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CONFIDENTIAL GlaxoSmithKline group of companies Project number: PRJ2414

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TITLE PAGE

Division: Worldwide Development

Information Type: Worldwide Epidemiology Study Protocol

Title: Phenotypes of Severe Asthma among Adults in Brazil: a

descriptive report of characteristics of subjects followed up in

the ProAR Cohort

Compound

Number:

[Mepolizumab]

Development

Phase

[IV]

Effective Date: 23-Oct-2017

Subject: [Severe asthma phenotypes]

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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CONFIDENTIAL Project number: PRJ2414

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TABLE OF CONTENTS

PAGE

Table of Contents

1. LIST OF ABBREVIATIONS ...................................................................................... 4

2. ABSTRACT .............................................................................................................. 8

3. AMENDMENTS AND UPDATES .............................................................................. 9

4. MILESTONES ........................................................................................................ 13

5. RATIONAL AND BACKGROUND .......................................................................... 13 5.1. Background ................................................................................................ 13 5.2. Rationale .................................................................................................... 14

6. RESEARCH QUESTION AND OBJECTIVE(S) ..................................................... 14

7. RESEARCH METHODS ........................................................................................ 15 7.1. Study Design .............................................................................................. 15 7.2. Setting ........................................................................................................ 18

7.2.1. Inclusion and exclusion criteria .................................................... 19 7.3. Variables .................................................................................................... 19

7.3.1. Severe asthma definition ............................................................. 19 7.3.2. Outcome definitions .................................................................... 20 7.3.3. Other variables .............................................................................. 24 7.3.4. Exposure definitions ...................................................................... 25 7.3.5. Confounders and effect modifiers .................................................... 26

7.4. Data sources ................................................................................................ 26 7.5. Sample size .................................................................................................. 26 7.6. Data management ......................................................................................... 26

7.6.1. Data handling conventions .............................................................. 26 7.6.2. Resourcing needs ........................................................................... 26 7.6.3. Timings of Assessment during follow-up .......................................... 26

7.7. Data analysis ................................................................................................ 27 7.7.1. Essential analysis ........................................................................... 27 7.7.2. Analysis Population ..................................................................... 27 7.7.3. Primary Analysis ......................................................................... 28 7.7.4. Other analysis ............................................................................. 32 7.7.5. Exploratory analysis .................................................................... 32

7.8. Quality control ............................................................................................ 32 7.9. Limitations of the research methods ........................................................... 33

8. PROTECTION OF HUMAN SUBJECTS ................................................................... 33 8.1. Ethical approval and subject consent ......................................................... 33 8.2. Subject confidentiality ................................................................................... 34

9. RECORD RETENTION ........................................................................................... 34


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10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .......... 34 10.1. Target Audience ........................................................................................... 34 10.2. Study reporting and publications .................................................................... 34

11. REFERENCES ........................................................................................................ 35


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1. LIST OF ABBREVIATIONS

ACQ6 Asthma Control Questionnaire- 6

CRF Case Report Form

CI Confidence Interval

CRP C-Reactive Protein

EQ-5D-3L EuroQol Qualit of Life questionnaire

FEV1 Forced expiratory volume in 1 second

FVC Forced Vital Capacity

GCP Good Clinical Practices

GINA Global Initiative for Asthma

GSK GlaxoSmithKline

HR-Qol Health-related quality of life

ICS Inhaled corticosteroid

IgE Immunoglobulin E

IL5 Interleukin 5

LABA Long-acting beta-adrenoceptor agonists

LSLV Last Subject Last Visit

PEF Peak Expiratory Flow

ProAr Program for Control of Asthma

SA population Severe asthma population

UFBA Federal University of Bahia

WPAI-GH Work Productivity and Activity Impairment Questionnaire: General

Health

WHO World Health Organization

Trademark Information

Trademarks of the GlaxoSmithKline

group of companies

Trademarks not owned by the

GlaxoSmithKline group of companies

None none


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SPONSOR SIGNATORY:

Karynna Pimentel Viana

LATAM Epidemiology Coordinator

Date

Sarah Landis

WWEpi Respiratory Lead

Date


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SPONSOR INFORMATION PAGE

WWEpi Project Identifier:

Sponsor Legal Registered Address:

GlaxoSmithKline - LATAM office

Estrada dos Bandeirantes, 8464.Third Floor.

Jacarepaguá. Rio de Janeiro, Brazil

CEP: 22783-110

Sponsor Contact Address




CEP: 22783-110 – LATAM Epidemiology Coordinator

Telephone:




CEP: 22783-110 – LATAM Epidemiology Director

Telephone:




CEP: 22783-110 – LATAM Clinical Project Management

Telephone:

Sponsor Country Contacts

Sponsor Medical Monitor Contact Information:

Sponsor Serious Adverse Events (SAE) Contact Information:

Regulatory Agency Identifying Number(s):

PPD

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PPD

PPD

PPD

PPD


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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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2. ABSTRACT

Background: Recent developments have shifted asthma treatment from nonspecific

medications to molecularly targeted therapies for defined phenotypes. Data describing the

various phenotypes of severe asthma and the identification of biomarkers for each phenotype is

essential for the improvement of patient care. In Brazil, phenotype data is scarce. Further, there

is a lack of understanding regarding the influence of local levels of endemic intestinal parasitic

infections on the inflammatory response for severe asthma patients, and consequently, the

expression of particular phenotypes.

Objective: To describe the proportion of severe asthma patients eligible for one or more

currently available monoclonal antibody treatments (mepolizumab, omalizumab reslizumab and

benralizumab) and to characterize the frequency of parasitic disease among eosinophilic asthma

patients. Also, this study will describe healthcare resource utilization, quality of life and asthma

control in the severe asthma population.

Patients and Methods: An observational, bidirectional, longitudinal study of patients with

severe asthma will be conducted. In the retrospective phase, the data analysed will be those from

the severe asthma patients that participated in a previously conducted case control study, these

data are considered the first visit (Visit 1). Also, medical charts will be reviewed to assess if the

prior asthma medications use can be collected in order to define an alternative severe asthma

population as consistent with GINA 2017. For the prospective phase, a new study visit (V2), at

least 1 year after the previous visit (Visit 1), will be scheduled to collect data on asthma control,

quality of life, healthcare resource utilization, and work absenteeism using patient

questionnaires.


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3. AMENDMENTS AND UPDATES

Amendment

or update no Date

Section of

study

protocol

Amendment or update Reason

1

08/08/2017 Section 4 Milestones update The study had a delay

and the interim report

will not be done

anymore.

08/08/2017 Section 7.1 Clarifications on data

collection.

The information

regarding the specific

data that will be

collected for

individuals who used

omalizumab previous

to visit 1 and those

who participated in a

clinical trial in the last

12 months previous to

visit 2 was clarified. 08/08/2017 Section 7.1

Section 7.6.3

The data collection year was

changed to 2017 on figure 1

and on the table describing

the data to be collected per

data source

(Study design)

We clarified on section

7.6.3 that the timeframe

between visit 1 to visit 2

will range from 2 to four

years.

The study was delayed

during the

implementation and

the data collection

initiated only in 2017

08/08/2017 Section 7.1 The Figure 2

(flowchart) was changed to

other model and to clarify

the data that will be

collected for patients using

Omalizumab

The Figure 2

(flowchart) used in the

original protocol

described an error in

the exclusion criteria,

which was conflicting

with the text described

above in the same

section.

08/08/2017 Section 7.2.1 Change the text in one of

the exclusion criteria

The text used in the

original document

described that patients,

who used omalizumab

in the last 12 months

would be excluded

from the study.


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The right text show be

that the patient will

only be excluded from

visit 2 (prospective

data) and they will be

excluded from the full

analysis set. However,

for these patients it

will be collected the

medication used in the

last 12 months and

minimal information

from the case-control

database will be

analyzed (gender, skin

color and age)

08/08/2017 Section 8.1 Change in this specific

section to clarify that the

ethical committee special

authorization would also

include the guarantee to

review the medical chart

and not only the database of

the case-control study as

described in other sections

of the original protocol

The text needed to be

changed because this

was not consistent

with other parts of the

protocol (Section 7.1).

In the original text of

the section 8.1, it was

not mentioned that the

special authorization

from the ethical

committee included

the review of the

medical chart for

patients who were loss

of follow-up or were

deceased. However, in

the original text, this

was correctly

described in the

section 7.1.

08/08/2017 Section 7.7.4 The text was changed to

reflect data collection field

in the CRF

The reason for the

patient consenting

only to the visit 1 re-

analyses will not be

collected anymore 1

08/08/2017 Annex 1

(table 36)

The table was changed to

reflect data collection field

in the CRF

The reason for the

patient consenting

only to the visit 1 re-

analyses will be not be

collected anymore.


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08/08/2017 Section 7.1,

Section

7.3.2,

Section 7.7.2

Section 7.7.3

Annex 1

We replaced GINA 2015 to

GINA 2017

As GINA 2017 was

already published, the

analysis will be

conducted considering

the GINA 2017

definition and not

GINA 2015

08/08/2017 Section 7.7

Section 7.3.1

Section 7.7.2

We replaced the sentence

explaining the severe

asthma definition by GINA

2017 “ie, ICS-LABA high dose or ICS-LABA plus other controller” to the following “i.e. treatment step 4 or step 5 according to GINA 2017).

We will describe the

definition of step 4 or

5 by medication used

in details in the study

analysis plan

08/08/2017 Section 7.3. It was included the following sentence “For the treatment schemes that are not clear defined on GINA 2017, respirologists or allergists will be consulted to defined the classification, ie, severe or non-severe asthma patient”

Some specialists will

be consulted to define

the severity

classification in cases

that it would be

difficult to classify the

patients as severe and

non-severe asthma

08/08/2017 Section 7.2

Section 7.2.1

It was removed the age limit

<40 years from the case-

control inclusion criteria and

it was removed the

exclusion criteria “Smokers

with greater than or equal to

10 pack-year“ in

the case-control exclusion criteria

These criteria were not

considered in the

previously conducted

case-control study and

we needed to edit this.

2 10/02/2017 Section 2,

Section 5.1

Section 6

Section 7.1

Section7.3.2

Section 7.7.3

We included as study

objective to analyze the

eligibility to Benralizumab.

