with multiple distinct phenotypes, clinical experience with targeted biological therapies for asthma is limited: omalizumab, an anti-immunoglobulin E (anti-IgE) therapy for allergic asthma has been the only marketed biological product for the last decade and NUCALA has been launched very recently for severe eosinophilic asthma. Therefore, observation of usage of NUCALA in clinical practice may provide additional understanding of effectiveness to clinicians as well as patients. This study aims to evaluate clinical outcomes, healthcare utilization and patients’ impact in real world clinical practice to provide a more complete understanding of the value of NUCALA for patients in routine clinical practice with severe asthma.

7. RESEARCH QUESTION AND OBJECTIVE(S)

In a cohort of participants with a clinical diagnosis of asthma that are newly prescribed NUCALA, we will collect a range of descriptors and outcomes in the pre-exposure and the 24-month post-exposure period with NUCALA (mepolizumab 100 mg, subcutaneous administration) for the following objectives.

Primary objective:

• To compare the rates of clinically significant asthma exacerbations in the pre-exposure and the 12-month post-exposure period with NUCALA treatment. A clinically significant asthma exacerbation is defined as deterioration in asthma requiring (1) use of systemic corticosteroids and/or (2) ED visit and/or hospital admission.

Secondary Objectives:

• Determine patterns of NUCALA usage including adherence/ persistence, duration of therapy, discontinuation and reasons for discontinuation.

• To compare the rates of clinically significant asthma exacerbations in the pre-exposure and the 24-month post-exposure period with NUCALA.

• Determine and compare the rate of asthma exacerbations requiring an ED visit or hospitalisation in the pre-exposure and the 12-month and 24-month post-exposure period with NUCALA.

• Determine and compare the rate of asthma exacerbations requiring hospitalization in the pre-exposure and the 12-month and 24-month post-exposure period with NUCALA.

• Describe change from baseline in OCS dose during the post-exposure period among participants on maintenance OCS.

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• Describe asthma related healthcare resource utilization including count of hospital admissions, ED visits, visits with HCPs, and prescription medication utilization for asthma.

• Determine and compare the level of asthma control as measured by an ACQ-5 at baseline and the 12- and 24-month post-exposure periods.

• Characterise and compare patterns of work status, productivity and absenteeism at baseline and the 12 and 24-month post-exposure periods as measured by WPAI.

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Other Objectives

Where data is available, additional objectives will be addressed which may include the following.

• Describe co-morbidities. • Describe participant satisfaction with NUCALA treatment. • Describe HCP satisfaction with NUCALA treatment. • Describe lung function using the change in forced expiratory volume in one

second (FEV1), forced vital capacity (FVC) and FEV1/FVC during the observation period.

• Describe the change in peripheral blood eosinophils during the post treatment period.

• Describe the change in fractional nitric oxide concentration in exhaled breath (FeNO) during the post treatment period.

• Describe the change in sputum cell counts during the post treatment period. • Compare data collected from EHR with eCRF data.

Exploratory Research

Within the study we also aim to determine the feasibility of utilizing interactive digital media to collect patient experience and outcome data in a real world setting. In this study interactive digital media is defined as the study specific Asthma Track app and a wearable activity monitor.

Objectives:

• Describe concordance between data collected using the Asthma Track app and activity monitor and data collected at clinic visits.

• Explore potential associations between patient characteristics and uptake of Asthma Track app and use of an activity monitor

• Describe the activity and sleep quality of patients using an activity monitor

• Explore associations between asthma exacerbations recorded at clinic visits and data collected through the Asthma Track app and activity monitor

• Describe participant satisfaction with their study experience and the digital media components using a Participant Study Experience Questionnaire

8. RESEARCH METHODS

8.1. Study Design

This is a prospective, self-controlled cohort study conducted to collect observational data from participants with a clinical diagnosis of severe eosinophilic asthma. To reflect the real world nature of the study, all eligible participants who have a physician decision to

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initiate NUCALA treatment and are consented for the study will be observed. The assignment of a patient to a particular therapeutic strategy is not decided in advance by the study protocol, but is determined by the usual practice of medicine, and the decision to prescribe a particular drug is clearly dissociated from the decision to include the patient in the study. No visits should be scheduled specifically for this observational study, data will be collected at usual asthma healthcare visits (routine or unscheduled).

If a participant is seen by their physician for monthly NUCALA injections, data for healthcare utilization, asthma medications and any recent lung function assessment will be collected on a monthly basis. When the participant is seen less frequently by their physician (for example when NUCALA injection is given at a different site) this data will be collected at usual asthma healthcare visits, which are likely to occur less frequently.

At aproximately 3 monthly intervals, patients will be offered short questionnaires for completion during usual asthma healthcare visits. The interval may be longer and may be irregular if that is the usual pattern of asthma healthcare visits.

Details of study data collection are shown in the Time and Events Table [Appendix 1]

Figure 1 Study Design

A 12-month period of relevant historical data is required prior to enrolment for all participants to allow for a standardised period of history to describe selected participant demographics, disease burden and previous medication use.

The index date will be defined as the date of the first NUCALA administration during the study (i.e. treatment initiation). To accommodate local healthcare practice, this may be on the same day as or up to 7 days prior to the date of enrolment or, in some instances, may occur several weeks post enrolment, according to local healthcare practice.

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1. The 12-month pre-enrolment period is defined as 365 days (+1 day) prior to the date of enrolment or index date, whichever occurs first.

2. The run-in period is defined as the period between enrolment and the index date (where the enrolment date is earlier than the index date) and can be of variable length. During the run-in period, participants receive the same care as provided during the pre-enrolment period.

3. For participants in many healthcare practices where enrolment and the index date occur on the same day (and for participants who have an index date prior to the enrolment date) there will be no run-in period.

4. The pre-exposure period of participants’ history will start from the index date and finish at a minimum 365 days (+1 day) prior. Any data on study outcomes or pre-defined study descriptors that occur during the run in period will be counted into the pre-exposure period for each participant.

5. The observation (post-exposure period) begins at the index date (+1 day) and ends on the date of patient censoring.

Participants will be observed from their index date until their censoring date, which is the earliest of the following events:

1. Death 2. Withdrawal of consent 3. End of 24-month observation period

The primary analysis will be conducted based on the 12-month prospective observation (post-exposure period) compared with the pre-exposure period for each individual participant. Secondary analyses will be conducted using both the 12- and 24-month post-exposure periods.

Data will be collected by entry into an electronic Case Report Form (eCRF). In addition to this in some countries, which have suitable records, this will be supplemented with data directly from electronic health record systems EHRs/ administrative claims data. The method of data collection for the primary outcome will be standardised across countries.

Relevant data will be collected from paper or EHR-based medical records supplemented with participant recall and/or administrative claims data for the 12-month pre-enrolment period. After enrolment, data will be collected prospectively as specified in the Time and Events Table [Appendix 1] until the censoring date. Data prospectively collected during the run-in period will be considered to form part of the pre-exposure data.

In cases where the index date occurs up to 7 days prior to enrolment, data for the period between index and enrolment date will be collected from medical records supplemented with participant recall.

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Enrolment for Use of Administrative Claims Data in the United States

In the United States (US) data for health resource utilization will be obtained from administrative claims. To that end, in the US, priority will be given to the recruitment of patients actively enrolled in an Anthem affiliated health plan with Anthem pharmacy benefits to meet the study endpoint. Should enrolment of such patients prove insufficient to meet the study enrolment goals, sites will be asked to enroll additional patients who are not members of the health plan in order to meet recruitment targets. Should this be required, the additional health resource utilization information will be collected by the provider and entered through the eCRF.

Potentially appropriate payer databases and electronic medical record (EMR) databases of affiliated research organizations will be evaluated to identify patients potentially eligible for the study. Patients may also be identified through review of provider databases. The inclusion/exclusion criteria will be applied to relevant databases to identify appropriate subjects.

8.1.1. Use of Interactive Digital Media

Study participants will be offered the option to experience an interactive smartphone app designed to assist in collecting study data. A subset of participants will also be offered a wearable activity monitor. Data captured using the app and activity monitors will be considered exploratory only and is not intended to be relied upon in assessing the study outcomes or for monitoring or otherwise managing the participant’s care. To align with the exploratory nature of the digital media interventions, participation will be voluntary.

Asthma Track Smartphone Application

A study specific smartphone app ‘Asthma Track’ has been developed for use on both iOS and Android mobile devices. Asthma Track is an interactive smartphone app designed with patient input to encourage engagement with the app and promote long term use. Asthma Track functionality enables manual recording by the participant of:

• OCS medication usage

• Participant perceived OCS side effects using a customised, non-validated, Asthma Steroid Questionnaire (ASQ)

• Asthma control using the validated Asthma Control Test (ACT) questionnaire

• Asthma exacerbations (hospitalisations, days missed from work)

• Reliever and preventer usage

• Lung function data

• Height and weight

To encourage participant engagement, Asthma Track also collates publically available local environmental data (pollen, weather, air quality) which is accessible within the app

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so that participants will be able to view possible triggers for their asthma. No treatment recommendations are provided

All new participants will be offered the opportunity to download the Asthma Track app at their enrolment visit (+ 4 weeks). The use of the app is subject to the compatability of the participant’s smartphone with the application. Asthma Track will remain live for the duration of the study but participant access will cease once their 24 month study period has completed. Participants will be prompted via app notifications to complete the ACT and ASQ questionnaires every 4 weeks. At all other times participants will interact with the app according to their own interest. The Investigator will not be required to promote on-going use of the app.

Full instructions on how to download, activate and use the Asthma Track app will be provided in Site and Subject Quick Reference Guides.

Activity Monitor

ActiGraph GT9X physical activity monitors (tri-axial accelerometers manufactured by and purchased from ActiGraph, LLC) are being use in the study to collect data on the following variables:

- Sleep quality and quantity - Daytime activity ( active vs sedentary bouts) - Energy expenditure - Steps

Acitivty monitors will be provided to approximately 200 participants in initially 4 countries (US, UK, Italy, Spain). The activity monitor will be offered to participants at the enrolment visit and use of the activity monitor is voluntary. Only participants who can complete enrolment and index on the same day will be offered an activity monitor. Paticipant’s who use the activity monitor will be able to view their activity and sleep data via the Asthma Track app. Participants will be asked to wear the activity monitor as much as possible from enrolment until 12 months have elapsed. During the study there will be 5 periods of intense wear; this is defined as wearing the activity monitor 24 hours per day for 14 days, except when charging of the activity monitor is required. The intense wear periods will be at the following time points: • From enrolment for 2 weeks

• 2 weeks preceeding the 3 month time point

• 2 weeks preceeding the 6 month time point

• 2 weeks preceeding the 9 month time point

• 2 weeks preceeding the 12 month time point

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Participants will be notified of the start and end of intense wear periods via SMS text message to their personal mobile device. Following completion of the 12 months wear period activity monitors will be returned to the Investigator site at the participant’s next asthma related healthcare visit. Full instructions on the set-up and use of the activity monitor and associated hardware will be provided in Investigator Site and Subject Guides.

