How to "Choosebetweenamab" for Severe Asthma, Comparing Treatment With Mepolizumab and Omalizumab for Patients With Severe Allergic and Eosinophilic Asthma.
Phase: PHASE4
Conditions: Asthma, Eosinophilic Asthma
Sponsor: University of Newcastle, Australia

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CHOOSING BETWEEN BIOLOGICAL AGENTS FOR SEVERE ALLERGIC 
EOSINOPHILIC ASTHMA 
 
INTRODUCTION 
 
Severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids 
plus a second controller (and/or systemic corticosteroids) to prevent it from becoming 
‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy 1. Only a small number of 
people with asthma have severe disease, as the majority are well controlled on low dose inhaled 
corticosteroids. However, those who suffer with severe asthma have a highly disproportionate 
burden of illness, with increased clinical morbidity, high economic costs2, and poor quality of life 3, 
making it an important chronic disease management problem for Australia and New Zealand. 
  
With severe asthma defined on the basis of disease that is refractory to usual treatments that work 
well in those with milder asthma, it is not surprising that those with severe asthma demonstrate 
many differences to those with milder disease.  Even within the group with severe asthma there is 
considerable heterogeneity; in terms of the natural history, pathology and expression of disease 
phenotypes, all of which have important implications for therapeutic control 4.  
 
The advent of biological agents that target specific inflammatory pathways in asthma has been the 
most important recent therapeutic advance in targeting those with severe asthma. Asthma therapies 
such as bronchodilators and corticosteroids work well in those with mild asthma, but demonstrate 
limited effectiveness in severe disease. In contrast the new biologic agents, specifically target 
dysregulated mechanisms of active disease in severe asthma. This offers the hope of precision 
medicine, tailoring the right therapy to the right patient. However, in a disease that is acknowledged 
as heterogeneous the contrary is also true and unless the right patient is identified, the maximum 
benefits of these increasingly expensive therapies will not be realized5. 
 
 Severe asthma clinicians in Australia now have the choice to access treatment with two biologic 
agents; Omalizumab or Mepolizumab. Patients in NZ only have access to Omalizumab currently, 
and Mepolizumab is expected to be funded in the next few months. Omalizumab is a monoclonal 
antibody directed against IgE and approved for use in severe allergic asthma; Mepolizumab is a 
monoclonal antibody against interleukin (IL)-5, for use in severe eosinophilic asthma. These agents 

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do not work in all patients with severe asthma. However, they are excellent examples of progress 
toward precision medicine in airway diseases, whereby management is based on the pathogenesis of 
the active disease process with efficacy limited to specific asthma disease phenotypes. The 
challenge for clinicians in their prescription of these treatments are those cases where two severe 
asthma phenotypes (i.e. severe allergic asthma and severe eosinophilic asthma) have significant 
overlap in the one individual in terms of disease expression, and there is, as a consequence, a lack 
of precision in regard to which treatment should be applied.  
 
While clinical trials have demonstrated the effectiveness of both agents against placebo, these trials 
were designed to maximise their treatment effect, against the broadest number of severe asthma 
patients. They have not directly compared these agents in terms of efficacy, nor have they provided 
sufficient clarity as to who may benefit more from one agent compared to the other.  These are 
highly important clinical questions, and there have been calls for this research in international 
journals 6.  
 
Hypothesis: in patients with the dual phenotypes of severe allergic and eosinophilic asthma, 
Mepolizumab is as effective as Omalizumab.  
 
We also propose that key clinical biomarkers will clarify which patients will respond best to 
each of these interventions. 
 
This study will be the first direct clinical comparison of these agents and will apply expert clinical 
characterisation, and incorporate cutting edge biotechnology to better inform treatment choices for 
severe asthma. There is an important and urgent management problem facing the Australian and 
New Zealand pharmaceutical schemes, where imprecision in prescribing will result in reduced 
clinical effectiveness as well as substantial and sustained economic cost.  
 