The same analysis that we

were proposing for

Omalizumab and

Reslizumab in the original

protocol will be also done to

Benralizumab. This new

objective included was

reflected on Study endpoint,

Study design, outcome

definitions, analyses

Beralizumab was not

in an advanced phase

of clinical

development when the

original protocol was

approved. However,

current this biological

is on Phase III and is

part of the group of

biological therapies

for severe asthma in

late phase

development


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population and primary

analysis.

2 10/02/2017 Figure 3 Include a Benralizumab in

the figure demonstrating the

patient eligibility and the

overlap between therapies.

10/02/2017 Annex 1 Table 1 Title changed to

include Benralizumab.

Original text:

Frequency of patients

eligible for Mepolizumab,

omalizumab and reslizumab

and overlap;

New text with inclusion of

Benralizumab:

Frequency of patients

eligible for Mepolizumab,

omalizumab, reslizumab and

Benralizumab overlap;

10/02/2017 Annex 1 In the list of tables

below, it was included a

column to included the

benralizumab data.

Table 1

Table 2

Table 4

Table 6

Table 8

Table 10

Table 16

Table 18


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Table 20

Table 22

Table 39

4. MILESTONES

Milestone Planned date

Start of data collection Jan 2017

End of data collection September 2017

Final study report December 2017

5. RATIONAL AND BACKGROUND

5.1. Background

Severe asthma is a heterogeneous disease characterized by the need for treatment with high doses

of inhaled corticosteroids (ICS) and includes several distinct clinical and pathophysiological

phenotypes1.

Recent developments have shifted asthma treatment from nonspecific medications, including

corticosteroids and bronchodilators, to molecularly targeted therapies for defined phenotypes.

Three monoclonal antibody-based drugs target immunologic mediators that are commonly

associated with specific phenotypes of severe asthma. Omalizumab (Xolair®) is a monoclonal

anti-IgE antibody that is already marketed in Brazil and has been reported to significantly benefit

a subset of patients with moderate-to-severe persistent allergic asthma inadequately controlled

with high-dose inhaled corticosteroids and long-acting β2-agonists2. Mepolizumab, reslizumab

and benralizumab are both monoclonal anti-IL-5 antibody treatments currently in development

and are targeted for asthma patients with eosinophilic inflammation and those who experience

exacerbations or require daily systemic corticosteroids to control their disease3.

As a result, the understanding of the prevalence for various severe asthma phenotypes and the

identification of biomarkers for each phenotype is essential for the improvement of patient care.

In Brazil, asthma phenotype data is scarce; only one previous study described the clinical

characteristics and phenotypes of adult patients with severe resistant asthma2 at a healthcare

centre in Brazil. However, this study did not specifically investigate the proportion

of patients that are eligible for treatment with mepolizumab, omalizumab, reslizumab or

benralizumab.

Another point of concern is the lack of understanding regarding the influence of local levels of

endemic intestinal parasitic infections on the inflammatory response among severe asthma

patients, and consequently, the expression of particular phenotypes. An increased blood

eosinophil level is widely used as a prognosis factor and may provide direction for treatment in

non-endemic countries. However, using increased blood eosinophil levels as a marker may

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jeopardize patient care in countries with endemic parasitic infections where higher levels of

eosinophils are expected as a consequence of these infections.

Furthermore, it is important to understand the impact of severe asthma on quality of life and

healthcare resource utilization as severe asthma accounts for a large proportion of overall asthma

costs4. One Brazilian study published in 2008 investigated the economic impact of severe

asthma; however, there is no recent healthcare utilization data available5.

This study aims to describe the healthcare resource utilization, health related quality of life and

asthma control in the severe asthma population. Also, this proposed study intends to identify the

proportion of severe asthma patients eligible for one or more of the current monoclonal antibody

treatments and to determine the frequency of eosinophils and distribution of blood eosinophil

levels in patients with or without the presence of parasitic disease.

5.2. Rationale

The purpose of this study is to identify the proportion of severe asthma patients eligible for one

or more of the three current monoclonal antibody treatments and to characterize the frequency

of eosinophilic patients with parasitic disease. Also, this study will describe healthcare resource

utilization, quality of life and asthma control in the severe asthma population.

6. RESEARCH QUESTION AND OBJECTIVE(S)

The following objectives will be addressed

Description of severe asthma

1a) To determine blood eosinophil levels in adults with severe asthma, stratified by

positive/negative status for parasites on stool examination;

1b) To assess the proportion of eosinophils based on different cut-off points in severe

asthma adult patients, stratified by positive/negative status for parasites on stool

examination;

1c) To assess the healthcare resource utilization for severe asthma patients;

1d) To describe health related quality of life (HR-Qol) and asthma control in severe

asthma patients;

1e) To describe the following baseline visit clinical assessments for severe asthma:

o Spirometry;

o Blood biomarkers;

o Atopy status

Eligibility for biological therapy

2a) To describe the population of adults with severe asthma that meet the eligibility

criteria for one or more of the following medication(s) mepolizumab (anti-IL5),

omalizumab (anti-IgE), reslizumab (anti-IL5) and benralizumab (anti-IL5);


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2b) To describe treatment patterns for severe asthma patients by eligibility criteria for

mepolizumab, omalizumab, reslizumab and benralizumab;

2c) To evaluate the following characteristics for subgroups defined by eligibility to

receive mepolizumab, omalizumab, reslizumab and benralizumab;

o Healthcare resource utilization;

o HR-Qol;

o Absenteeism;

o Asthma symptoms (GINA 2014 criteria);

o Asthma control (ACQ6);

2d) To describe the clinical, demographic, and health characteristics of the severe

asthma patient population, stratified by the eligibility for mepolizumab

positive/negative status for parasites on stool examination; omalizumab, reslizumab

and benralizumab eligibility;

2e) To describe healthcare resource utilization and asthma control (ACQ6) results of the

severe asthma patient population, stratified by the eligibility for mepolizumab and

positive/negative status for parasites on stool examination.

7. RESEARCH METHODS

7.1. Study Design

This is an observational bidirectional longitudinal study.

The Program for Control of Asthma (ProAR) in Salvador, Bahia – Brazil started in 2003 and

provides multidisciplinary management, including education and free medication, for over 3,000

patients with severe untreated asthma enrolled in 4 treatment clinics. From January 2013 until

July 2015, the ProAr team conducted a study titled, “Risk factors, endophenotypes and

biomarkers of severe asthma” for which data related to demographic, clinical, biological and

genetic information was collected for adults with severe asthma, mild asthma or no asthma.

Patients with severe asthma (N=544) were followed in the ProAr cohort and participated as cases

in the case-control study; community-based patients without asthma or mild asthma served as

the control subjects. The severe asthma definition used was based on WHO experts and GINA

2002 (See section 7.3.1).

The project proposed herein is a bidirectional cohort study of the subjects with severe asthma

included in the previous case-control study that met the inclusion criteria of this study (See

section 7.2.1). This population is called severe asthma population. In the retrospective phase of

the new proposed study, information related to severe asthma patients will be obtained from the

database used for the case-control study. The first visit (Visit 1) for the present study is the visit

included in the previously completed case-control study. In addition, medical charts will be

reviewed to assess if the prior asthma medications use can be collected in order to define an

alternative severe asthma population as consistent with GINA 2017. Optimally, according to

GINA 2017and in alignment with other GSK observational studies, we would define severe

asthma based on chronic medication use over a period of a minimum of 12 months (i.e. treatment


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step 4 or step 5 according to GINA 2017). This population will be called severe asthma GINA

2017 population.

For the prospective phase of the proposed study, a second study visit (Visit 2) will be scheduled

to coincide with the patient’s regular visits to the severe asthma clinic, at least 1 year after the

first visit (Visit 1). The Visit 1 may occur from 2013 through 2015, leading to significant

differences regarding the time between Visit 1 to Visit 2 for study subjects. This may add bias

to the results of healthcare resource utilization, ACQ6, EQ5D and asthma symptoms that will be

collected in visit 2.

Information collected at Visit 1 will be used to estimate the frequency of patients eligible for

mepolizumab, omalizumab, reslizumab and benralizumab. Blood eosinophil counts and the

proportion of patients with severe asthma, with and without positive parasitic disease, will also

be described. At Visit 2, new data will be collected using patient questionnaires to assess asthma

control, quality of life, healthcare resource utilization, and work absenteeism. Figure 1 depicts

the study design.

Figure 1: Study design

Variables collected according to the data source:

Medical chart (year previously to the

case-control visit)

It will be assessed if the prior asthma

medications use can be collected in

order to define an alternative severe

asthma population as consistent with

GINA 2017.

Database re-analysis of data as of Visit

1(case-control study) • Demographic data;

• Co-morbidities;

• Eosinophils level;

• Stool examination results;

Those with severe asthma that participated in the case control study will be selected

2013-2015

Visit 1: re-analysis of the database from the case-control study

Case-control study “Risk factors, Endophenotypes and biomarkers of severe Asthma”

2017

Visit 2: data collection

Review the medical chart


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• Hospital Admission in the last 12

months due to severe asthma;

• Emergency visit in the last 12 months

due to severe asthma;

• ACQ6;

• Asthma Disease History

Prospective data (Visit 2)– interview in

2017 • Demographic data;

• Co-morbidities;

• Hospital Admission in the last 12

months due to severe asthma or

respiratory symptoms

• Emergency visit due to severe asthma

or respiratory symptoms in the last 12

months

• Medication used in the last year.

• GINA 2014 asthma control

• ACQ6

• WPAI-GH

• EQ5D

After the ethical/regulatory approvals are obtained and contracts are established, the ProAr

team will be authorized to start enrolment. To start, the site staff will identify the severe asthma

patients in the study database from the previously conducted case-control study. All severe

asthma patients who participated in the study and still being followed at the study site at the start

date for this proposed study will be contacted during the next routine medical visit. At the time

of the medical visit, the patient will be invited to take part in the proposed study. Patients who

agree to participate will sign the Informed Consent Form (ICF) before any data collection or data

re-analysis will take place. A special authorization from the ethics committees for medical chart

data collection and database re-analysis will be requested for patients identified as eligible, but

who could not be found for any reason (lost to follow-up) or are known to be deceased. It will

be not considered in the analysis the patients that used omalizumab previous to the visit in the

case-control study. However, it will be collected the medication used in the 12 months previous

to visit 1 for these patients.