8.2. Study Population and Setting

The intention is to recruit patients at centres in Belgium, France, Germany, Italy, Spain, the United Kingdom, Canada, and the United States.

NUCALA therapies may be added on to existing treatments. Prior use of other biological medications will be allowed.

Inclusion Criteria

The assignment of a patient to a particular therapeutic strategy is not decided in advance by the study protocol, but is determined by the usual practice of medicine, and the decision to prescribe a particular drug is clearly dissociated from the decision to include the patient in the study.

In the Unites States priority will be given to the recruitment of patients actively enrolled in an Anthem affiliated health plan with Anthem pharmacy benefits to meet the study endpoint. Should enrolment of such patients prove insufficient to meet the study enrollment goals, sites will be asked to enroll additional patients who are not members of the health plan in order to meet recruitment targets.

A patient will be eligible for inclusion in this study if all of the following criteria apply:

1. Informed Consent: Prior to commencing any study related activities, participants must be able and willing to provide written informed consent.

2. Participants must have a current clinical diagnosis of asthma.

3. Physician decision to initiate treatment with NUCALA.

4. Relevant paper or EHR-based medical records available for at least 12-months

prior to enrolment date. 5. Adults aged 18 years or over.

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Exclusion Criteria

A participant will not be eligible for inclusion in this study if any of the following criteria apply:

1. NUCALA injection during the 12 months prior to enrolment (note: an injection up to 7 days prior to enrolment is permitted if required for logistical reasons).

2. Participation in an interventional clinical trial in which the treatment regimen and/or monitoring is dictated by a protocol during the previous 12-months.

8.3. Variables

8.3.1. Exposure definitions

Participants will be observed from their date of first administration (index date) until their censoring date for exposure to NUCALA. Each individual exposure will start at the administration date and be given a default length of 28 days. For all administrations of NUCALA, the dates of prescription and/or dispensation may not be equivalent to the actual date of administration; however, these dates may be used in place of date of administration if this is missing.

Currently exposed to NUCALA (i.e. “on treatment”) will be defined as the period starting from the index date and continuing until the earliest of the censoring date or discontinuation of prescribing. Discontinuation is considered to have occurred if there is either:

• A break of at least 90 days between prescriptions. Ninety days will be measured from the end of the last known prescription and/or dispensation (prescription start date plus 28 days). The discontinuation date will be set at 28 days after the last known final prescription (prescription start date plus 28 days).

or

• Never receiving another NUCALA prescription within the study period. The discontinuation date is set at 28 days after the last known final prescription (prescription start date plus 28 days).

It will not be possible to determine whether a participant discontinues NUCALA if they are censored between 29 and 90 days after their last prescription. For these participants, the period up to 28 days following last prescription will be included in the currently exposed period.

If a participant discontinues taking NUCALA but resumes treatment at a later date, the second exposure period will also be considered as part of “currently exposed” time.

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8.3.2. Outcome definitions

Data, as described below, will be captured from various sources including paper or electronic medical record and patient recall. In addition, supplementary exploratory outcomes based on participants’ experience with NUCALA will be collected through digital media including a smartphone app and a wearable activity monitor.

8.3.2.1. Summary of Patient Characteristics

Characteristics of participants will be collected for the pre-exposure period and at index date. Examples of such data are as follows:

• Demographic characteristics • History of asthma and healthcare utilisation including

o History of asthma exacerbations o ER visits, outpatient visits, hospital admissions o Allergic condition (IgE, skin prick test) o Concurrent medications including details of treatment with oral/ systemic

corticosteroids • Details of current asthma status

o Classification of asthma severity according to Global Initiative for Asthma (GINA) guidelines

o Lung function data o Peripheral blood eosinophils o FeNO o Sputum cell counts

• Co-morbidities • Herpes zoster vaccination

At enrolment, the ACQ-5 and WPAI will be offered for completion by participants. If NUCALA treatment initiation is at the same site then, if possible, the questionnaires should be completed prior to NUCALA injection. This will ensure that the responses to questions are not influenced by treatment procedures.

See Section 8.3.2.3 Secondary Outcomes: ACQ-5 and WPAI for a description of these measures.

8.3.2.2. Primary outcome: Clinically Significant Asthma exacerbations

A clinically significant asthma exacerbation is defined as deterioration in asthma requiring (1) use of systemic corticosteroids and/or (2) ED visit and/or hospital admission. The frequency of clinically significant exacerbations will be captured for each participant for the pre-exposure and post- exposure periods. Use of systemic corticosteroids is defined as oral steroids (e.g. prednisone) for at least 3 days or a single systemic (intravenous [IV] or intramuscular corticosteroid dose due to worsening of asthma symptoms). For participants on maintenance systemic corticosteroids, at least double the existing maintenance dose for at least 3 days is required. Exacerbations treated with courses of corticosteroids separated by less than 7 days will be treated as a continuation of the same exacerbation.

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8.3.2.3. Secondary outcomes

Patterns of NUCALA usage including adherence/persistence, duration of therapy, discontinuation and reasons for discontinuation

Adherence will be defined by Medication Possession Ratio (MPR) and Proportion of Days Covered (PDC). Definitions will be included in the Reporting and Analysis Plan (RAP). Participant reported reasons for treatment discontinuation will be captured. HCP reported reasons for treatment discontinuation will also be collected.

Rate of clinically significant asthma exacerbations in the pre-exposure and the 24-month post-exposure period with NUCALA

The rate of clinically significant exacerbations in the pre-exposure period (as defined for the primary outcome) will be compared for the 24-month post- exposure period.

Rate of asthma exacerbations requiring an ED visit or hospitalisation in the pre-exposure and the 12-month and 24-month post-exposure period with NUCALA

The number of asthma exacerbations requiring either ED visit or hospital admission with overnight stay will be collected and compared during the pre exposure and 12- and 24-month post-exposure periods.

Proportion of participants experiencing 1 or more exacerbations requiring ED visits and/or hospitalization during the pre-exposure and 12- and 24-month post-exposure periods will also be collected and compared.

Rate of asthma exacerbations requiring hospitalization in the pre-exposure and the 12-month and 24-month post-exposure period with NUCALA.

The number of asthma exacerbations requiring hospital admission with overnight stay and the length of stay will be collected and compared during the pre exposure and 12 and 24-month post exposure periods.

Proportion of participants experiencing 1 or more exacerbation requiring hospitalization during the pre-exposure and 12- and 24-month post-exposure periods will also be collected.

Describe change from baseline in OCS dose during the post-exposure period among participants on maintenance OCS. An OCS prescription and the associated dose, number of days supplied, and the dates of administration (start date and end date) will be captured for the pre-exposure and 12-and 24-month post-exposure periods.

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The average OCS daily dose will be expressed as prednisone equivalent dose in mg per day over a pre-defined period of time. The average daily dose of participants on maintenance OCS at baseline and in the 12-month and 24-month observation period will also be compared.

Asthma related healthcare resource utilization including count of hospital admissions, ED visits, visits with HCPs, and prescription medication utilisation for asthma.

Health-care utilization will be collected in order to describe the frequency of events in the cohort during the pre-exposure and 12 and 24 month post-exposure periods as well as to support post-hoc economic analysis and may include:

• Count of asthma hospitalizations events • Count of asthma ED events: emergency department visits due to asthma

symptoms not requiring overnight stay in a hospital • Count of outpatient events: general practitioner/PCP, asthma specialist visits (e.g.,

allergist/allergologist, chest physicians/pulmonologist, internal medicine physicians).

• Asthma medications inclusive of relievers, controllers, and therapy for asthma exacerbations, including acute and chronic treatment with OCS. Where feasible, the asthma-related OCS prescriptions will be ascertained.

• Length of hospital stay • Hospital readmission

Asthma medication groups will be described according to the categories listed in Table 1: Asthma medications. Groups of medications that are not approved for the treatment of asthma, but which may be prescribed for symptom relief are also listed.

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Table 1: Asthma medications

Category Description Short-acting bronchodilator(SABD)

Short-Acting Beta2-Agonist (SABA) Short-Acting Anticholinergic (SAMA) Fixed Combinations of SABA/ Cromoglycate Fixed Combinations of SABA/SAMA

ICS and SABA/ICS Inhaled Corticosteroids OR Fixed Combination of Short-Acting Beta2-Agonist and Inhaled Corticosteroid

LABA Long-Acting Beta2-Agonists ICS/LABA Fixed Combination of Inhaled Corticosteroid and Long-Acting Beta2-Agonist

OR Open combination of Inhaled Corticosteroid and Long-Acting Beta2-Agonist in two devices (LABA script overlaps with ICS by at least one day)

LAMA Long-Acting Muscurinic Antagonist ICS/LAMA Open combination of Inhaled Corticosteroid and Long-Acting Muscurinic Antagonist in two

devices LAMA/LABA Fixed Combination of Long-Acting Beta2-Agonist along with a Long-Acting Muscurinic

Antagonist OR Open combination of Long-Acting Beta2-Agonist and Long-Acting Muscurinic Antagonist in two devices

“Open triple” of ICS, LABA, and LAMA

Fixed Combination of Inhaled Corticosteroid and Long-Acting Beta2-Agonist along with a Long-Acting Muscurinic Antagonist in two devices OR Open combination of Inhaled Corticosteroid and Long-Acting Beta2-Agonist and Long-Acting Muscurinic Antagonist in three devices OR Fixed combination of Long-Acting Beta2-Agonist and Long-Acting Anticholinergic along with Inhaled Corticosteroid in two devices

Theophylline Theophylline and its derivates Other non biologics Roflumilast (Oral phosphodiesterase type 4 (PDE4) inhibitor) Oral corticosteroids Xolair Reslizumab Other Biologics Other medications for asthma

Leukotriene receptor antagonist (LTRA)

For SABD, the count and percent of participants with more than four prescriptions will be described.

For OCS, we will describe only “chronic use” which is defined as at least four prescription records with a maximum gap between two prescriptions equal to 30 days.

The level of asthma control as measured by an ACQ-5 at baseline and the 12- and 24-month post-exposure periods. The ACQ-5 will be offered to participants for completion on a voluntary basis at enrolment and, no more frequently than every 3 months, at usual asthma healthcare visits. When a NUCALA injection is administered on the same day as the questionnaire is completed then, if possible, the questionnaire should be completed prior to the injection.