For all patients with a signed ICF or special authorization, the study staff will review the medical

records as part of the study feasibility to determine, if the prior asthma medications use can be

collected in order to define an alternative severe asthma population as consistent with GINA

2017.

For the patients no longer followed at the study site or those who did not sign the ICF for visit

2, no further data will be collected. However, for patients who sign the ICF for visit 1 re-analysis

or those no longer followed that the special permission is granted by ethics committee the data

from medical chart and from the case-control study database will be used. For patients who are

still followed at the study site and consented to participate in visit 2, previous participation in a

clinical trial during the last 12 months will be confirmed. Those who participated in a clinical

trial in the last 12 months and/or those who were using Omalizumab in the 12 months previous


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to visit 1 will not be included in visit 2. The remaining subjects will participate in visit 2 for the

assessment of asthma control, quality of life, work absenteeism, and medication history.

Figure 2: Study Flowchart

*At the time of visit 2, patients may consent just for the re-analysis of the case-control study (Visit 1) and medical

chart data collection. If this happen, they will be included in the database re-analysis and medical chart review

(Visit 1) and no further data will be collected for such patient.

**For patients using omalizumab in the 12 months previous to visit 1, the medical chart data will be collected and

just the following Data from the database will be analysed:

- Age;

-skin colour;

-Gender

***Medical chart review will be performed to assess the medication used before to Visit 1 ( the case-control

study).

7.2. Setting

The subjects included in the current study are those diagnosed with severe asthma that

were previously enrolled and followed up in the ProAr severe asthma program and included in

the case-control study “Risk Factors, endophenotypes and biomarkers of severe asthma”, i.e.,

met the inclusion/exclusion criteria of the case-control study (See section 7.2.1). The diagnosis

of asthma was validated through a medical chart review by two experts and complemented with

a full clinical re-evaluation to assess current asthma control. A spirometry was mandatory,

performed with a KoKo® spirometer (Software PDS Instrumentation, Inc., Louisville, CO,

USA), according to the norms of the American Thoracic Society, but using the parameters of

normality devised by Pereira et al for Brazilians. Chest X-Rays were performed to rule out other


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lung diseases. The classification of asthma severity followed criteria proposed by GINA in 2002

and WHO experts (See section 7.3.1), taking into consideration the frequency of symptoms,

limitation on activities, use of rescue medication and forced expiratory volume in 1 second

(FEV1).

7.2.1. Inclusion and exclusion criteria

Inclusion criteria:

• Subject recorded on the database of the case-control study as severe asthma

patients**;

• Patients who agree to participate in the study by signing an ICF* or Patients who

meet at least one criteria for a special authorization from the ethics committees (See

Section 8.1).

Exclusion criteria:

• Patients using Omalizumab at least once in the last 12 months before visit 1 will be

excluded from visit 2

• Patients that participated in an interventional clinical trial in the last 12 months

before the visit 2 will be excluded from visit 2.

*Patients may consent to allow just the analysis of the case-control database and medical chart

(retrospective part) and also may consent for both retrospective and prospective phase (visit 2).

** The inclusion/exclusion criteria for the severe asthma of the previously conducted case-

control study “Risk factors, endophenotypes and biomarkers of severe asthma” were:

- Inclusion criteria:

• Subjects enrolled in the outpatient clinics of ProAR, which met the criteria of

diagnosis of asthma (See section 7.3.1). Patients classification included a chart audit

by two experts in asthma to validate the diagnosis of asthma;

• Aged ≥ 18 years

- Exclusion criteria:

• Previous diagnosis of Chronic Obstructive Pulmonary Disease (COPD);

• Patients did not sign the ICF;

7.3. Variables

7.3.1. Severe asthma definition

The asthma diagnosis and severity were audited by two experts who reviewed the clinical records

and complementary tests diagnosis. Both experts completed a standard assessment. Considering

that an asthma diagnosis is subjective, the options for the experts were: A) The patient has

asthma; B) The patient probably has asthma; C) The patient does not have asthma. In the case-

control study, only patients for whom both experts marked the option A were included. In


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summary, the asthma diagnosis was confirmed if the patient had recurrent dyspnea that improves

using a bronchodilator. Self-reported wheezing by the patient and the presence of bronchodilator

reversible obstructive airways disease reinforced the diagnosis. Severe asthma categorization

was determined upon enrollment on the basis of the classification of asthma severity proposed

by WHO experts and GINA in 2002 (GINA Strategy 2002). Patients were classified with severe

asthma if at least one of the following criteria were met:

• Daily asthma symptoms;

• Exacerbation or frequent nocturnal symptoms;

• Limitation of physical activity;

• Reduced lung function (FEV1 or PEF ≤60%) or variability of FEV1 or PEF >30%.

Severe asthma ascertainment was based on a physician clinical judgement supported by fulfilling

criteria presented above. This severe asthma definition is consistent with the current clinical

label for a persistent severe asthma.

As a part of the study feasibility, it will be determined if the prior asthma medications use can

be collected in order to define an alternative severe asthma population as consistent with GINA

2017. Optimally, according to GINA 2017 and in alignment with other GSK observational

studies, we would define severe asthma based on chronic use over a period of a minimum of 12

months (i.e. treatment step 4 or step 5 according to GINA 2017). This population will be called

severe asthma GINA 2017. For the treatment schemes that are not clearly defined on GINA

2017, respirologists or allergists will be consulted to define the classification, i.e., severe or non-

severe asthma patient.

7.3.2. Outcome definitions

DESCRIPTION OF SEVERE ASTHMA

• Blood eosinophil level in severe asthma patients by Positive/Negative status for

parasites on stool examination: median, mean, maximum-minimum and inter-

quartile range of blood eosinophils (cells/µL) by presence of parasites on stool

examination at visit 1 among severe asthma patients and among the severe asthma

GINA 2017 population.

• Eosinophils by positive/negative status for parasites on stool examination:

proportion of eosinophilic patients considering different eosinophil cutoffs (i.e., 150,

200, 300, and 400 cells/μL) by presence of parasites on stool examination at visit 1

among severe asthma patients and among the severe asthma GINA 2017 population.

• Hospital admission due to asthma or respiratory symptoms during the last 12

months in severe asthma patients: Number, median, mean, maximum-minimum,

inter-quartile range and standard deviation of hospital admission due to asthma or

respiratory symptoms during the last 12 months self-reported at Visit 1 and at Visit

2 for all severe asthma patients and for the severe asthma GINA 2017 population.

• Intubation or mechanical ventilation due to asthma or respiratory symptoms during the last 12 months in severe asthma patients: median, mean, maximum-

minimum, inter-quartile range and standard deviation of hospital admission due to

asthma or respiratory symptoms that required intubation or mechanical ventilation


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during the last 12 months self-reported at Visit 1 and Visit 2 for all severe asthma

patients and for the severe asthma GINA 2017 population.

• Emergency department visits due to asthma or respiratory symptoms in the last

12 months in severe asthma patients: Number, median, mean, maximum-

minimum, inter-quartile range and standard deviation of emergency visits due to

asthma or respiratory symptoms during the last 12 months self-reported at Visit1 and

Visit 2 for all severe asthma patients and for the severe asthma GINA 2017

population;

• Length of hospital admission stay due to asthma or respiratory symptoms during the last 12 months in severe asthma patients: median, mean, maximum-

minimum, inter-quartile range and standard deviation of length of each hospital

admission during the last 12 months due to asthma or respiratory symptoms self-

reported at Visit 1 and Visit 2 for all severe asthma patients and for the severe asthma


• ACQ6 (Juniper) in severe asthma patients: distribution (median, mean,

maximum-minimum, inter-quartile range and standard deviation) of ACQ6 score

obtained at Visit 1 and Visit 2 for severe asthma patients and for the severe asthma

GINA 2017 population;

• Asthma symptom control in severe asthma patients: percentage of severe asthma

patients at Visit 2 classified as well controlled, partially controlled and uncontrolled

according to the criteria of GINA 2014 for all severe asthma patients and for the

severe asthma GINA 2017 population. The following four questions will be

responded by the patients on visit 2:

1. Daytime symptoms more than twice/week? (Yes) (No)

2. Any night waking due to asthma? (Yes) (No)

3. Reliever needed more than twice/week? (Yes) (No)

4. Any activity limitation due to asthma? (Yes) (No)

The severe asthma patients will be classified as the following:

o Well controlled – those that does not marked “Yes” in any of the 4

questions;

o Partially Controlled - those that marked “Yes” in 1-2 questions;

o Uncontrolled - those that marked “Yes” in 3-4 questions;

• EQ-5D-5L in severe asthma patients: distribution (median, mean, maximum-

minimum, inter-quartile range and standard deviation) of EQ-5D score obtained at

Visit 2 for all severe asthma patients and for the severe asthma GINA 2017

population.

• Work Productivity and Activity Impairment Index, General Health V2.0

(WPAI-GH) in severe asthma patients: distribution (median, mean, maximum-

minimum, inter-quartile range and standard deviation) of WPAI-GH score obtained

at Visit 2 for all severe asthma patients and for the severe asthma GINA 2017

population;


22

• Spirometry: Mean and median for pre- and post-bronchodilator FEV1/FVC, pre-

and post-bronchodilator FEV1 and FVC, and airway reversibility status at Visit 1

for the severe asthma and severe asthma GINA 2017 population.

• Blood biomarkers in severe asthma patients:

o Total IgE: median, mean, maximum-minimum, inter-quartile range and

standard deviation blood IgE (IU/µL) at visit 1 for the severe asthma and severe

asthma GINA 2017 population.

o Biomarkers of inflammation: median, mean, maximum-minimum, inter-

quartile range and standard deviation levels for biomarkers of inflammation

(Sedimentation rate, C-Reactive Protein (CRP), interleukin (IL)-4, IL13 and Th2

cytokines) at visit 1 for the severe asthma and severe asthma GINA 2017

population.

• Atopy status: percentage and 95% CI of patients classified with atopy. Skin prick

test with a broad panel of aeroallergens was performed at visit 1 to define whether

or not each subject was atopic for the severe asthma and severe asthma GINA 2017

population.

ELIGIBILITY BY BIOLOGICAL THERAPY

• Severe asthma patients eligible for mepolizumab – Percentage of patients at

visit 1 meeting the criteria for mepolizumab treatment among the severe asthma


• Severe asthma patients eligible for omalizumab - Percentage of patients at

visit 1 meeting the criteria for omalizumab treatment among the severe asthma GINA

2017 population.