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This will ensure that the responses to questions are not influenced by treatment procedures. Should ACQ-5 not be completed at either the enrolment or index visit then paticipants should not be offered ACQ-5 questionnaires for completion at subsequent visits

The ACQ-5 is a five-item questionnaire, which has been developed as a measure of asthma control that can be quickly and easily completed [Juniper, 2005], and is suitable for use in clinical trials as well as in clinical practice to monitor asthma control. The questions are designed to be self-completed by the participant. The five questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) enquire about the frequency and/or severity of symptoms over the previous week. The response options for all these questions range on a scale from zero (no impairment/limitation) to six (total impairment/ limitation) scale. The recall period is the previous 7 days.

Patterns of work status, productivity and absenteeism at baseline and the 12 and 24-month post-exposure periods as measured by WPAI questionnaire

The WPAI questionnaire will be offered to participants for completion on a voluntary basis at enrolment and, no more frequently than every 3 months, at usual asthma healthcare visits. When a NUCALA injection is administered on the same day as the questionnaire is completed, then the questionnaire should be completed prior to the injection. This will ensure that the responses to questions are not influenced by treatment procedures. Should the WPAI questionnaire not be completed at either the enrolment or index visit then paticipants should not be offered WPAI questionnaires for completion at subsequent visits.

WPAI measures impact due to poor health on work, described as absenteeism or percent of time missed from work; presenteeism or percent of impairment while working; percent overall work productivity impairment which considers both absenteeism and presenteeism; and percent impairment in daily activities [Reilly, 1993]. Higher percentages indicate greater impairment and less productivity. The recall period is the previous 7 days.

8.3.2.4. Other outcomes

Participant and HCP Satisfaction with NUCALA treatment

The participants and HCPs will be asked to rate their response to therapy. Lung Function: FEV1 and FVC

Where available, FEV1 (in L), FVC, and the FEV1/FVC will be compared using the historical value nearest to the index date in the pre-exposure period. Lung function data available during the post-exposure period will be also collected.

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Pre- and post-bronchodilator values will be collected as respective separate categories. If it is not known whether the reading is pre- or post-bronchodilator, this will be collected as unknown.

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Peripheral blood eosinophils

Where available, peripheral blood eosinophil levels will be collected using the historical value nearest to the index date in the pre-exposure period. Any relevant cell count data available during the post-exposure period will be also collected. Both percent of eosinophils and cells per microliter will be collected.

FeNO

Where available, an absolute number of FeNO will be collected using the historical value nearest to the index date in the pre-exposure period.

Sputum Cell Counts

Where available, sputum eosinophil and neutrophil cell counts will be collected using the historical value nearest to the index date in the pre-exposure period.

EHR, eCRF Comparison

Data collected using EHRs and/or administrative claims data will be compared with that collected using eCRF.

8.3.2.5. Exploratory Outcomes

Exploratory participant experience outcomes may be voluntarily reported by participants using the Asthma Track app and a wearable activity monitor. The feasibility of utilizing the smartphone app and the activity monitor to collect this type of data in a real world setting will be assessed.

Concordance between data collected using the Asthma Track app and activity monitor and data collected at clinic visits will be assessed.

Potential associations between patient characteristics and the uptake of the Asthma Track app and use of an activity monitor will be explored.

Activity and sleep quality data from patients using an activity monitor will be described.

Potential associations between asthma exacerbations recorded at clinic visits and data collected through the Asthma Track app and activity monitor will be explored.

Participant satisfaction with their study experience and the digital media components using a Participant Study Experience Questionnaire will be described

Equivalent outcome data collected by digital modalities will be compared against eCRF data (and claims/EMR where possible) and the details will be provided in the RAP. All remaining analysis related to digital components will be explored in a Supplementary RAP.

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8.3.2.6. Confounders and effect modifiers

These will be described in the study RAP.

8.4. Data sources

Data sources are described in Section 8.9 Data Management.

8.5. Study size

This study is observational. Analyses will focus on within-participant comparisons of post-index date versus the pre-exposure period.

The target number of participants enrolled in the study should be sufficient to be powered for the primary outcome of clinically significant exacerbations and the secondary outcome of exacerbations requiring ED visits or hospitalisations.

The current target for enrolment is 860 participants, but this will be reviewed and may be revised prior to last subject last visit (LSLV).

8.6. Sample size assumptions

The primary analysis will compare the exacerbation rate observed during the pre-exposure period with the rate observed during 12-months post exposure to NUCALA. This calculation is based on data from the MEA115661 (GlaxoSmithKline Document Number 2015N236032_01) extension study, where 159 participants switched from placebo in MEA115588 (GlaxoSmithKline Document Number 2013N178278_02) to NUCALA in MEA115661 and completed both studies. Among these participants the exacerbation rate dropped from 1.9/year (yr) from the end of MEA115588 to 1.1/yr in MEA115661 on NUCALA (a 42% decrease). A total of 25% of participants were assumed to withdraw over the course of the study, 20% in the first and 5% in the second year. Withdrawers in the first and second year of the study were assumed to provide 4 and 18 months of analysable data, respectively. Following these assumptions, a study with 12-months of NUCALA treatment designed to detect a 35% decrease with 90% power at the two-sided 5% level would require approximately 200 participants (with an assumed dispersion parameter of 0.8).

Exacerbations requiring ED visits or hospitalisation are the main secondary outcome and will be assessed at the end of 2 years of observation. Based on an exacerbation rate of 0.2/yr (observed within placebo patients in MEA115588), a study with 2 years of NUCALA treatment designed to detect a 35% decrease with 90% power at the two-sided 5% level would require approximately 860 participants assuming 20% and 5% of total participants in the study withdraw in the first and second year, respectively, and a dispersion parameter of 3.0.

8.7. Sample Size Sensitivity

There were large uncertainties regarding the assumptions made for sample size calculations, particularly for the outcome of exacerbations requiring ED visits or

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hospitalisation, and therefore alternative sets of reasonable assumptions were considered as sensitivity. Firstly, the rate of exacerbations in the pre-exposure period is difficult to predict due to variations in eligibility criteria in each country, and around the percentage of participants being initiated on treatment with an aim to reduce maintenance OCS use, who may potentially not have any history of exacerbations. Particularly for exacerbations requiring ED visits or hospitalisation, small changes on the assumed rate has a substantial impact on sample size estimates. However, exacerbation rates in the MEA115575 (GlaxoSmithKline Document Number 2013N177150_01) study were higher than in MEA115588 study despite the lack of inclusion criteria for exacerbations, as shown in the table below.

There are additional uncertainties in the sample size calculation for the secondary outcome of exacerbations requiring ED visits/hospitalisation. For this outcome, the estimated range of the dispersion parameter k was 2 to 6. The assumed value of this parameter has a substantial impact on sample size estimates. Finally, small changes on the assumed reduction in the rate of exacerbations will also impact significantly. The assumed reduction of 35% in the sample size calculations aims to account for the uncertainty in the potential reduction in the real world setting and can be considered a conservative estimate in light of reductions of 42% and 64% observed in MEA115588 and MEA115575 studies, respectively.

Table 2: Rate of Clinically Significant Exacerbations in Previous NUCALA Studies

MEA115588 (MENSA) ≥2 exacerbations in previous year, 25% of participants on

maintenance OCS

MEA115575 (SIRIUS) All participants on

maintenance OCS, no exacerbation requirement

Rate of clinically significant exacerbations within study among placebo participants

1.9 2.2

Rate of clinically significant exacerbations in MEA115661 (COSMOS) extension among participants previously on placebo

1.1 0.8

Reduction in exacerbations in MEA115661 (COSMOS) among participants previously on placebo

42% 64%

Rate of clinically significant exacerbations requiring ED visits/hospitalisation within study among placebo subjects

0.20 0.22

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The impact of changes in assumed parameters for the sample size calculations for the primary outcome of clinically significant exacerbations are shown below. The base case calculation is shown in bold, and modified parameters are underlined. If the assumed rate of exacerbations in the pre-exposure period was 1.5/yr rather than 1.9/yr, the sample size required would be 220 instead of 200. For a rate of 2.2/yr, the sample size required would decrease to 180. A reduction in exacerbations from of 35% would require a sample size of 280, and a small increase in the dispersion parameter k would lead to an increased sample size of 220 subjects.

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Table 3: Impact of Changes in Assumptions of Sample Size Estimations for Clinically Significant Exacerbations

Assumed exacerbation rate in the pre-exposure period

Reduction in exacerbations post-exposure compared to pre-exposure

Dispersion parameter k

Sample size Required for 90% power

1.5/yr 35% 0.8 220 1.9/yr 35% 0.8 200 2.2/yr 35% 0.8 180 1.9/yr 30% 0.8 280 1.9/yr 35% 1.0 220

The impact of changes in assumed parameters for the sample size calculations for the secondary outcome of clinically significant exacerbations requiring ED visits or hospitalisation are shown below. The base case calculation is shown in bold, and modified parameters are underlined. Small changes in the assumed rate of exacerbations in the pre-exposure period have considerable impact on sample size estimates: a decrease of 0.05 to 0.15 increases the sample size required to 1000 participants whereas an equivalent increase reduced the sample size required to 770. Changes in the assumed value of k within the ranges observed in previous trials results resulted in a considerably large sample size range of 720 to 1270 subjects. Finally, assumptions on the reduction in exacerbations also considerably impacted on sample size estimates, with 1100 partcipants estimated for a 30% reduction compared to 560 for a 40% assumed reduction.

Table 4: Impact of Changes in Assumptions on Sample Size Estimations for Exacerbations Requiring ED visits/ hospitalisations

Assumed exacerbation rate in the pre-exposure period

Reduction in exacerbations post-exposure compared to pre-exposure

Dispersion parameter k

Sample size Required for 90% power

0.15/yr 35% 3.0 1000 0.20/yr 35% 3.0 860 0.25/yr 35% 3.0 770 0.20/yr 35% 2.0 720 0.20/yr 35% 4.0 1000 0.20/yr 35% 6.0 1270 0.20/yr 30% 3.0 1220 0.20/yr 40% 3.0 630

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8.8. Sample size review

Due to substantial uncertainties in the assumed values for the sample size calculation for the secondary outcome of exacerbations requiring ED visits or hospitalisation, a sample size review will be carried out prior to LSFV in order to verify observed values for the exacerbations in the pre-exposure period and the dispersion parameter k and compare these to the values assumed in the sample size calculations.

8.9. Data management

Data will be collected for the 12 months pre-enrolment and during the study period by entry into an eCRF. In addition to this in some countries, which have suitable records , the study data will be collected using a mixture of eCRF and EHRs/ administrative claims data. Data collection for the primary outcome will be standardised across countries.

Exploratory participant reported outcome data will be collected, where appropriate, using interactive digital media including a smartphone application and a wearable activity monitor. Data from these devices will be securely transferred from the device and stored on the device vendor servers. Final analytical files will be electronically transmitted from the vendors to GSK for exploratory analysis.

Data sources will be defined in a data management plan.

All data sources will be transmitted electronically to GSK or designee.

8.10. Data analysis

All pre-specified analyses will be described in detailed in a RAP.