• Severe asthma patients eligible for reslizumab - Percentage of patients at visit 1

meeting the criteria for reslizumab treatment among the severe asthma GINA 2017

population.

• Severe asthma patients eligible for benralizumab - Percentage of patients at visit

1 meeting the criteria for benralizumab treatment among the severe asthma GINA

2017 population.

• Asthma Medication used for all severe asthma patients: Percentage and 95% CI

for each self-reported asthma medications and the respective dosage used in the year

before of Visit 2 for all severe asthma patients and for the severe asthma GINA 2017

population and stratified by eligibility criteria for mepolizumab, omalizumab,

benralizumab and reslizumab.

• Mepolizumab eligibility and positive/negative status for parasites on stool

examination: proportion of the patients in each of the four subgroups below

according to the eligibility for mepolizumab positive/negative parasite status on

stool examination at visit 1:

A) Mepolizumab eligible with positive for parasites on stool examination;

B) Mepolizumab eligible with negative for parasites on stool examination;

C) Not eligible for Mepolizumab and positive for parasites on stool examination;

D) Not eligible for Mepolizumab and negative for parasites on stool examination.


23


months by eligibility criteria: number, median, mean, maximum-minimum, inter-

quartile range and standard deviation of hospital admission due to asthma or

respiratory symptoms during the last 12 months reported in Visit 1 and Visit 2,

stratified by eligibility criteria (mepolizumab, omalizumab, reslizumab and

benralizumab).


months by mepolizumab eligibility and positive/negative status for parasites on

stool examination: number, median, mean, maximum-minimum, inter-quartile

range and standard deviation of hospital admission due to asthma or respiratory

symptoms during the last 12 months reported in Visit 1 and Visit 2, stratified by

eligibility for mepolizumab and positive/negative status for parasites on stool

examination.

• Length of hospital admission stay by eligibility criteria: number, median, mean,

maximum-minimum, inter-quartile range and standard deviation of the length of

each hospital admission during the last 12 months due to asthma or respiratory

symptoms reported in Visit 1 and Visit 2, stratified by eligibility criteria

(mepolizumab, omalizumab,reslizumab and benralizumab eligible patients).

• Length of hospital admission stay by mepolizumab eligibility and

positive/negative status for parasites on stool examination: number, median,

mean, maximum-minimum, inter-quartile range and standard deviation of the length

of each hospital admission during the last 12 months due to asthma or respiratory

symptoms reported at Visit 1 and Visit 2, stratified by eligibility to mepolizumab

and positive/negative status for parasites on stool examination.

• Intubation or mechanical ventilation by eligibility criteria: number, median,

mean, maximum-minimum, inter-quartile range and standard deviation of hospital

admission due to asthma or respiratory symptoms that required intubation or

mechanical ventilation during the last 12 months as reported at Visit 1 and Visit 2,

stratified by eligibility criteria (mepolizumab, omalizumab,reslizumab and

benralizumab).

• Intubation or mechanical ventilation by mepolizumab eligibility and

positive/negative status for parasites on stool examination: number, median,

mean, maximum-minimum, standard deviation and distribution of hospital

admission due to asthma or respiratory symptoms that required intubation or

mechanical ventilation during the last 12 months as reported at visit 1 and Visit 2,

stratified by eligibility for mepolizumab and positive/negative status for parasites on

stool examination.

• Emergency visits for asthma or respiratory symptoms during the last 12 months

by eligibility criteria: number, median, mean, maximum-minimum, standard

deviation and distribution of self-reported ED visits due to asthma or respiratory

symptoms during the last 12 months as reported at Visit 1 and Visit 2, stratified by

eligibility criteria (mepolizumab, omalizumab, reslizumab and benralizumab

eligible patients).


24

• Emergency visits for asthma or respiratory symptoms during the last 12 months

by eligibility for mepolizumab and positive/negative status for parasites on stool

examination: number, median, mean, maximum-minimum, inter-quartile range and

standard deviation of self-reported number of ED visits due to asthma or respiratory

symptoms during the last 12 months as reported at Visit 1 and Visit 2 by, stratified

by eligibility to mepolizumab and positive/negative status for parasites on stool

examination.

• ACQ6 (Juniper) by eligibility criteria: median, mean, maximum-minimum, inter-

quartile range and standard deviation of ACQ6 score obtained at Visit 1 and Visit 2,

stratified by eligibility criteria (mepolizumab, omalizumab, reslizumab and

benralizumab eligible patients);

• ACQ6 (Juniper) by eligibility for mepolizumab and positive/negative status for

parasites on stool examination: median, mean, maximum-minimum, inter-quartile

range and standard deviation of ACQ6 score obtained at Visit 1 and Visit 2, stratified

by eligibility to mepolizumab and positive/negative status for parasites on stool

examination;

• Asthma symptom control by eligibility criteria: percentage of patients at Visit 2

classified as controlled, partially controlled and uncontrolled according to GINA

2014 guidelines, stratified by eligibility criteria (mepolizumab, omalizumab,

reslizumab and benralizumab);

• Asthma symptom control by mepolizumab eligibility and positive/negative

status for parasites on stool examination: percentage of patients at Visit 2

classified as controlled, partially controlled and uncontrolled according GINA 2014

guidelines, stratified by eligibility for mepolizumab and positive/negative status for

parasites on stool examination;

• EQ-5D by eligibility criteria: median, mean, maximum-minimum, inter-quartile

range and standard deviation of the EQ-5D score obtained at Visit 2 by eligibility

criteria (mepolizumab, omalizumab, reslizumab and benralizumab);

• Work Productivity and Activity Impairment Index: General Health V2.0

(WPAI-GH) by eligibility criteria: median, mean, maximum-minimum, inter-

quartile range and standard deviation of the WPAI-GH score obtained at Visit 2 by

eligibility criteria (mepolizumab, omalizumab, reslizumab and benralizumab);

7.3.3. Other variables

➢ Sociodemographic (Visit 1)

• Gender

• Age

• Estimated average family income (monthly)

• Education (illiterate, elementary, high school, college, university).

• Skin colour (black, white, mixed, native Brazilian, Asiatic) - this type of variable

approximates ethnicity in an absence of the actual race/ethnicity data

• Weight

• Height


25

• BMI (Body Mass Index, kg/m2)

➢ Asthma Disease History (Visit 1)

• Age at first asthma symptoms as reported in the (Visit 1);

• Duration of asthma – calculated in years, the difference between the age at the

baseline visit (Visit 1) minus the age of first asthma symptoms.

• Mean follow up time –calculated in days, the difference of the date at the visit 1

and the date at the visit 2.

➢ Comorbidity (Visit 1)

Within the database from the case-control study, we will investigate the prevalence of

comorbidities that were previous collected through a questionnaire at the baseline visit (visit 1).

The comorbidities of interest include the following:

• Osteoporosis;

• Hypertension;

• Dyslipidemia;

• Diabetes mellitus;

• Hypothyroidism;

• Hyperthyroidism;

• Psychiatric disorder;

• Gastro-oesophageal reflux disease (GERD) ;

• Overweight and obesity - BMI data will be obtained from the database using cut-off

values for obesity and overweight as follows:

Table 2: BMI classification

Category Children (5-19) Adults (>19)

Obese Body mass index (BMI) >2

standard deviations above

the WHO growth standard

median

BMI≥ 30

Overweight BMI> 1 standard deviation

above the WHO growth

standard median

BMI between 25 and 29.9

• Rhinitis

• Other illness;

7.3.4. Exposure definitions

No particular exposures of interest will be investigated for this study. However, an exploratory

analysis could be performed to evaluate the association of positive parasitic disease status and

blood eosinophil levels.


26

7.3.5. Confounders and effect modifiers

This is a descriptive study. It is not a study to investigate potential associations; therefore,

potential confounding will not be investigated.

7.4. Data sources

The data sources of this study include the following:

1- The database from the case-control study conducted from 2013 until 2015 entitled “Risk

factors, endophenotypes and biomarkers of severe asthma” (retrospective data);

2- The medical chart records before entry (visit 1) into the case-control study;

3- Prospective data that will be collected at least one year after visit 1 in the case-control

study at a second patient visit (visit 2).

7.5. Sample size

The population includes patients with severe asthma that participated in the previous case-

control study, “Risk factors, endophenotypes and biomarkers of severe asthma.” A total of 544

patients with severe asthma participated and were evaluated in that study, concluded in July

2015. All patients that met the inclusion criteria among the 544 patients will be included in the

current study.

7.6. Data management

7.6.1. Data handling conventions

Data from Visit 1 of the previous “Risk factors, endophenotypes and biomarkers of severe

asthma” case-control study was recorded initially in a paper case report form (CRF) and entered

into the database application (STATA). In the prospective study, for Visit 2, patient data will be

entered using the same procedure for the same database application in order to create a combined

data set with data from both visits (Visit 1 and Visit 2).

7.6.2. Resourcing needs

For this study, all analyses and data collection will be conducted by the ProAR team. The ProAR

study team will include the principal investigator (Dr , the statistician and a project

coordinator.

7.6.3. Timings of Assessment during follow-up

Visit 1 for all patients occurred from 2013 through 2015 and Visit 2 will take place in 2017.

Therefore, the time elapsed between the two visits will range from two to four years. The

questions used to assess healthcare resource utilization will refer to the year prior to the date of

Visit 2.

PPD


27

7.7. Data analysis

7.7.1. Essential analysis

Descriptive statistics will be used for this study. Categorical data will be presented in counts (n)

and proportions (%) with 95% confidence intervals (95% CIs). 95% CIs will be calculated either

based on the normal distribution or based on the binomial distribution.

For continuous data, the following summary statistics will be presented: n, mean, standard

deviation (SD), median, inter-quartile range, minimum and maximum. The number of missing

values will be presented where necessary.

Mean and median values will be reported to one decimal place greater than the original data

while the SD will be reported to two decimal places greater than the original data however, even

if the value is 0.00. Minimum and maximum values will be reported with the same precision as

they were collected.

Percentages will be reported in integers. Confidence intervals will be presented to two decimal

places.

7.7.2. Analysis Population

The population subsets for analysis are:

• Severe asthma population: This population will consist of all severe asthma patients

that met the inclusion criteria, i.e. those that was recorded on the database of the case-

control study “Risk factors, endophenotypes and biomarkers of severe asthma” AND

met the inclusion criteria.