8.10.1. Analysis populations

Population Definition / Criteria Analyses Evaluated All Subjects Enrolled (ASE)

• This population will comprise of all subjects enrolled into the study meeting the inclusion criteria for the study. This population will be used for reporting of reasons for failure of NUCALA treatment initiation.

• Study Population

Treated Population (TP)

• This population will comprise of all subjects in the ASE study population who have received at least 1 injection of NUCALA following physician decision.

• Study Population • Efficacy • Health Outcomes • Safety

8.10.2. Protocol Deviations

• This study does not include a per protocol population.

• Important protocol deviations (including deviations related to studyinclusion/exclusion criteria) will be summarised and listed.

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• Protocol deviations will be tracked by the study team throughout the conduct of the study in accordance with the Protocol Deviation Management Plan.

o Data will be reviewed prior to freezing the database to ensure all important deviations are captured and categorised on the protocol deviations dataset.

o This dataset will be the basis for the summaries and listings of protocol deviations.

• A separate summary and listing of all inclusion/exclusion criteria deviations will also be provided. This summary will be based on data as recorded on the inclusion/exclusion page of the eCRF.

8.10.3. Summary of patient characteristics

Characteristics of enrolled participants collected for the pre-exposure period and at index date will be described. This will include demographic information as well as disease characteristics. These results will be used to describe the population included in the study. This analysis is planned to be performed prior to or at LSFV, depending on recruitment, and will not require formal statistical analysis. This analysis will not lead to a decision to amend the design or stop the study, and will be described further in the RAP.

8.10.4. Interim analysis

An interim analysis will be carried out including data on all participants enrolled up to 1 year after LSFV to allow for all participants to accrue at least 12 months follow-up in the post-exposure period. This analysis will not lead to a decision to amend the design or stop the study.

This interim analysis will include results of the final analysis for outcomes defined at 12 months post-exposure. These include the primary outcome of reduction in clinically significant asthma exacerbations, and a number of secondary outcomes (See Section 8.3.2.3). This interim analysis will also include analyses of all other secondary outcomes using interim data.

Additional interim analyses may be performed to meet individual country evidence requirements.

All planned analyses will be described in further detail in the RAP and Supplementary RAP.

8.10.5. Primary analysis

The primary objective of this study is to compare the rates of clinically significant asthma exacerbations in the pre-exposure period and the 12-month post-exposure period of treatment with NUCALA. This will be achieved by performing an analysis of the frequency of clinically significant exacerbations 12-months after the index date (initiation of NUCALA treatment) compared to the pre-exposure period. All available data up to 12-

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months post-exposure will be included for all participants, including those withdrawing prematurely, according to population definition. Exacerbations separated by less than 7 days will be treated as a continuation of the same exacerbation.

The exacerbation rate will be analysed using a Negative Binomial regression via generalised estimating equations with covariates of time period (pre-, post-exposure) and country. The variance of the mean estimate will be corrected for within-subject correlation. The logarithm of time on treatment in each period will be used as an offset variable. If convergence is not possible with country as a covariate, the countries may be grouped into regions, for which a system will be defined in the RAP.

The analysis will be performed on the TP (Treated Population) populationA sensitivity analysis using a Bayesian analysis model will also be performed. The number of exacerbations in each period will be assumed to follow a Negative Binomial distribution. The model will also include a covariate for country. The logarithm of time on treatment will be used as an offset variable. A random effects parameter for subject will be included and shared across all periods to describe the number of exacerbations for that subject. Further details will be provided in the RAP.

8.10.6. Secondary analyses

The outcomes to be evaluated for the secondary objectives of this study are described in the Table 5: Outcomes for Secondary Objectives, below :

Table 5: Outcomes for Secondary Objectives

Secondary objective Outcome to be reported

• Describe patterns of NUCALA usage including duration of therapy and discontinuation and reasons for discontinuation.

• Medication possession ratio (MPR)

• Proportion of days covered (PDC)

• Reasons for treatment discontinuation

• To compare the rates of clinically significant asthma exacerbations in the pre- and the 24-month post-exposure period with NUCALA.

• Frequency of clinically significant asthma exacerbations prior to and after 24-months treatment with NUCALA

• Determine and compare the rate of asthma exacerbations requiring an ED visit or hospitalisation in the pre- and the 12-month and 24-month post-exposure period with NUCALA.

• Frequency of exacerbations requiring ED visits and/or hospitalization (12- and 24-month post-exposure periods)

• Proportion of participants experiencing 1 or more exacerbations requiring ED visits and/or hospitalization (12 and

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Secondary objective Outcome to be reported

24-month post-exposure periods)

• Determine and compare the rate of asthma exacerbations requiring hospitalization in the pre- and the 24-month post-exposure period with NUCALA.

• Frequency of exacerbations requiring hospitalization (12- and 24-month post-exposure periods)

• Proportion of participants experiencing 1 or more exacerbation requiring hospitalization (12 and 24-month post-exposure periods)

• Describe changes from baseline in OCS dose during the post-exposure period among participants on maintenance OCS.

• Change in daily maintenance OCS dose (12- and 24-month post-exposure periods)

• Change in total OCS dose (12- and 24-month post-exposure periods)

• Describe asthma related healthcare resource utilization including count of hospital admissions, ED visits, visits with HCPs, and prescription medication utilization for asthma.

• Frequency of events pre- and post-exposure

• Count of asthma hospitalizations events

• Count of asthma ED events • Count of outpatient events • Count of asthma pharmacy • Length of hospital stay • Hospital readmission

• Determine and compare the level of asthma control as measured by an ACQ-5 at baseline and the 12- and 24-month post-exposure periods.

• Mean change from baseline in ACQ-5 score (12- and 24-month post-exposure periods)

• Characterise and compare patterns of work status, productivity and absenteeism at baseline and the 12 and 24-month post-exposure periods as measured by WPAI

• Mean change from baseline in WPAI score (12- and 24-month post-exposure periods)

The secondary outcomes of clinically significant exacerbations (24-months), exacerbations requiring ED visits and/or hospitalisation (12- and 24-months) and exacerbations requiring hospitalization (12- and 24-months) will be analysed using

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negative binomial regression via generalised estimating equations, as described for the primary outcome. Full details of the analyses to be performed on all outcomes will be given in the RAP.

8.10.7. Other analyses

A descriptive analysis will be performed for other outcomes listed in Section 8.3.2.4, and will be described in detail in the RAP.

8.10.8. Exploratory analyses

Exploratory PROs will be voluntarily reported through a study specific smartphone app downloaded to the participants own device. Participant satisfaction with their study experience and the digital media components will be assessed using a Participant Stduy Experience Questionnaire.

These will be summarized descriptively in the supplementary RAP.

8.10.9. Country Based Analyses

Analyses will be performed on a subset of data if this is required in individual countries.

8.11. Quality control and Quality Assurance

Quality control measures are in place throughout the entire period of data collection and data entry. Training and retraining of study staff will be monitored per Study Monitoring Plan. Data exported for analyses for this study will be checked for logical errors, and range checks will be performed. Final data sets will be cleaned and utilized for preparation of the analyses and study reports. All analyses (coding and output) are reviewed by the lead study statistician and at least one other staff statistician. Study reports will be reviewed by the Study Lead.

8.12. Limitations of the research methods

Potential limitations of the study design and measures proposed to address them include the following:

Enrolment bias: sites will be expected to enrol all eligible patients that present at their site and maintain screening logs of all patients meeting eligibility criteria, along with reasons for non-enrolment of otherwise eligible patients.

Channelling bias: factors associated with treatment decision include prescribing pattern differences across practices and countries and reimbursement differences. Patients newly prescribed NUCALA and enrolled in this study may not be representative of all patients who will be prescribed NUCALA.

Inconsistent interpretation of eCRF by participating centres: all centres/sites will undergo standardised training and utilise standardised documentation for completing of case report forms at enrolment and for each assessment during the observation period.

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Follow-up bias: a lost to follow-up rate of 20% is expected in the 12-months exposure period and 5% is predicted during the 12-24-months expsoure period. This high predicted lost to follow-up rate may increase the risk of bias that could result, for example, if participants with AEs were less likely to return to the HCP for follow-up.

Representativeness of severe eosinophilic asthma population: the study’s new user design will recruit and enrol patients newly prescribed NUCALA for asthma. Although the selection of study sites and countries will be planned to be reflective of the subpopulation of asthma patients initiating treatment with NUCALA according to the label and local reimbursement guidelines physicians may also prescribe NUCALA to a broader range of patients according to clinical need. Although this is not a limitation or challenge to the internal validity of the study in addressing its primary and secondary objectives among patients meeting the study inclusion and exclusion criteria, it should be noted as a potential limitation to the long term extrapolation of the results to the broader population of severe eosinophilic asthma patients.

Recruitment of patients treated with newly approved medications: uptake of new respiratory products is unpredictable across different countries and has the potential to impact the feasibility of meeting the recruitment targets.

Under representation of asthma exacerbations: for patients on maintenance systemic corticosteroids, an increase in the use of the systemic corticosteroid to treat an exacerbation may be missed.

8.12.1. Study closure/uninterpretability of results

The planned study closure is 2024, at the scheduled time of the final report of results. The study can be terminated at any time for any reason by GSK. The investigator may be informed of additional procedures to be followed in order to ensure that adequate consideration is given to the protection of the patient’s interests. The investigator will be responsible for informing institutional review board (IRB)/independent ethics committee (IEC) of the early termination of the study. The early termination of the study is considered a major amendment; therefore, the relevant competent authorities will be notified before a final decision is made and approval for termination is granted.

9. PROTECTION OF HUMAN SUBJECTS

9.1. Ethical approval and subject consent

An informed consent form (ICF) must be signed by the participant before his or her participation in the study. The medical file for each participant must document the informed consent process and that written informed consent was obtained prior to participation in the study. A copy of each signed ICF must be provided to the participant or the participant’s legally authorised representative. If applicable, it will be provided in a certified translation of the local language. All signed and dated ICFs must remain in each participant’s study file and must be available for verification by study monitors at any time.

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The ICF must be revised whenever there are changes to procedures outlined in the informed consent or when new information becomes available that may affect the willingness of the participant to participate. For any updated or revised ICFs, the medical file for each participant must document the informed consent process and that written informed consent was obtained for the updated/revised ICF for continued participation in the study.

Participants will also be asked to provide a secondary contact for follow-up should the participant be unreachable. All participant facing documents, including the informed consent, will undergo local language translation and back translation with a qualified vendor. A translation certificate will be provided for all such translations.

9.2. Subject confidentiality

In order to maintain participant confidentiality, each participant will be assigned a unique participant identifier upon study enrolment. This participant identifier will be used in place of participant name for the purpose of data analysis and reporting. Medical record number or other local reference identifiers are not collected as part of the study database. All parties will ensure protection of participant personal data and will not include participant names on any study forms, reports, publications, or in any other disclosures, except where required by law. In accordance with local regulations in each of the countries in which the study is implemented, participants will be informed about data handling procedures and asked for their consent. Data protection and privacy regulations will be observed in capturing, forwarding, processing, and storing participant data. Every effort will be made to protect participant confidentiality in compliance with Safe Harbour privacy principles.

The database will be housed in a physically and logically secure computer system maintained in accordance with a written security policy. The system meets approved established standards for the security of health information and is validated. The system also meets the standards of the International Conference on Harmonisation (ICH) guideline E6R1 regarding electronic study data handling and is available for audit upon request. The data from the app and activity monitor will be stored in the vendor secure storage facilities. These storage facilities meet approved standards for the security of health information. Participant confidentiality will be strictly maintained.

10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS

This study adopts the following ICH definitions:

Adverse event: Any untoward medical occurrence in a patient or clinical investigation

subject administered a pharmaceutical product and which does not necessarily have to

have a causal relationship with this treatment.

An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding) symptom or disease (new or exacerbated)

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temporally associated with the use of a Medicinal Product. For a marketed Medicinal Product, this can also include failure to produce expected benefits (i.e. lack of efficacy, with or without an adverse event), and adverse events associated with circumstances of Overdose whether accidental or intentional, Medication Errors, Abuse or effects of drug withdrawal, or Misuse.

Serious adverse event: any untoward medical occurrence that at any dose that 1) results

in death, 2) is life threatening, 3) requires inpatient hospitalization or prolongs existing

hospitalization, 4) results in persistent or significant disability/incapacity or 5) is a

congenital anomaly.

• Medical and scientific judgement should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or may require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation; or development of drug dependency or drug abuse.

All serious and non-serious AEs, pregnancy exposures, and incidents identified as explicitly attributed to any GSK product (including products not covered in the specific study objective) will be collected and reported to the Sponsor’s safety department. All serious AEs, pregnancy exposures, and incidents explicitly attributed to any GSK product will be reported to the Sponsor within 24 hours of recognition. All non-serious AEs explicitly attributed to any GSK product will be reported to the Sponsor within 5 calendar days of recognition A Safety Management Plan will be developed for this study and will provide detailed information on the study specific pharmacovigilance processes and procedures.

10.1. Medical Device Incidents (Including Malfunctions)

A medical device is being provided for use in this study for the purpose of evaluating physical activity (activity monitor). In order to fulfil regulatory reporting obligations worldwide, the investigator is responsible for the detection and documentation of events meeting the definitions of incident or malfunction that occur during the study with such devices.

10.1.1. Medical Device Incident Definition

• A medical device incident is any malfunction or deterioration in the characteristics and/or performance of a device as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, might lead to or

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might have led to the death of a participant/user/other person or to a serious deterioration in his/her state of health.

• Not all incidents lead to death or serious deterioration in health. The nonoccurrence of such a result might have been due to other fortunate circumstances or to the intervention of health care personnel.

It is sufficient that:

• An incident associated with a device happened and

• The incident was such that, if it occurred again, might lead to death or a serious deterioration in health.

A serious deterioration in state of health can include any of the following:

• Life-threatening illness

• Permanent impairment of body function or permanent damage to body structure

• Condition necessitating medical or surgical intervention to prevent one of the above

• Fetal distress, fetal death, or any congenital abnormality or birth defects

Examples of incidents

• A participant, user, caregiver, or healthcare professional is injured as a result of a medical device failure or its misuse.

• A participant’s study treatment is interrupted or compromised by a medical device failure.

• A misdiagnosis due to medical device failure leads to inappropriate treatment. • A participant’s health deteriorates due to medical device failure.

10.1.2. Detecting and Reporting Medical Device Incidents

Medical device incidents or malfunctions of the activity monitor that result in an incident will be detected, documented, and reported during all periods of the study in which the activity monitor is used. If the Investigator learns of any incident at any time after a participant has ceased wearing the activity monitor, and such incident is considered reasonably related to the activity monitor provided for the study, the investigator will promptly notify the sponsor. Medical device incidents will be reported to the sponsor within 24 hours after the investigator determines that the event meets the protocol definition of a medical device incident.

The Investigator must complete the Medical Device Incident Form for each participant

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who has a medical device incident with the GSK activity monitor provided for use during the study period. All of the header information in the form must be completed before sending to the sponsor. Original documents should be filed in the site study file. A copy of the form must also be sent to the study monitor.

For incidents fulfilling the definition of an AE or SAE, the appropriate pages of the eCRF must be completed. If there is an SAE, the completed eCRF pages should be sent together with the Medical Device Incident Form.

10.1.3. Documenting Medical Device Incidents

Any medical device incident occurring during the study will be documented in the participant’s medical records, in accordance with the Investigator’s normal clinical practice. For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE eCRF page will be completed. The form will be completed as thoroughly as possible and signed by the Investigator before transmittal to the Sponsor’s safety department. It is very important that the Investigator provides his/her assessment of causality (relationship to the activity monitor provided by GSK) at the time of the initial report and describes any corrective or remedial actions taken to prevent recurrence of the incident. A remedial action is any action other than routine maintenance or servicing of a medical device where such action is necessary to prevent recurrence of an incident. This includes any amendment to the device design to prevent recurrence.

10.1.4. Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed and reported in the same manner as other AEs. This applies to all participants, including any participant who chooses to withdraw from the study. The Investigator is responsible for ensuring that follow-up includes any supplemental investigations as indicated to elucidate the nature and/or causality of the incident. New or updated information will be recorded on the originally completed form with all changes signed and dated by the investigator.

10.1.5. Regulatory Reporting Requirements for Medical Device Incidents

The Investigator will promptly report all incidents occurring with any medical device provided for use in the study in order for the sponsor to fulfill the legal responsibility to notify appropriate regulatory authorities and other entities about certain safety information relating to medical devices being used in clinical studies.

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The Investigator, or responsible person according to local requirements (e.g., the head of the medical institution), will comply with the applicable local regulatory requirements relating to the reporting of incidents to the IRB/IEC.

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11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS

Target Audience

The information generated by this study will contribute to the published literature and provide HCPs with information about the use of NUCALA. GSK stakeholders also have an interest in the information generated by this study. The results may be disseminated externally via manuscripts or presentations.

Interim reports

Interim reports containing a description of the population characteristics at treatment index date will be produced. Other interim analyses may be reported according to country requirements.

Final analyses and reporting

A final study report will be generated after all data collection is complete.The final report will encompass all planned analyses, including a description of the complete study population, as described above and in the RAP.

The study protocol will be entered into the GSK Clinical Trials Register before the start of data collection.

Any publication of the results from this study will be consistent with GSK’s publication policy and guided by the International Committee of Medical Journal Editors[ICMJE, 2016]. Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals [December 2016] Available from: http://www.ICMJE.org. The rights of the Investigator and of the Sponsor with regard to publication of the results of this study are described in the Investigator contract.

All reporting will be consistent with Strengthening the Reporting of Observational studies in Epidemiology [Von, 2008]

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12. REFERENCES

Albert RK. "Lies, damned lies." and observational studies in comparative effectiveness research. Am J Respir Crit Care Med. 2013;187(11):1173-7.

Bel EH, Sousa A, Fleming L et al. Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI). Thorax 2011;66:910-7.

Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189-97.

Brusselle G, Maes T, Bracke K. Eosinophilic airway inflammation in nonallergic asthma. Nat Med. 2013;19:977-9.

Chen H, Blanc P, Hayden M, Bleecker E, Chawla A, Lee JH et al. Assessing productivity loss and activity impairment in severe or difficult-to-treat asthma. Value Health 2008;11:231-9.

Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43:343-73.

Colice G, Ostrom N, Geller D, Anolik R, Blaiss M, et al. The CHOICE survey: high rates of persistent and uncontrolled asthma in the United States. Ann Allergy Asthma Immunol 108 (2012) 157–162.

Demoly P. Annunziata K, Gubba E Adamek L. Repeated cross-sectional survey of patient reported asthma control in Europe in the past 5 years. Eur Resp Rev 2012;123:66-74.

GlaxoSmithKline Document Number 2013N177150_01, MEA115575. A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multicenter Study of Mepolizumab Adjunctive Therapy to Reduce Steroid Use in Subjects with Severe Refractory Asthma (SIRIUS Study). 07 August 2014.

GlaxoSmithKline Document Number 2013N178278_02, MEA115588. A randomised, double-blind, double-dummy, placebo-controlled, parallelgroup, multi-centre study of the efficacy and safety of mepolizumab adjunctive therapy in subjects with severe uncontrolled refractory asthma (MENSA Study). 31 March, 2015.

GlaxoSmithKline Document Number 2015N236032_01, MEA115661. A multi-centre, open-label, long-term safety study of mepolizumab in asthmatic subjects who participated in the MEA115588 or MEA115575 trials (COSMOS Study). 29 July, 2015.

Hartley R, Berair R, Brightling C. Severe asthma: novel advances in the pathogenesis and therapy. Pol Arch Med Wewn. 2014;124 (5): 247-54.

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Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respiratory Medicine 2005 (99): 553–558).

Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn E, Leigh R et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy, Asthma & Clinical Immunology 2013, 9:30.

Ortega H, Liu M, Pavord I, Brusselle G, FitzGerald M, Chetta A et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-207.

Patterson M, Borish L, Kennedy J. The past, present, and future of monoclonal antibodies to IL-5 and eosinophilic asthma: a review. Journal of Asthma and Allergy 2015:8 125-34.

Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. PharmacoEconomics 1993; 5:353-65.

Romagnoli M, Vachier I, Tarodo de la Fuente P, Meziane H, Chavis C Bousquet J et al . Eosinophilic inflammation in sputum of poorly controlled asthmatics. Eur Respir J. 2002;20:1370-7.

Rosenberg H, Dyer K, Foster P. Eosinophils: changing perspectives in health and disease. Nat Rev Immunol 2013;13:9-22.

Saturni S, Bellini F, Braido F, Paggiaro P, Sanduzzi A, Scichilone N et al. Randomized controlled trials and real life studies. Approaches and methodologies: a clinical point of view. Pulm Pharmacol Ther 2014;27:129-38.

International Committee of Medical Journal Editors(ICMJE). Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals [December 2016] Available from: http://www.ICMJE.org.

Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP STROBE Initiative.The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008 Apr;61(4):344-9. doi: 10.1016/j.jclinepi.2007.11.008

Wener R, Bel E. Severe refractory asthma: an update. Eur Respir Rev 2013; 22: 227–35.

Wenzel SE. Eosinophils in asthma-closing the loop or opening the door? N Engl J Med 2009;360:1026-8.

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13. APPENDICES

13.1. Appendix 1 Time and Events Table

Please note : no visits should be planned solely for the purposes of the study. When data collection at index date is not possible, this data should be collected at enrolment.