• Severe asthma population GINA 2017: severe asthma based on chronic use over a

period of a minimum of 12 months (i.e. treatment step 4 or step 5 according to GINA

2017 ).


28

Figure 3: Data source and population dataset

7.7.3. Primary Analysis

Objective 1a) Among the severe asthma population and the severe asthma GINA

2017population, the median, mean, standard deviation, inter-quartile range, min-max, and

distribution of eosinophils (number/µL) recorded on visit 1 will be calculated. It will be

conducted the log transformation of the EOS data before to calculate the descriptive measures.

An additional subgroup analysis will be conducted for positive/negative status of parasites on

stool examination on visit 1.

Case-control study

- Severe asthma;

- Mild Asthma

- No Asthma

Severe asthma GINA 2017

Severe asthma

Eligible to Mepolizumab

treatment

Eligible to Reslizumab treatment

Eligible to Omalizumab

treatment

Eligible to Benralizumab

treatment


29

Objective 1b) The percentage and 95% exact confidence interval of the patients with eosinophils

will be calculation considering the eosinophils in different cutoffs (i.e., 150, 200, 300, and 400

cells/μL) among the severe asthma population and the severe asthma GINA 2017 population on

visit 1. The result will be presented for all severe asthma population and will be also analyzed

separately for those with positive parasite status on stool examination and those with negative

positive parasite on stool examination at visit 1.

Objective 1c)

For the severe asthma population and the severe asthma GINA 2017population, the following

will be described:

o Mean, median, inter-quartile range, standard deviation and min-max of hospital

admission, length of hospital admission stay, emergency visits and intubation or

mechanical ventilation during the last 12 months before Visit 1 and the 12 months prior

to visit 2.

Objective 1 d)

For the severe asthma population and the severe asthma GINA 2017population, the following

will be described:

o ACQ6 (Juniper) score distribution (mean, median, inter-quartile range, standard

deviation, min-max) at Visit 1 and visit 2;

o EQ-5D-5L score distribution (mean, median, inter-quartile range, standard deviation min-

max) at Visit 2;

o Work Productivity and Activity Impairment Index: General Health V2.0 (WPAI-GH)

distribution (mean, median, inter-quartile range, standard deviation, min-max) of WPAI-

GH score at Visit 2;

o Asthma Symptoms:

The following four questions will be responded by the patients on visit 2:

Daytime symptoms more than twice/week? (Yes) (No)

Any night waking due to asthma? (Yes) (No)

Reliever needed more than twice/week? (Yes) (No)

Any activity limitation due to asthma? (Yes) (No)


o Well controlled – those that does not marked “Yes” in any of the 4

questions;

o Partly Controlled - those that marked “Yes” in the 1-2 questions;

o Uncontrolled - those that marked “Yes” in the 3-4 questions;

Percentage and the 95% exact confidence interval of the severe asthma patients that were

classified as “Well controlled”, “Partly Controlled” and “uncontrolled”.

Objective 1e)


30

A description of clinical assessment including spirometry and biomarkers of the severe asthma

population and the severe asthma GINA 2017 population at visit 1 will be conducted, as follows:

o Spirometry: the mean and median pre- and post-bronchodilator FEV1/FVC, pre- and

post-bronchodilator FEV1 and FVC, and airway reversibility at visit 1 will be calculated;

o Blood Biomarkers: mean, median, inter-quartile range, standard deviation and min-max

for the following biomarkers will be calculated:

- Total IgE (IU/µL);

- Sedimentation rate;

- C-Reactive Protein;

- IL4;

- IL13 ;

- Th2 cytokines.

o Atopy status in visit 1: Percentage and 95% CI of patients with positive skin prick test

will be calculated.

Objective 2a) Percentage and the 95% exact confidence interval will be calculated for the severe

asthma GINA 2017population on visit 1 that meet the criteria for one or more of the following

medication(s) mepolizumab, omalizumab, reslizumab and benralizumab. The intersection

among these will be also calculated with the following categories:

a. Any mepolizumab

a. Any omalizumab

b. Any reslizumab

c. Any Benralizumab

d. Mepolizumab only

e. Omalizumab only

f. Reslizumab only

g. Mepolizumab + Omalizumab

h. Mepolizumab + Reslizumab

i. Omalizumab + Reslizumab

j. Mepolizumab + Benralizumab

k. Omalizumab + Benralizumab

l. Reslizumab + Benralizumab

m. Mepolizumab + Omalizumab + Reslizumab + Reslizumab

n. None

Objective 2b) These factors will be described for all patients in the severe asthma GINA 2017

population:


31

o The list of asthma medication with the respective dosage used in the past year and reported

at visit 2;

o The percentage and CI 95% of the most common medication used at visit 2;

This analysis will all be reported separately for all patients eligible for each biological therapy

(Mepolizumab, omalizumab, reslizumab and benralizumab).

Objective 2c) For the severe asthma GINA 2017 population by eligibility criteria for the three

biological therapies it will be described:

o Mean, median, inter-quartile range, standard deviation, min-max of hospital admission,

length of hospital admission stay, emergency visit and intubation or mechanical

ventilation during the last 12 months before Visit 1 and 12 months before Visit 2.

o ACQ6 (Juniper) score distribution (mean, median, inter-quartile range, standard

deviation, min-max) at Visit 1 and visit 2;

o EQ-5D score distribution (mean, median, standard deviation, inter-quartile range, min-

max) at Visit 2;

o Work Productivity and Activity Impairment Index: General Health V2.0 (WPAI-GH)

distribution (mean, median, standard deviation, inter-quartile range, min-max) of WPAI-

GH score at Visit 2;

o Asthma Symptom:

The following four questions will be responded by the patients at visit 2:

A) Daytime symptoms more than twice/week? (Yes) (No)

B) Any night waking due to asthma? (Yes) (No)

C) Reliever needed more than twice/week? (Yes) (No)

D) Any activity limitation due to asthma? (Yes) (No)


• Well controlled – those that did not marked “Yes” in any of the 4 questions;

• Partly Controlled - those that marked “Yes” in the 1-2 questions;

• Uncontrolled - those that marked “Yes” in the 3-4 questions;

Percentage and the 95% exact confidence interval will be calculated for patients classified as

“Well controlled”, “Partly Controlled” and “uncontrolled”.

Objective 2d)

The severe asthma population, GINA 2017 population, mepolizumab eligible and

omalizumab eligible, reslizumab eligible and benralizumab eligible will be described

according to the variables listed on section 7.3.3.

Also, from the severe asthma GINA 2017 population on visit 1, four subgroups will be

determined based on the eligibility for mepolizumab and positive/negative status for parasites

on stool examination:

o Mepolizumab eligible and positive for parasites on stool examination;

o Mepolizumab eligible and negative for parasites on stool examination;


32

o Not eligible for mepolizumab and positive for parasites on stool examination;

o Not eligible for mepolizumab and negative for parasites on stool examination

Those subgroups will be described according to the variables listed on section 7.3.3. For the

categorical variables, the percentage and 95% CI will be calculated and for continuous

variables the median, mean, inter-quartile range, max-min and standard deviation will be

calculated.

Objective 2e)

For the severe asthma GINA 2017 population stratified by mepolizumab eligibility and

positive/negative status for parasites on stool examination at visit 1, the following will be

described:

o Mean, median, inter-quartile range, standard deviation and min-max of hospital

admission, length of hospital admission stay, emergency visits and intubation or

mechanical ventilation during the last 12 months before Visit 1 and 12 months before visit

2.

o ACQ6 (Juniper) score distribution (mean, median, inter-quartile range, standard deviation

and min-max) at Visit 1 and visit 2;

7.7.4. Other analysis

For subjects who did not agree to participate in the retrospective and prospective phase no data

will be collected.

For the patients that were not included because they are using omalizumab previous to the

case-control study, the following data will be used:

o Gender;

o Skin Colour;

o Age;

Also the data about medication used 12 months previous the visit 1 will be collected from

medical chart

For patients who only agree to participate in the retrospective phase it will be used data from

medical chart and the analysis of the database from the case control study.

7.7.5. Exploratory analysis

No specific exploratory analyses are planned.

7.8. Quality control

As previously described, the data of the visit 1 was recorded initially in a paper CRF and entered

in the data entry application (STATA). The data entry application performed a variety of edit

checks to assure that ineligible values were not allowed and suspect values were verified. For all


33

database fields, a mandatory double entry was applied and in case of any disagreement, the

source document was consulted for correction.

For the prospective phase of the study, the same procedures will be applied. Additionally, in

accordance with applicable regulations including GCP, and GSK procedures, GSK monitors will

contact the site staff prior to the start of the study to review the protocol, study requirements,

and responsibilities to satisfy regulatory, ethical, and GSK requirements.

• When reviewing data collection procedures, the discussion will also include identification,

agreement and documentation of data items for which the CRF will serve as the source

document.

GSK will monitor the study and site activity to verify that the:

• Data are authentic, accurate, and complete.

• Safety and rights of subjects are being protected.

• Study is conducted in accordance with the currently approved protocol and any other study

agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees to allow the

monitor direct access to all study-related records during scheduled monitoring visits. The data

analysis will be conducted by the ProAr team.

7.9. Limitations of the research methods

The low sensitivity of stool examination for the diagnosis of parasitic infections could generate

a misclassification bias of the exposure status that needs to be taken into consideration in the

analysis of those results. Recall bias may influence the results of healthcare resource utilization

in visit 1 and visit 2. The Visit 1 may occur from 2013 through 2015, leading to significant

differences regarding the time between Visit 1 to Visit 2 for study subjects. This may add bias

to the results of healthcare resource utilization, ACQ6, EQ5D and asthma symptoms. Patients

in the ProAR cohort are enrolled by specialized departments. Patients followed in such clinics

are expected to be representative of the typical severe asthma patient; however, we cannot rule

out the possibility that these patients could be more severe or differently managed than those

seen in other specialized clinics elsewhere.

8. PROTECTION OF HUMAN SUBJECTS

8.1. Ethical approval and subject consent

The current study includes a re-analysis of a previously conducted study by the ProAr team

titled, “Risk factors, endophenotypes and biomarkers of severe asthma”. Before re-analyzing

medical chart data from Visit 1 and collecting data at Visit 2, the study must be approved by the

Ethics Review Board of the Federal University of Bahia (UFBA) and subjects must sign the

informed consent form. A special authorization from the ethics committees for the re-analysis

of visit 1 data from the previous case-control study conducted by the ProAr team and the medical


34

chart review will be requested for patients identified as eligible but could not be found (lost to

follow-up) or are deceased.