Procedures

PRE EXPOSURE OBSERVATION PERIOD (‘POST EXPOSURE’)

Enrolment5 12-months Pre-enrolment

History8

Treatment Index10,5

Data collected at usual asthma related healthcare visits ( no more frequently than monthly (±10 days))

Questionnaires offered at usual asthma healthcare visits, immediately prior to NUCALA injection, if this is possible; no more frequently than every 3 months (±20days).

Time period ( ie weeks post enrolment) for which data should

be collected at usual asthma healthcare vists

Week 0 Week 0 to day of NUCALA first

injection

Week 4 to 104

Week 4 t to 100 Week 104 (End of study)

Informed consent X Demography X Asthma diagnosis X Medical History / co-morbidities X X11 Details of NUCALA Administration1 X X Asthma Exacerbations X X X Asthma Related Outpatient visits X X X Asthma Related ER visits X X X Asthma Related Hospital admissions

X X X

Oral/Systemic corticosteroids usage

X X X

ACQ-5 X6 X6 X6,7 X6,7 WPAI X6 X6

X6,7 X6,7

Patient satisfaction questionnaire X6 X6

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Procedures

PRE EXPOSURE OBSERVATION PERIOD (‘POST EXPOSURE’)

Enrolment5 12-months Pre-enrolment

History8

Treatment Index10,5

Data collected at usual asthma related healthcare visits ( no more frequently than monthly (±10 days))

Questionnaires offered at usual asthma healthcare visits, immediately prior to NUCALA injection, if this is possible; no more frequently than every 3 months (±20days).

Time period ( ie weeks post enrolment) for which data should

be collected at usual asthma healthcare vists

Week 0 Week 0 to day of NUCALA first

injection

Week 4 to 104

Week 4 t to 100 Week 104 (End of study)

Physician satisfaction questionnaire X6 X6

Participant Study Experience questionnaire X

Asthma and concurrent medications

X X X

Lung function2 X X X Peripheral Blood eosinophils2 X X X Sputum cell counts and FeNO2

X X X

Details of Herpes Zoster vaccination

X9

Offer initiation of smartphone App3 X Offer initiation of Acitivity Monitor4 X X Return of Activity Monitor X

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1. Administration will be at the discretion of the physician. To include date of administration as well as date and reasons for discontinuation. 2. Spirometry, peripheral blood eosinophils, sputum cell counts and FeNO will be noted when the information is available as part of normal care. Baseline values to be

collected using the historical value nearest to the treatment index date during the previous 12-months. 3. The Smartphone App should be offered to all patients at enrolment (+ 4 weeks). Only patients with compatible devices will be able to download the App. Use of the

Smartphone App is voluntary. 4. The activity monitor will only be offered to a sub set of patients (see Section 8.1.1).The activity monitor must only be offered to patients who can complete enrolment and

index on the same day. 5. Enrolment and the Index Date (first NUCALA injection) may occur on the same day. When data collection at index date is not possible, this data should be collected at

enrolment 6. At baseline, the questionnaires may be completed either at enrolment or at index date. When offered on the same day, the questionnaires should be completed PRIOR

to NUCALA injection, if possible. 7. If questionnaires are not completed at enrolment or index they should not be offered at subsequent visits. 8. The 12-month participant’s history will start from the date of enrolment and finish at minus 365 days (+1day) ( except when index date preceeds enrolment by up to 7

days, in which case the 12- month history will start at treatment initiation minus 365 days (+1day) 9. Details of Herpes Zoster vaccination will also be recorded 12 months (±3 months) after NUCALA index date ( treatment initiation). 10. Events to be collected throughout the period between enrolment and treatment initiation. 11. All medical history is collected at enrolment including IgE and skin prick tests

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13.2. Appendix 2: Protocol Changes

13.2.1. Amendment 01

Date of Original Protocol: 8th June 2016

The purpose of the amendment is to include wording mandated by Spanish regulatory authorities and update the protocol to include collection of sputum cell counts. Other changes have also been made as listed below.

This amendment was completed prior to IRB and ethics approval.

1. To increase the emphasis on observational nature of study design, the following wording has been added to Section 3. ABSTRACT: Study Design p12, Section 8. RESEARCH METHODS. 8.1 Study Design p16 and Inclusion Criteria p18: The assignment of a patient to a particular therapeutic strategy is not decided in advance by the study protocol, but is determined by the usual practice of medicine, and the decision to prescribe a particular drug is clearly dissociated from the decision to include the patient in the study.

2. To clarify that sputum cell counts will be collected the following wording has been added:

• Section 7 RESEARCH QUESTION AND OBJECTIVES: Other Objectives p16: ‘’Describe the change in sputum cell counts during the post treatment period’’.

• Summary of Patient Chararcteristics: Characteristics of participants will be collected for the pre-exposure period and at date. Examples of such data are as follows.....Details of current asthma status.....’’Sputum cell counts’’ has been added.

• 8.3.2.4 Other outcomes p24 Sputum Cell Counts: ‘’Where available, sputum eosinophil and neutrophil cell counts will be collected using the historical value nearest to the index date in the pre-exposure period.’’

• Time and Events Table. A row has been added for sputum cell counts and FeNO. • The following wording has been added to Footnote 2: ‘’ sputum cell counts’’

3. Change to T and E table to

a. allow questionnaires to be offered to patients for completion at enrolment and at a healthcare visit unrelated to NUCALA administration

b. removal of defined study visits to clarify the request for data collection at usual healthcare visits.

4. Reference to the use of administrative claims data has also been included for clarity, as follows:

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Enrollment for Use of Administrative Claims Data in the United States

In the United States ( US) data for health resource utilization will be obtained from administrative claims. To that end, in the US, priority will be given to the recruitment of patients actively enrolled in an Anthem affiliated health plan with Anthem pharmacy benefits to meet the study endpoint. Should enrolment of such patients prove insufficient to meet the study enrollment goals, sites will be asked to enroll additional patients who are not members of the health plan in order to meet recruitment targets. Should this be required, the additional health resource utilization information will be collected by the provider and entered through the eCRF

Potentially appropriate payer databases and electronic medical record (EMR) databases of affiliated research organizations will be evaluated to identify patients potentially eligible for the study. Patients may also be identified through review of provider databases. The inclusion/exclusion criteria will be applied to relevant databases to identify appropriate subjects.

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13.2.2. Amendment 02

Date of Original Protocol: 9th Sept 2016

The purpose of this amendment it to remove wording relating to collection of supplementary exploratory data based on participant’s experience with NUCALA using interactive digital media including an application for mobile devices and a wearable activity monitor. The following wording has been removed:

1. Section 3. ABSTRACT: Data Sources p12: Supplementary exploratory data based on participant’s experience with NUCALA will be collected using interactive digital media including an application for mobile devices and a wearable activity monitor.

2. Section 7. RESEARCH QUESTION AND OBJECTIVE(S): Exploratory Objectives p18: Whole section removed.

Exploratory Objectives

• Describe participant experience outcomes using interactive digital media including an application for mobile devices and a wearable activity monitor.

• Compare the demographic and asthma descriptor of the participant population that uses digital media with those who do not.

3. Section 8.1. Study Design p 20: In addition to the information collected at usual asthma healthcare visits, study participants will be offered the option to collect supplemental data using interactive digital media including an application for mobile devices. A subset of participants will also be offered a wearable activity monitor. Outcomes captured using interactive digital media will be considered as exploratory only.

4. To align with the observational nature of this study, participation in the collection of data through mobile devices or any other means will be voluntary.

5. Section 8.3.2. Outcome Definitions p22: In addition, supplementary exploratory outcomes based on participants’ experience with NUCALA will be collected through digital media including an application for mobile devices and a wearable activity monitor.

6. Section 8.3.2.5. Exploratory Outcomes p28: Exploratory participant experience outcomes may be voluntarily reported by participants using interactive digital media including an application for mobile devices and a wearable activity monitor. There will also be a demographic and asthma descriptor comparison of the participant population that uses the digital application with those who do not.

7. Section 8.9. Data Management p32: Exploratory patient reported outcome data will be collected, where appropriate, using interactive digital media including an application for mobile devices and a wearable activity monitor.

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8. Section 8.10.7. Exploratory analyses p36: Whole section removed

Exploratory analyses

Exploratory PROs may be voluntarily reported through study specific digital interface by the participant using their own electronic devices. These will be summarized descriptively in the RAP.

9. Change to T & E table to remove Offer Initiation of a Smartphone App and Actigraph Activity Monitor at enrollment with associated Footnote 8.

Other changes have also been made as listed below.

10. Section 11. PLANS FOR DISSEMINTATION AND COMMUNICATION OF STUDY RESULTS: Final Analysis and Reporting p39. clinicaltrials.gov replaced with GSK Clinical Trials Register.

This amendment was completed prior to IRB and ethics approval.

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13.2.3. Amendment 03

Date of Original Protocol: 8th Nov 2016

Detailed descriptions of substantive changes to the protocol are listed below. Additional administrative and minor typographical/editorial changes have also been made and are not listed. Substantive changes: 1. Title Page: Addition of REALITI-A as study name: A Multinational, Single Arm, Observational Study to Evaluate the Real-world Effectiveness and Pattern of Use of Mepolizumab in Patients with Severe Eosinophilic Asthma (204710; the REALITI-A study). 2. Title Page: Short title added: REAL world effectiveness of mepolizumab In paTIent care – Asthma (REALITI-A) 3. Inclusion of supplementary exploratory outcomes based on participants’ experience

with NUCALA collected using an interactive study specific smartphone app and a wearable activity monitor. Associated updates to Data Management and subjection confidentiality have been added:

o Abstract Data Sources p13 text added: Supplementary exploratory data based on

participant’s experience with NUCALA will be collected using interactive digital media, including a smartphone application (app) and a wearable activity monitor.

o Section 7, Research Question and Objective p18 text added: Exploratory Research

Within the study we also aim to determine the feasibility of utilizing interactive digital media to collect patient experience and outcome data in a real world setting. In this study interactive digital media is defined as the study specific Asthma Track app and a wearable activity monitor.

Objectives:

• Describe concordance between data collected using the Asthma Track app and activity monitor and data collected at clinic visits.

• Explore potential associations between patient characteristics and uptake of Asthma Track app and use of an activity monitor

• Describe the activity and sleep quality of patients using an activity monitor

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• Explore associations between asthma exacerbations recorded at clinic visits and data collected through the Asthma Track app and activity monitor

• Describe participant satisfaction with their study experience and the digital media components using a Participant Study Experience Questionnaire

o Section 13.2.4 Use of Interactive Digital Media p21. New section added: Study participants will be offered the option to experience an interactive smartphone app designed to assist in collecting study data. A subset of participants will also be offered a wearable activity monitor. Data captured using the app and activity monitors will be considered exploratory only and is not intended to be relied upon in assessing the study outcomes or for monitoring or otherwise managing the participant’s care. To align with the exploratory nature of the digital media interventions, participation will be voluntary.

Asthma Track Smartphone Application

A study specific smartphone app ‘Asthma Track’ has been developed for use on both iOS and Android mobile devices. Asthma Track is an interactive smartphone app designed with patient input to encourage engagement with the app and promote long term use. Asthma Track functionality enables manual recording by the participant of:

• OCS medication usage

• Participant perceived OCS side effects using a customised, non-validated, Asthma Steroid Questionnaire (ASQ)

• Asthma control using the validated Asthma Control Test (ACT) questionnaire

• Asthma exacerbations (hospitalisations, days missed from work)

• Reliever and preventer usage

• Lung function data

• Height and weight

To encourage participant engagement, Asthma Track also collates publically available local environmental data (pollen, weather, air quality) which is accessible within the app so that participants will be able to view possible triggers for their asthma. No treatment recommendations are provided

All new participants will be offered the opportunity to download the Asthma Track app at their enrolment visit (+ 4 weeks). The use of the app is subject to the compatability of the participant’s smartphone with the application. Asthma Track will remain live for the duration of the study but participant access will cease once their 24 month study period has completed. Participants will be prompted via app notifications to complete the ACT and ASQ questionnaires every 4 weeks. At all other times participants will interact with

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the app according to their own interest. The Investigator will not be required to promote on-going use of the app.

Full instructions on how to download, activate and use the Asthma Track app will be provided in Site and Subject Quick Reference Guides.

Activity Monitor

ActiGraph GT9X physical activity monitors (tri-axial accelerometers manufactured by and purchased from ActiGraph, LLC) are being use in the study to collect data on the following variables:

- Sleep quality and quantity - Daytime activity ( active vs sedentary bouts) - Energy expenditure - Steps Acitivty monitors will be provided to approximately 200 participants in initially 4 countries (US, UK, Italy, Spain). The activity monitor will be offered to participants at the enrolment visit and use of the activity monitor is voluntary. Only participants who can complete enrolment and index on the same day will be offered an activity monitor. Paticipant’s who use the activity monitor will be able to view their activity and sleep data via the Asthma Track app. Participants will be asked to wear the activity monitor as much as possible from enrolment until 12 months have elapsed. During the study there will be 5 periods of intense wear; this is defined as wearing the activity monitor 24 hours per day for 14 days, except when charging of the activity monitor is required. The intense wear periods will be at the following time points: • From enrolment for 2 weeks

• 2 weeks preceeding the 3 month time point

• 2 weeks preceeding the 6 month time point

• 2 weeks preceeding the 9 month time point

• 2 weeks preceeding the 12 month time point

Participants will be notified of the start and end of intense wear periods via SMS text message to their personal mobile device. Following completion of the 12 months wear period activity monitors will be returned to the Investigator site at the participant’s next asthma related healthcare visit. Full instructions on the set-up and use of the activity monitor and associated hardware will be provided in Investigator Site and Subject Guides.

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o Section 8.3.2 Outcome Definitions p24 text added: In addition, supplementary exploratory outcomes based on participants’ experience with NUCALA will be collected through digital media including a smartphone app and a wearable activity monitor. o Section 8.3.2.5 Exploratory Outcomes p30. New Section added: Exploratory participant experience outcomes may be voluntarily reported by participants using the Asthma Track app and a wearable activity monitor. The feasibility of utilizing the smartphone app and the activity monitor to collect this type of data in a real world setting will be assessed.

Concordance between data collected using the Asthma Track app and activity monitor and data collected at clinic visits will be assessed.

Potential associations between patient characteristics and the uptake of the Asthma Track app and use of an activity monitor will be explored.

Activity and sleep quality data from patients using an activity monitor will be described.

Potential associations between asthma exacerbations recorded at clinic visits and data collected through the Asthma Track app and activity monitor will be explored.

Participant satisfaction with their study experience and the digital media components using a Participant Study Experience Questionnaire will be described

Equivalent outcome data collected by digital modalities will be compared against eCRF data (and claims/EMR where possible) and the details will be provided in the RAP. All remaining analysis related to digital components will be explored in a Supplementary RAP.

o Section 8.9 Data management p 34 text added: Exploratory participant reported outcome data will be collected, where appropriate, using interactive digital media including a smartphone application and a wearable activity monitor. Data from these devices will be securely transferred from the device and stored on the device vendor servers. Final analytical files will be electronically transmitted from the vendors to GSK for exploratory analysis. o Section 9.2 Subject confidentiality p41 text added: The data from the app and activity monitor will be stored in the vendor secure storage facilities. These storage facilities meet approved standards for the security of health information. 4. Inclusion of a Participant Study Experience Questionnaire to assess participant

satisfaction with their study experience and the digital media components.

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o Section 8.3.2.5 Exploratory Outcomes p30. New Section added: Participant satisfaction with their study experience and the digital media components using a Participant Study Experience Questionnaire will be described o Section 8.10.8 Exploratory analysis p 39 text added:

Participant satisfaction with their study experience and the digital media components will be assessed using a Participant Stduy Experience Questionnaire. 5. Analysis populations have been updated to reduce complexity and are limited to

populations that are defined at index. Sub-groups will be described in the RAP. o Section 8.10.1 Analysis Populations p34 Text removed:

1. All Subjects Enrolled (ASE) Population: this population will comprise of all participants enrolled into the study. This population will be used for the reporting of reasons for failure of NUCALA treatment initiation.

2. Intent-to-treat (ITT) Population: this population will comprise of all participants

enrolled into the study who are prescribed NUCALA following physician decision. This will be the primary population for all analysis and will include data on the entire pre- and post-exposure follow-up period.

3. As treated (AT): this population will comprise of all participants enrolled into the

study who are prescribed NUCALA following physician decision. Data from these participants will be included up to discontinuation of NUCALA, defined as the absence of administration/prescription of NUCALA in the remainder of the observation period, or administration/prescription of another biologic (e.g. Xolair, Cinqair) for the treatment of asthma. In these cases, data up to 28 days after the final administration/prescription of NUCALA will be included for analysis. This population will be used as a secondary population.

4. Exposed to treatment (ETT): this population will comprise of all participants

enrolled into the study who are prescribed NUCALA following physician decision. Only data in the “currently exposed to NUCALA" (i.e. on-treatment) period will be included for analysis. This population will be used as a secondary population.

5. As per Label (APL) Population: this population will comprise of all participants

enrolled into the study who are prescribed NUCALA and who meet the relevant label indication. This population will be used as a secondary population of interest for key efficacy analyses. Data included for analysis may defined be as per ITT, AT, or ETT populations, leading to three potential population classifications (APL, APL-AT, APL-ETT, respectively).

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6. As per Local Guidelines (APG): this population will comprise of all participants

enrolled into the study who are prescribed NUCALA and who meet the relevant label indication as well as local treatment / reimbursement guidelines. This population will be used as a secondary population of interest for analyses presented by country or in individual countries of interest. Data included for analysis may defined be as per ITT, AT, or ETT populations, leading to three potential population classifications (APG, APG-AT, APG-ETT, respectively).

Text added: Population Definition / Criteria Analyses Evaluated All Subjects Enrolled (ASE)

• This population will comprise of all subjects enrolled into the study meeting the inclusion criteria for the study. This population will be used for reporting of reasons for failure of NUCALA treatment initiation.

• Study Population

Treated Population (TP)

• This population will comprise of all subjects in the ASE study population who have received at least 1 injection of NUCALA following physician decision.

• Study Population • Efficacy • Health Outcomes • Safety

6. Additional section on Protocol Deviations added. o Section 8.10.2 Protocol Deviations p35 text added: • This study does not include a per protocol population.

• Important protocol deviations (including deviations related to studyinclusion/exclusion criteria) will be summarised and listed.

• Protocol deviations will be tracked by the study team throughout the conduct of the study in accordance with the Protocol Deviation Management Plan.

o Data will be reviewed prior to freezing the database to ensure all important deviations are captured and categorised on the protocol deviations dataset.

o This dataset will be the basis for the summaries and listings of protocol deviations. • A separate summary and listing of all inclusion/exclusion criteria deviations will

also be provided. This summary will be based on data as recorded on the inclusion/exclusion page of the eCRF.

7. Inclusion of the potential for additional interim analyses to be performed to meet individual country evidence requirements.

o Section 8.10.1 Interim Analysis p36 text added: Additional interim analyses may be

performed to meet individual country evidence requirements. 8. AE and SAE definitions added and timelines for reporting of non-serious AEs

explicitly attributed to any GSK product have been clarified .

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o Section 10 Management and reporting of adverse events/adverse reactions p42. Text removed: If, during the study, an adverse event (AE) (serious or non serious) is identified as explicitly attributed to any GSK product (including products not covered in the specific study objective), this will be reported to the sponsors safety department within 24 hours of first becoming aware of the event. Text added: This study adopts the following ICH definitions:

Adverse event: Any untoward medical occurrence in a patient or clinical investigation

subject administered a pharmaceutical product and which does not necessarily have to

have a causal relationship with this treatment.

An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding) symptom or disease (new or exacerbated) temporally associated with the use of a Medicinal Product. For a marketed Medicinal Product, this can also include failure to produce expected benefits (i.e. lack of efficacy, with or without an adverse event), and adverse events associated with circumstances of Overdose whether accidental or intentional, Medication Errors, Abuse or effects of drug withdrawal, or Misuse.

Serious adverse event: any untoward medical occurrence that at any dose that 1) results

in death, 2) is life threatening, 3) requires inpatient hospitalization or prolongs existing

hospitalization, 4) results in persistent or significant disability/incapacity or 5) is a

congenital anomaly.

• Medical and scientific judgement should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or may require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation; or development of drug dependency or drug abuse.

All serious and non-serious AEs, pregnancy exposures, and incidents identified as explicitly attributed to any GSK product (including products not covered in the specific study objective) will be collected and reported to the Sponsor’s safety department. All serious AEs, pregnancy exposures, and incidents explicitly attributed to any GSK product will be reported to the Sponsor within 24 hours of recognition. All non-serious AEs

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explicitly attributed to any GSK product will be reported to the Sponsor within 5 calendar days of recognition 9. Instructions on the identification and reporting of Medical Device Incidents

(including malfunctions) have been added in relation to the inclusion of the activity monitor in the study.

o Section 10.1 Medical device incidents (including malfunctions) p43. New section

added: Medical Device Incidents (Including Malfunctions)

A medical device is being provided for use in this study for the purpose of evaluating physical activity (activity monitor). In order to fulfil regulatory reporting obligations worldwide, the investigator is responsible for the detection and documentation of events meeting the definitions of incident or malfunction that occur during the study with such devices. o Section 10.1.1 Medical Device Incident Definition p43. New section added: Medical Device Incident Definition

• A medical device incident is any malfunction or deterioration in the characteristics and/or performance of a device as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, might lead to or might have led to the death of a participant/user/other person or to a serious deterioration in his/her state of health.