8.2. Subject confidentiality

Anonymized data was previously collected. All subjects will sign the informed consent at the

time of study initiation and the study sponsors have ensured confidentiality of the data.

9. RECORD RETENTION

Following closure of the study, the investigator or head of the medical institution (where

applicable) must maintain all site study records (except for those required by local regulations

to be maintained elsewhere) in a safe and secure location. The records must be easily accessible

when needed (e.g., for a GSK audit or regulatory inspection) and must be available for review

in conjunction with an assessment of the facility, supporting systems and relevant site staff.

The investigator must retain the site records in order to comply with all applicable regulatory

requirements during 25 years from final Clinical Study Report (CSR) date.

The investigator must notify GSK of any changes in the archival arrangements including, but

not limited to, archival of records at an off-site facility or transfer of ownership of the records

in the event that the investigator is no longer associated with the site

10. PLANS FOR DISSEMINATING AND COMMUNICATING

STUDY RESULTS

The results summary will be posted to the Clinical Study Register no later than eight months

after the final primary completion date, the date that the final subject was examined or received

an intervention for the purposes of final collection of data for the primary outcome. In addition,

a manuscript will be submitted to a peer reviewed journal for publication no later than 18 months

after the last subject’s last visit (LSLV). When manuscript publication in a peer reviewed journal

is not feasible, a statement will be added to the register to explain the reason for not publishing.

Two manuscripts will be progressed for publication in the scientific literature if the results

provide important scientific or medical knowledge.

10.1. Target Audience

This study will contribute evidence to the scientific debate on asthma phenotype. The results

will be disseminated in a form of manuscripts and scientific presentations.

10.2. Study reporting and publications

Manuscript describing the proportion of patients eligible for each one of the three biological

(Mepolizumab, reslizumab, omalizumab and reslizumab) and describing the parasitic disease in

eosinophilic asthma patients.


35

11. REFERENCES

1. Campo P, Rodriguez F, Sanchez-Garcia S, Barranco P, Quirce S, et al. (2013) Phenotypes

and endotypes of uncontrolled severe asthma: new treatments. J Investig Allergol Clin

Immunol 23(2): 76-88.

2. Humbert M, Beasley R, Ayres J et al. Benefits of omalizumab as add-on therapy in patients

with severe persistent asthma who are inadequately controlled despite best available therapy

(GINA 2002 step 4 treatment): INNOVATE. Allergy 2005;60:309-316.

3. Pavord ID, Korn S, Howarth P et al. Mepolizumab for severe eosinophilic asthma (DREAM):

a multicentre, double-blind, placebo-controlled trial. The Lancet 2012;380:651.

4. Wenzel S. Severe asthma in adults. Am J Respir Crit Care Med 2005;172:149–160.

5. Franco R, Nascimento HF, Cruz AA, et al. The economic impact of severe asthma to low-

income families. Allergy 2009;64:478–83.


36

ANNEX 1. LIST OF STAND-ALONE DOCUMENTS

Tables

Table1. Frequency of patients eligible for Mepolizumab, omalizumab, reslizumab and

benralizumab and overlap

Table 2: Demographic baseline characteristics in severe asthma GINA 2017 and by eligibility

Table 3: Demographic baseline characteristics in Severe asthma

Table 4: Demographic characteristics at visit 2 in severe asthma GINA 2017 and by eligibility


Table 6: Co-morbidities in Severe asthma GINA 2017 and by eligibility at the baseline (Case-

control study)

Table 7: Co-morbidities in Severe asthma

Table 8: Co-morbidities in Severe asthma GINA 2017and by eligibility at visit 2

Table 9: Co-morbidities in Severe asthma at visit 2

Table 10: Time of follow up from visit 1 to visit 2 in severe asthma GINA 2017 and by

eligibility

Table 11: Time of follow up from visit 1 to visit 2 in Severe asthma

Table 12: Levels of eosinophils in severe asthma GINA 2017 adult patients with positive and

negative examination for parasites

Table 13: Levels of eosinophils in severe asthma adult patients with positive and negative

examination for parasites

Table 14: Proportion of eosinophils using different cutoff by positive/negative parasite on

stool examination in Severe asthma GINA 2017.

Table 15: Proportion of eosinophils using different cut-offs by positive/negative parasites on

stool examination in Severe asthma

Table 16: Healthcare resources used in Visit 1 Severe Asthma population GINA 2017 by

biologic eligibility

Table 17: Healthcare resources used in Visit 1 Severe Asthma population

Table 18: Healthcare resources used in Visit 2 in Severe asthma GINA 2017 by biologic

eligibility

Table 19: Healthcare resources used in Visit 2 in severe asthma


37

Table 20: Patient reported outcomes on Visit 1in severe asthma GINA 2017 by eligibility

Table 21: Patient reported outcomes on Visit 1

Table 22: Patient reported outcomes on Visit 2 by eligibility


Table 24: Spirometry measures at visit 1 in severe asthma GINA 2017population

Table 25: Spirometry measures at visit 1 in severe asthma population

Table 26: Blood biomarkers in severe asthma patients in visit 1 in severe asthma GINA 2017

Table 27: Blood biomarkers in severe asthma patients in visit 1 in severe asthma

Table 28: Demographic baseline characteristics by the eligibility criteria for mepolizumab and

by positive/negative parasites on stool examination at visit 1 and visit 2

Table 29: Co-morbidities in study population by the eligibility criteria for mepolizumab and

by positive/negative parasites on stool examination at visit 1 and at visit 2

Table 30: Healthcare resources used in Visit 1 by eligibility for mepolizumab and positive

/negative parasites on stool examination



Table 32: ACQ6 results by eligibility for mepolizumab and positive /negative parasites on

stool examination in visit 1



Table 34: Asthma symptom control by eligibility for mepolizumab and positive/negative

parasites on stool examination

Table 35: Patients that did not meet the inclusion criteria

Table 36: Patients that participated on visit 1, but not on visit 2

Table 37: Patients that met the GINA 2017 criteria

Table 38: Medication used before to the case-control study among the severe asthma

population

Table 39: Medication used in the year before to the study 2 by eligibility criteria


38

Table1. Frequency of patients eligible for Mepolizumab, omalizumab, reslizumab and

benralizumab and overlap

N; %; 95% CI

– Severe

asthma GINA

2017

Patients eligible for

mepolizumab


omalizumab


reslizumab


benralizumab


mepolizumab only


omalizumab only


Reslizumab only


Benralizumab only


mepolizumab and

omalizumab


mepolizumab and

reslizumab


omalizumab and

reslizumab


mepolizumab,


39

Table 2: Demographic baseline characteristics in severe asthma GINA 2017 and by eligibility

Severe

asthma

GINA

2017

Mepolizumab

eligible

patients

Omalizumab

eligible

patients

Reslizumab

eligible

patients

Benralizumab

eligible patients

n(%) n(%) n(%)

Age n

mean (SD)

median

Q1-Q3

min-max

Height n

mean (SD)

median

omalizumab and

reslizumab


Mepolizumab and

Benralizumab


Omalizumab and

Benralizumab


Reslizumab and

Benralizumab

Patients no eligible

for any of the four

monoclonal

antibody

treatments


40

Q1-Q3

min-max

Weight n

mean (SD)

median

Q1-Q3

min-max

Gender n

Female %

Skin

Colour

n

Black

White

Mixed

Native

Brazilian

Asiatic

Schooling n

Illiterate

(%)

Elementary

(%)

High

School (%)

University

(%)

Estimated

average

Quintile 1

(%)


41

family

income

by month

Quintile 2

(%)

Quintile 3

(%)

Quintile 4

(%)

Quintile 5

(%)

BMI 20 – 25

(%)

25-30 (%)

>30 (%)

≥ 40 (%)

Other (%)

Age that

asthma

symptom

have

started

n

mean (SD)

median

Q1-Q3

min-max

Duration

of asthma

n

mean (SD)

median

Q1-Q3

min-max

min-max



42

Severe

asthma

Age n

mean (SD)

median

Q1-Q3

min-max

Height n

mean (SD)

median

Q1-Q3

min-max

Weight n

mean (SD)

median

Q1-Q3

min-max

Gender n

Female %

Skin

Colour

n

Black

White

Mixed

Native

Brazilian


43

Asiatic

Schooling n

Illiterate

(%)

Elementary

(%)

High

School (%)

University

(%)

Estimated

average

family

income

by month

Quintile 1

(%)

Quintile 2

(%)

Quintile 3

(%)

Quintile 4

(%)

Quintile 5

(%)

BMI 20 – 25

(%)

25-30 (%)

>30 (%)

≥ 40 (%)

Other (%)

Age that

asthma

symptom

has

started

n

mean (SD)

median

Q1-Q3


44

min-max

Duration

of asthma

n

mean (SD)

median

Q1-Q3

min-max

min-max

Table 4: Demographic characteristics at visit 2 in severe asthma GINA 2017 and by eligibility

Severe

asthma

GINA

2017

Mepolizumab

eligible

patients

Omalizumab

eligible

patients

Reslizumab

eligible

patients

Benralizuma

b eligible

patients

n(%) n(%) n(%)

Age n

mean (SD)

median

Q1-Q3

min-max

Height n

mean (SD)

median

Q1-Q3

min-max

Weight n

mean (SD)


45

median

Q1-Q3

min-max

Gender n

Female %

Skin

Colour

n

Black

White

Mixed

Native

Brazilian

Asiatic

Schooling n

Illiterate

(%)

Elementary

(%)

High

School (%)

University

(%)

Estimated

average

family

income

by month

Quintile 1

(%)

Quintile 2

(%)

Quintile 3

(%)

Quintile 4

(%)


46

Quintile 5

(%)

BMI 20 – 25

(%)

25-30 (%)

>30 (%)

≥ 40 (%)

Other (%)

Age that

asthma

symptom

have

started

n

mean (SD)

median

Q1-Q3

min-max

Duration

of asthma

n

mean (SD)

median

Q1-Q3

min-max

min-max

Table 5: Demographic characteristics in Severe asthma at visit 2

Severe

asthma

Age n

mean (SD)