• Not all incidents lead to death or serious deterioration in health. The nonoccurrence of such a result might have been due to other fortunate circumstances or to the intervention of health care personnel.

It is sufficient that:

• An incident associated with a device happened and

• The incident was such that, if it occurred again, might lead to death or a serious deterioration in health.

A serious deterioration in state of health can include any of the following: • Life-threatening illness

• Permanent impairment of body function or permanent damage to body structure

• Condition necessitating medical or surgical intervention to prevent one of the above

• Fetal distress, fetal death, or any congenital abnormality or birth defects

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Examples of incidents

• A participant, user, caregiver, or healthcare professional is injured as a result of a medical device failure or its misuse.

• A participant’s study treatment is interrupted or compromised by a medical device failure.

• A misdiagnosis due to medical device failure leads to inappropriate treatment. • A participant’s health deteriorates due to medical device failure. o Section 10.1.2 Detecting and Reporting Medical Device Incidents p44. New section

added: Detecting and Reporting Medical Device Incidents

Medical device incidents or malfunctions of the activity monitor that result in an incident will be detected, documented, and reported during all periods of the study in which the activity monitor is used. If the Investigator learns of any incident at any time after a participant has ceased wearing the activity monitor, and such incident is considered reasonably related to the activity monitor provided for the study, the investigator will promptly notify the sponsor. Medical device incidents will be reported to the sponsor within 24 hours after the investigator determines that the event meets the protocol definition of a medical device incident.

The Investigator must complete the Medical Device Incident Form for each participant who has a medical device incident with the GSK activity monitor provided for use during the study period. All of the header information in the form must be completed before sending to the sponsor. Original documents should be filed in the site study file. A copy of the form must also be sent to the study monitor.

For incidents fulfilling the definition of an AE or SAE, the appropriate pages of the eCRF must be completed. If there is an SAE, the completed eCRF pages should be sent together with the Medical Device Incident Form.

o Section 10.1.3 Documenting Medical Device Incidents p44. New section added: Documenting Medical Device Incidents

Any medical device incident occurring during the study will be documented in the participant’s medical records, in accordance with the Investigator’s normal clinical practice. For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE eCRF page will be completed. The form will be completed as thoroughly as possible and signed by the Investigator before transmittal to the Sponsor’s safety department.

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It is very important that the Investigator provides his/her assessment of causality (relationship to the activity monitor provided by GSK) at the time of the initial report and describes any corrective or remedial actions taken to prevent recurrence of the incident. A remedial action is any action other than routine maintenance or servicing of a medical device where such action is necessary to prevent recurrence of an incident. This includes any amendment to the device design to prevent recurrence. o Section 10.1.4 Follow-up of Medical Device Incidents p44. New section added: Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed and reported in the same manner as other AEs. This applies to all participants, including any participant who chooses to withdraw from the study. The Investigator is responsible for ensuring that follow-up includes any supplemental investigations as indicated to elucidate the nature and/or causality of the incident. New or updated information will be recorded on the originally completed form with all changes signed and dated by the investigator. o Section 10.1.5 Regulatory Reporting Requirements for Medical Device Incidents

p45. New section added:

Regulatory Reporting Requirements for Medical Device Incidents

The Investigator will promptly report all incidents occurring with any medical device provided for use in the study in order for the sponsor to fulfill the legal responsibility to notify appropriate regulatory authorities and other entities about certain safety information relating to medical devices being used in clinical studies.

The Investigator, or responsible person according to local requirements (e.g., the head of the medical institution), will comply with the applicable local regulatory requirements relating to the reporting of incidents to the IRB/IEC. 10. The Time & Events table has been updated to include the offer of the smartphone

app and the activity monitor, and the include of the Patient Study Experience Questionnaire. The opportunity has been taken to make additional updates to the Time & Events table to aid clarity.

o Section 13.1 Appendix 1 Time and Events Table.

Previous table:

Procedures PRE EXPOSURE OBSERVATION PERIOD (‘POST EXPOSURE’)

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Enrolment6

12-months Pre-

enrolment

History4

Treatment Index

3,6

Data collected at usual

asthma related healthcare visits ( no

more frequently than monthly (±10

days))

Questionnaires offered at usual asthma healthcare visits, immediately prior to NUCALA injection, if this is possible; no more frequently than every 3 months (±20days).

Time period ( ie weeks post

enrolment) for which data should be

collected at usual asthma healthcare

vists

Week 0 Week 0 to day

of NUCALA first

injection

Week 4 to 104 Week 4 to 12 Week 16 to 104

Informed consent X Demography X Asthma diagnosis X Medical History / co-morbidities

X X7

Details of NUCALA Administration

X1 X

Asthma Exacerbations X X X Asthma Related Outpatient visits

X X X

Asthma Related ER visits

X X X

Asthma Related Hospital admissions

X X X

Oral/Systemic corticosteroids usage

X X X

ACQ-5 X5 X5 X5 WPAI X5 X5 X5 Patient satisfaction questionnaire X5

Physician satisfaction questionnaire X5

Asthma and concurrent medications

X X X

Lung function2 X X X Peripheral Blood eosinophils

X2 X2 X2

Sputum cell counts and FeNO

X2 X2 X2

Details of Herpes Zoster vaccination

X8

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Procedures

PRE EXPOSURE OBSERVATION PERIOD (‘POST EXPOSURE’)

Enrolment6

12-months Pre-

enrolment

History4

Treatment Index

3,6

Data collected at usual

asthma related healthcare visits ( no

more frequently than monthly (±10

days))

Questionnaires offered at usual asthma healthcare visits, immediately prior to NUCALA injection, if this is possible; no more frequently than every 3 months (±20days).

Time period ( ie weeks post

enrolment) for which data should be

collected at usual asthma healthcare

vists

Week 0 Week 0 to day

of NUCALA first

injection

Week 4 to 104 Week 4 to 12 Week 16 to 104

1. Administration will be at the discretion of the physician. To include date of administration as well as date

and reasons for discontinuation. 2. Spirometry, peripheral blood eosinophils, sputum cell counts and FeNO will be noted when the

information is available as part of normal care. Baseline values to be collected using the historical value nearest to the treatment index date during the previous 12-months.

3. Events to be collected throughout the period between enrolment and treatment initiation. 4. The 12-month participant’s history will start from the date of enrolment and finish at minus 365 days

(+1day) ( except when index date preceeds enrolment by up to 7 days, in which case the 12- month history will start at treatment initiation minus 365 days (+1day)

5. At baseline, the questionnaires may be completed either at enrolment or at index date. When offered on the same day,. the questionnaires should be completed PRIOR to NUCALA injection, if possible.

6. Patient Enrolment and the Index Date (first NUCALA injection) may occur on the same day. When data collection at index date is not possible, this data should be collected at enrolment

7. To include any allergic conditions ( e.g. IgE,Skin prick test). 8. Details of Herpes Zoster vaccination will also be recorded 12 months (±3 months) after NUCALA index

date ( treatment initiation).

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New table:

Procedures

PRE EXPOSURE OBSERVATION PERIOD (‘POST EXPOSURE’)

Enrolment5

12-months

Pre-enrolm

ent History8

Treatment

Index10,5

Data collected at usual

asthma related healthcare

visits ( no more frequently than monthly (±10

days))

Questionnaires offered at usual asthma healthcare visits, immediately prior to NUCALA injection, if this is possible; no more frequently than every 3 months (±20days).

Time period ( ie weeks post enrolment) for

which data should be collected at usual asthma healthcare

vists

Week 0 Week 0 to day

of NUCALA

first injection

Week 4 to 104

Week 4 t to 100 Week 104 (End of study)

Informed consent X Demography X Asthma diagnosis X Medical History / co-morbidities

X X11

Details of NUCALA Administration1

X X

Asthma Exacerbations X X X Asthma Related Outpatient visits

X X X

Asthma Related ER visits

X X X

Asthma Related Hospital admissions

X X X

Oral/Systemic corticosteroids usage

X X X

ACQ-5 X6 X6 X6,7 X6,7 WPAI X6 X6

X6,7 X6,7

Patient satisfaction questionnaire X6 X6

Physician satisfaction questionnaire X6 X6

Participant Study Experience questionnaire

X

Asthma and concurrent medications

X X X

Lung function2 X X X Peripheral Blood eosinophils2

X X X

Sputum cell counts and FeNO2

X

X X

Details of Herpes Zoster vaccination

X9

Offer initiation of smartphone App3

X

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Procedures

PRE EXPOSURE OBSERVATION PERIOD (‘POST EXPOSURE’)

Enrolment5

12-months

Pre-enrolm

ent History8

Treatment

Index10,5

Data collected at usual

asthma related healthcare

visits ( no more frequently than monthly (±10

days))

Questionnaires offered at usual asthma healthcare visits, immediately prior to NUCALA injection, if this is possible; no more frequently than every 3 months (±20days).

Time period ( ie weeks post enrolment) for

which data should be collected at usual asthma healthcare

vists

Week 0 Week 0 to day

of NUCALA

first injection

Week 4 to 104

Week 4 t to 100 Week 104 (End of study)

Offer initiation of Acitivity Monitor4

X X

Return of Activity Monitor

X

1. Administration will be at the discretion of the physician. To include date of administration as well as

date and reasons for discontinuation. 2. Spirometry, peripheral blood eosinophils, sputum cell counts and FeNO will be noted when the

information is available as part of normal care. Baseline values to be collected using the historical value nearest to the treatment index date during the previous 12-months.

3. The Smartphone App should be offered to all patients at enrolment (+ 4 weeks). Only patients with compatible devices will be able to download the App. Use of the Smartphone App is voluntary.

4. The activity monitor will only be offered to a sub set of patients (see Section 8.1.1).The activity monitor must only be offered to patients who can complete enrolment and index on the same day.

5. Enrolment and the Index Date (first NUCALA injection) may occur on the same day. When data collection at index date is not possible, this data should be collected at enrolment

6. At baseline, the questionnaires may be completed either at enrolment or at index date. When offered on the same day, the questionnaires should be completed PRIOR to NUCALA injection, if possible.

7. If questionnaires are not completed at enrolment or index they should not be offered at subsequent visits.

8. The 12-month participant’s history will start from the date of enrolment and finish at minus 365 days (+1day) ( except when index date preceeds enrolment by up to 7 days, in which case the 12- month history will start at treatment initiation minus 365 days (+1day)

9. Details of Herpes Zoster vaccination will also be recorded 12 months (±3 months) after NUCALA index date ( treatment initiation).

10. Events to be collected throughout the period between enrolment and treatment initiation. 11. All medical history is collected at enrolment including IgE and skin prick tests