47

median

Q1-Q3

min-max

Height n

mean (SD)

median

Q1-Q3

min-max

Weight n

mean (SD)

median

Q1-Q3

min-max

Gender n

Female %

Skin

Colour

n

Black

White

Mixed

Native

Brazilian

Asiatic

Schooling n

Illiterate

(%)


48

Elementary

(%)

High

School (%)

University

(%)

Estimated

average

family

income

by month

Quintile 1

(%)

Quintile 2

(%)

Quintile 3

(%)

Quintile 4

(%)

Quintile 5

(%)

BMI 20 – 25

(%)

25-30 (%)

>30 (%)

≥ 40 (%)

Other (%)

Age that

asthma

symptom

have

started

n

mean (SD)

median

Q1-Q3

min-max

Duration

of asthma

n

mean (SD)


49

median

Q1-Q3

min-max

min-max

Table 6: Co-morbidities in Severe asthma GINA 2017 and by eligibility at the baseline (Case-

control study)

Severe

asthma

GINA

2017

Mepolizumab

eligible

patients

Omalizumab

eligible

patients

Reslizumab

eligible

patients

Benralizumab

eligible patients

Comorbidities

(%)

n(%) n(%) n(%)

Osteoporosis;

Hypertension;

Dislipidemia;

Diabetes mellitus;

Hypotiroidism;

Hypertyroidism;

Psychiatric

disorder;

Gastro-esophageal

reflux disease

(GERD);

Rhinitis;

Overweight

Obesity

Other illness


50

Table 7: Co-morbidities in Severe asthma

Severe

asthma

Comorbidities

(%)

Osteoporosis;

Hypertension;

Dislipidemia;

Diabetes mellitus;

Hypotiroidism;

Hypertyroidism;

Psychiatric

disorder;

Gastro-esophageal

reflux disease

(GERD);

Rhinitis;

Overweight

Obesity

Other illness

Table 8: Co-morbidities in Severe asthma GINA 2017 and by eligibility at visit 2 (Case-

control study)

Severe

asthma

GINA

2017

Mepolizumab

eligible

patients

Omalizumab

eligible

patients

Reslizumab

eligible

patients

Benralizumab

eligible patients

Comorbidities

(%)

n(%) n(%) n(%)


51

Osteoporosis;

Hypertension;

Dislipidemia;

Diabetes mellitus;

Hypotiroidism;

Hypertyroidism;

Psychiatric

disorder;

Gastro-esophageal

reflux disease

(GERD);

Rhinitis;

Overweight

Obesity

Other illness

Table 9: Co-morbidities in Severe asthma at visit 2

Severe

asthma

Comorbidities

(%)

Osteoporosis;

Hypertension;

Dislipidemia;

Diabetes mellitus;

Hypotiroidism;

Hypertyroidism;


52

Psychiatric

disorder;

Gastro-esophageal

reflux disease

(GERD);

Rhinitis;

Overweight

Obesity

Other illness

Table 10: Time of follow up from visit 1 to visit 2 in severe asthma GINA 2017 and by

eligibility

Severe

asthma

GINA

2017

Mepolizumab

eligible Omalizumab

eligible Reslizumab

eligible Benralizumab

eligible patients

Time of follow up

Mean (SD)

Median

Q1 - Q3

Max - Min

Table 11: Time of follow up from visit 1 to visit 2 in Severe asthma

Severe

asthma

Time of follow up

Mean (SD)

Median

Q1 - Q3

Max - Min

Table 12: Levels of eosinophils in severe asthma GINA 2017 adult patients with positive and

negative examination for parasites


53

Positive

parasite on

stool

examination

Negative

parasite on

stool

examination

Total Severe

asthma GINA

2017

N; %

Eosinophils

Median

Mean (SD)

Min- Max

Table 13: Levels of eosinophils in severe asthma adult patients with positive and negative

examination for parasites

Positive

parasite on

stool

examination

Negative

parasite on

stool

examination

Severe asthma

N; %

Eosinophils

Median

Mean (SD)

Min- Max

Table 14: Proportion of eosinophils using different cutoff by positive/negative parasite on

stool examination in Severe asthma GINA 2017 .

Positive

parasite on

stool

examination

Negative

parasite on stool

examination

Total Severe

asthma GINA

2017

Eosinophils

% Cutoff≥ 150


54

% Cutoff≥ 200

% Cutoff≥ 300

% Cutoff≥ 400

Table 15: Proportion of eosinophils using different cut-offs by positive/negative parasites on

stool examination in Severe asthma

Positive

parasite on

stool

examination

Negative

parasite on stool

examination

Total Severe

asthma

Eosinophils

% Cutoff≥ 150

% Cutoff≥ 200

% Cutoff≥ 300

% Cutoff≥ 400

Table 16: Healthcare resources used in Visit 1 Severe Asthma population GINA 2017 by

biologic eligibility

Severe

Asthma

population

GINA

2017

Mepolizumab

eligible

patients

Omalizumab

eligible

patients

Reslizumab

eligible

patients

Benralizumab

eligible

patients

N

Hospital admission

due to asthma or

respiratory

symptoms in the last

12 months

mean (SD)

Median

Q1-Q3

min-max


55

Length of hospital

admission due to

asthma or

respiratory


12 months

mean (SD)

Median

Q1-Q3

min-max

Emergency visit due

to asthma or

respiratory

symptoms

mean (SD)

Median

Q1-Q3

Min-max

Intubation or

mechanical

ventilation due to

asthma or

respiratory

symptoms during

the last 12 months in

severe asthma

patients

mean (DP)

Median

Q1-Q3

min-max

Table 17: Healthcare resources used in Visit 1 Severe Asthma population

Severe Asthma

population

N

Hospital admission due to asthma or

respiratory symptoms in the last 12

months

mean (SD)

Median

Q1-Q3


56

min-max

Length of hospital admission due to

asthma or respiratory symptoms in the

last 12 months

mean (SD)

Median

Q1-Q3

min-max

Emergency visit due to asthma or


mean (SD)

Median

Q1-Q3

Min-max

Intubation or mechanical ventilation

due to asthma or respiratory symptoms

during the last 12 months in severe

asthma patients

mean (DP)

Median

Q1-Q3

min-max

Table 18: Healthcare resources used in Visit 2 in Severe asthma GINA 2017 by biologic

eligibility

Severe asthma

GINA 2017

Mepolizumab

eligible patients

Omalizumab

eligible

patients

Reslizumab

eligible patients

Benralizumab

eligible patients

N

Hospital admission

due to asthma or


in the last 12 months

mean (DP)

median

Q1-Q3

min-max

Length of hospital

admission in the last

12 months


57

mean (SD)

median

Q1-Q3

min-max

Emergency visit in the

last 12 months due to

asthma or respiratory

symptoms

mean (SD)

median

Q1-Q3

min-max

Intubation or

mechanical ventilation

due to asthma or


during the last 12

months in severe

asthma patients

mean (SD)

median

Q1-Q3

min-max

Table 19: Healthcare resources used in Visit 2 in severe asthma

Severe asthma

N

Hospital admission due to

asthma or respiratory

symptoms in the last 12

months

mean (DP)

median

Q1-Q3

min-max

Length of hospital

admission in the last 12

months

mean (SD)


58

median

Q1-Q3

min-max

Emergency visit in the last

12 months due to asthma

or respiratory symptoms

mean (SD)

median

Q1-Q3

min-max

Intubation or mechanical

ventilation due to asthma

or respiratory symptoms

during the last 12 months

in severe asthma patients

mean (SD)

median

Q1-Q3

min-max

Table 20: Patient reported outcomes on Visit 1 in severe asthma GINA 2017 by eligibility

Severe

asthma

GINA

2017

Mepolizumab

eligible

Omalizumab

eligible

Reslizumab

eligible

Benralizumab

eligible

patients

ACQ6

N

Mean (SD)

Median

Q1 – Q3

Max – Min



59

Severe

asthma

ACQ6

N

Mean (SD)

Median

Q1 – Q3

Max – Min

Table 22: Patient reported outcomes on Visit 2 in severe asthma GINA 2017 by eligibility

Severe asthma

GINA 2017

Mepolizumab

eligible

Omalizumab

eligible

Reslizumab

eligible

Benralizumab

eligible

Eq5D-5L

N

Mean (SD)

Median

Q1 – Q3

Max – Min

WPAI-GH

N

Mean (SD)

Median

Q1 – Q3

Max – Min

Asthma

Symptoms

(GINA 2014)


60

Well Controlled

N;% (95% CI)

Partly controlled

N;% (95% CI)

Uncontrolled

N;% (95% CI)

ACQ 6

N

Mean (SD)

Median

Q1 – Q3

Max – Min


Severe asthma

patients

Eq5D-5L

N

Mean (SD)

Median

Q1 – Q3

Max – Min

WPAI-GH

N

Mean (SD)

Median

Q1 – Q3


61

Max – Min

Asthma

Symptoms

(GINA 2014)

Well Controlled

N;% (95% CI)

Partly controlled

N;% (95% CI)

Uncontrolled

N;% (95% CI)

ACQ 6

N

Mean (SD)

Median

Q1 – Q3

Max – Min

Table 24: Spirometry measures at visit 1 in severe asthma GINA 2017 population

Severe asthma GINA

2017 N;%(95% CI)

Spirometry

Pre- and post-

bronchodilator FEV1/FVC

Mean

Median

Pre- bronchodilator FEV1

Mean

Median


62

Post- bronchodilator

FEV1

Mean

Median

Pre-bronchodilator FVC

Mean

Median

Post-bronchodilator FVC

Mean

Median

Reversibility

Mean

Median

Table 25: Spirometry measures at visit 1 in severe asthma population

Severe asthma

N;%(95% CI)

Spirometry

Pre- and post-

bronchodilator FEV1/FVC

Mean

Median

Pre- bronchodilator FEV1

Mean

Median

Post- bronchodilator

FEV1


63

Mean

Median

Pre-bronchodilator FVC

Mean

Median

Post-bronchodilator FVC

Mean

Median

Reversibility

Mean

Median

Table 26: Blood biomarkers in severe asthma patients in visit 1 in severe asthma GINA 2017

Severe asthma GINA

2017

Total IgE

Mean

Median

Q1-Q3

Min-Max

Sedimentation rate

Mean (SD)

Median

Q1-Q3

Min-Max


64

C-reactive Protein

Mean (SD)

Median

Q1-Q3

Min-Max

IL4

Mean (SD)

Median

Q1-Q3

Min-Max

IL13

Mean (SD)

Median

Q1-Q3

Min-Max

Th2 Cytokines

Mean (SD)

Median

Q1-Q3

Min-Max

Atopy status

Yes (N;% (95% CI)

No (N;% (95% CI)

Table 27: Blood biomarkers in severe asthma patients in visit 1 in severe asthma


65

Severe asthma

Total IgE

Mean

Median

Q1-Q3

Min-Max

Sedimentation rate

Mean (SD)

Median

Q1-Q3

Min-Max

C-reactive Protein

Mean (SD)

Median

Q1-Q3

Min-Max

IL4

Mean (SD)

Median

Q1-Q3

Min-Max

IL13

Mean (SD)

Median

Q1-Q3


66

Min-Max

Th2 Cytokines

Mean (SD)

Median

Q1-Q3

Min-Max

Atopy status

Yes (N;% (95% CI)

No (N;% (95% CI)

Table 28: Demographic baseline characteristics by the eligibility criteria for mepolizumab and

by positive/negative parasites on stool examination at visit 1 and visit 2

Visit 1 Visit 2

GINA

2017

severe

asthma

Mepoli

zumab

eligible

patient

s and

positive

parasit

es on

stool

examin

ation

Mepoliz

umab

eligible

patients

and

negative

parasite

s on

stool

examin

ation

No

eligible

for

Mepolizu

mab

patients

and

positive

parasites

on stool

examinati

on

No

eligible

for

Mepolizu

mab

patients

and

negative

parasites

on stool

examinati

on

Mepoliz

umab

eligible

patients

and

positive

parasite

s on

stool

examin

ation

Mepoliz

umab

eligible

patients

and

negativ

e

parasite

s on

stool

examin

ation

No

eligibl

e for

Mepol

izuma

b

patien

ts and

positiv

e

parasi

tes on

stool

exami

nation

No

eligibl

e for

Mepol

izuma

b

patien

ts and

negati

ve

parasi

tes on

stool

exami

nation

n(%) n(%) n(%) n(%) n(%) n(%) n(%) n(%) n(%)

Age

n

mean (SD)

median

Q1-Q3


67

min-max

Height

n

mean (SD)

median

Q1-Q3

min-max

Weight

n

mean (SD)

median

Q1-Q3

min-max

Gender

n

Female %

Skin

Colour

n

Black

White

Mixed

Native

Brazilian

Asiatic

Schooling

n

Illiterate

Elementary

High

School


68

University

Estimated

average

family

income

by month

Quintile 1

Quintile 2

Quintile 3

Quintile 4

Quintile 5

BMI

20 - 25

25-30

>30

≥ 40

Other

Age that

asthma

symptom

have

started

n

mean (SD)

median

Q1-Q3

min-max

Duration

of asthma

n

mean (SD)

median

Q1-Q3

min-max

Mean

follow up

time

n

mean (SD)

median


69

Q1-Q3

min-max

Table 29: Co-morbidities in study population by the eligibility criteria for mepolizumab and

by positive/negative parasites on stool examination at visit 1 and at visit 2

Visit 1 Visit 2

GINA

2017

severe

asthm

a

Mepoliz

umab

eligible

patients

and

positive

parasite

s on

stool

examin

ation

Mepolizu

mab

eligible

patients

and

negative

parasites

on stool

examinati

on

No

eligible

for

Mepolizu

mab

patients

and

positive

parasites

on stool

examinati

on

No

eligible

for

Mepolizu

mab

patients

and

negative

parasites

on stool

examinati

on

Mepolizu

mab

eligible

patients

and

positive

parasites

on stool

examinati

on

Mepolizu

mab

eligible

patients

and

negative

parasites

on stool

examinati

on

No

eligible

for

Mepolizu

mab

patients

and

positive

parasites

on stool

examinati

on

No

eligible

for

Mepolizu

mab

patients

and

negative

parasites

on stool

examinati

on

Comorbiditie

s (%)

n(%)

n(%) n(%) n(%) n(%) n(%) n(%) n(%) n(%)

Osteoporosis;

Hypertension;

Dyslipidemia;

Diabetes

mellitus;

Hipothyroidis

m;

Hyperthyroidi

sm;

Psychiatric

disorder;


70

Gastro-

esophageal

reflux disease

(GERD);

Rhinitis;

Obesity

Overweight

Other illness



Mepolizumab eligible

and positive parasite

Mepolizumab

eligible and

negative parasite

No eligibility for

Mepolizumab and

positive parasite

No eligibility for

Mepolizumab and

negative parasite

N

Hospital admission

due to asthma or

respiratory


12 months

mean (SD)

Median

Q1-Q3

min-max

Time of hospital

admission due to

asthma or

respiratory


12 months

mean (SD)

Median

Q1-Q3

min-max

Intubation or

mechanical

ventilation due to


71

asthma or

respiratory

symptoms during the

last 12 months in

severe asthma

patients

mean (SD)

Median

Q1-Q3

min-max

Emergency visit in

the last 12 months

due to asthma or

respiratory

symptoms

mean (SD)

Median

Q1-Q3

min-max



Mepolizumab

eligible and positive

parasite

Mepolizumab

eligible and

negative parasite

No eligibility for

Mepolizumab and

positive parasite

No eligibility for

Mepolizumab and

negative parasite

N

Hospital admission

due to asthma or

respiratory


12 months

mean (SD)

Median

Q1-Q3

min-max

Time of hospital

admission due to

asthma or

respiratory


12 months


72

mean (SD)

Median

Q1-Q3

min-max

Intubation or

mechanical

ventilation due to

asthma or

respiratory

symptoms during

the last 12 months in

severe asthma

patients

mean (SD)

Median

Q1-Q3

min-max

Emergency visit in

the last 12 months

due to asthma or

respiratory

symptoms

mean (SD)

Median

Q1-Q3

min-max



Mepolizumab

eligible patients and

positive parasites on

stool examination


patients and negative

parasites on stool

examination

No eligible for

Mepolizumab

patients and

positive parasites

on stool

examination

No eligible for

Mepolizumab

patients and

negative

parasites on stool

examination

n(%) n(%) n(%) n(%)

ACQ6

N

Mean

(SD)

Median

Q1 – Q3


73

Max –

Min



Mepolizumab

eligible patients

and positive

parasites on stool

examination


patients and negative

parasites on stool

examination

No eligible for

Mepolizumab

patients and

positive parasites

on stool

examination

No eligible for

Mepolizumab

patients and

negative

parasites on stool

examination

n(%) n(%) n(%) n(%)

ACQ6

N

Mean (SD)

Median

Q1 – Q3

Max – Min

Table 34: Asthma symptom control by eligibility for mepolizumab and positive/negative

parasites on stool examination


74


p

a

t

i

e

n

t

s

a

n

d

p

o

s

i

t

i

v

e

p

a

r

a

s

i

t

e

s

o

n

s

t

o

o

l

e

x

a

m

i

n

a

t

i

o

n


p

a

t

i

e

n

t

s

a

n

d

n

e

g

a

t

i

v

e

p

a

r

a

s

i

t

e

s

o

n

s

t

o

o

l

e

x

a

m

i

n

a

t

i

o

n

No eligible for

M

e

p

o

l

i

z

u

m

a

b

p

a

t

i

e

n

t

s

a

n

d

p

o

s

i

t

i

v

e

p

a

r

a

s

i

t

e

s

o

n

s

t

o

o

l

e

x

a

m

i

n

a

t

i

o

n

No eligible for

M

e

p

o

l

i

z

u

m

a

b

p

a

t

i

e

n

t

s

a

n

d

n

e

g

a

t

i

v

e

p

a

r

a

s

i

t

e

s

o

n

s

t

o

o

l

e

x

a

m

i

n

a

t

i

o

n

n(%) n(%) n(%) n(%)

Asthm

a

Sympt


75

oms

(GINA

2014)

Well

Control

led

N;%

(95%

CI)

Partly

control

led

N;%

(95%

CI)

Uncont

rolled

N;%

(95%

CI)

Table 35: Patients that did not meet the inclusion criteria

Total screen failures

n(%)

Gender n

Female %

Skin

Colour

n

Black

White

Mixed

White

Native Brazilian

Asiatic


76

Age n

mean (SD)

median

Q1-Q3

Min-max

Reason to

be not

included

in the

study

Patients used

omalizumab

Patient refused to

sign the ICF

Table 36: Patients that participated on visit 1, but not on visit 2

Total screen failures

n(%)

Gender n

Female %

Skin

Colour

n

Black

White

Mixed

White

Native Brazilian

Asiatic


77

Age n

mean (SD)

median

Q1-Q3

Min-max

Table 37: Patients that met the GINA 2017 criteria

Total n(%)

Total

Severe

asthma

patients

Patients

that met

the GINA

2017

criteria

Table 38: Medication used before to the case-control study among the severe asthma

population

Medication used N%

Anti-IgE

Anticholinergics

Antihistamines

Inhaled corticosteroids low

dose

Inhaled corticosteroids High

dose


78

Inhaled corticosteroids low

dose + LABA

Inhaled corticosteroids high

dose + LABA

Leukotriene antagonist

Phosphodiesterase 4 inhibitor

Short-acting β2 agonist

Systemic corticosteroid

Xanthine and adrenergics

Others*

*Please, include as a new row every medicine reported that does not fit in any of the other

categories. Each medicine reported should be added as a new row.

Table 39: Medication used in the year before to the study 2 by eligibility criteria

Medication used Severe

asthma

GINA

2017

severe

asthma

Mepolizumab

eligible

Omalizumab

eligible

Reslizumab

eligible

Benralizumab

eligible

Anti-IgE

Anticholinergics

Antihistamines

Inhaled

corticosteroids

low dose

Inhaled

corticosteroids

High dose

Inhaled

corticosteroids

low dose + LABA

Inhaled

corticosteroids


79

high dose +

LABA

Leukotriene

antagonist

Phosphodiesterase

4 inhibitor

Short-acting β2

agonist

Systemic

corticosteroid

Xanthine and

adrenergics

Others*

*Please, include as a new row every medicine reported that does not falls out in any of the

other categories. Each medicine reported should be entered as a new row.

confidential glaxosmithkline group of companies project … · 2020-07-09 · confidential project...

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