 

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RESEARCH PROPOSAL  
 
Background 
 
While only 3 to 10% of patients with asthma have severe disease 7,  they suffer a high symptom 
burden and highly impaired health status 3,8. Severe asthma in fact is responsible for the majority of 
health care expenditure for asthma with per patient costs for severe asthma ten times that for mild 
disease9, making it a priority area for research in asthma, the most prevalent chronic respiratory 
condition affecting Australians. 
 
Independently, a number of studies that have used unbiased population cluster analysis of asthma 
populations have demonstrated that severe asthma is a heterogeneous disease 10-12. It is likely the 
result of genetic, epigenetic and multiple precipitating environmental factors that occur to varying 
degrees throughout life. This results in various clinical phenotypes of disease, many with 
overlapping features and many that remain poorly defined4. Early onset or childhood asthma tends 
be associated closely with allergy and expresses an inflammatory phenotype characterised by type 2 
inflammation and airway eosinophilia and often is associated with other allergic diseases. In adults 
the relationship with allergy is less, and in those with late onset disease, asthma can be associated 
with airway eosinophilia and type 2 inflammation, refractory to inhaled corticosteroids as well as 
subgroups with minimal airway inflammation, or airway neutrophilia, obesity and fixed airflow 
obstruction 13. This heterogeneity of disease means that a single therapeutic intervention is unlikely 
ever to be the answer to controlling severe asthma. While the occurrence each of these severe 
asthma clinical phenotypes are relatively small in number, the morbidity and cost of the disease 
justifies an approach that will carefully define what these clinical phenotypes are, the dysregulated 
disease mechanisms involved and research-based strategies to target therapies to correct or mitigate 
against the symptoms.   
 
New monoclonal treatments for severe asthma 
 
The emergence of monoclonal antibodies as treatments that target specific aspects of asthmatic 
inflammation offers considerable promise. In the past disease control in severe asthma was poor 
despite optimal inhaled therapies, leading to a reliance on oral corticosteroids with their limited 
efficacy and severe side effects. Conversely, the specificity of biologic agents means that their 
optimal performance will require careful characterization of severe asthmatic phenotypes.  
 

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Mepolizumab 
 
Mepolizumab provides an excellent example of this dilemma. Mepolizumab is a monoclonal 
antibody directed against IL-5 and prevents the recruitment of eosinophils to the airway, which is 
known to be associated often, but not always with, disease activity14. The initial phase three trial of 
mepolizumab recruited participants with symptomatic asthma that was not controlled despite 
inhaled corticosteroids and while a significant reduction in peripheral blood eosinophils was 
demonstrated, there was no effect on asthma symptoms, lung function or exacerbation frequency 15. 
However, when investigators selected subjects with truly corticosteroid refractory asthma: 
symptomatic, with exacerbations and with persistent airway eosinophilia despite inhaled (ICS) or 
oral corticosteroids 16, Mepolizumab led to a reduction in exacerbations of approximately 50%, and 
improvements in quality of life. These observations prompted further larger scale phase three trials 
and selecting patients with refractory airway eosinophilia using peripheral blood eosinophils and 
severe asthma, investigators demonstrated a similar reduction in exacerbations 17. 
 
Omalizumab 
 
Omalizumab, is a monoclonal antibody directed against IgE, a molecule that plays a critical role in 
allergic inflammation, though not specifically asthma. In contrast to Mepolizumab, identifying 
those who will benefit most from Omalizumab is not so clear and a biomarker such as blood or 
airway eosinophilia remains elusive. Omalizumab exerts its benefits in those with moderate to 
severe allergic asthma, with the greatest benefit seen in exacerbation and hospitalisation reduction, 
though oral steroid reduction has not been documented 18. People with persistent symptoms and 
evidence of type 2 inflammation; exhaled nitric oxide, blood eosinophilia and serum periostin 
despite ICS appear to derive the most benefits 19while Omalizumab is of no demonstrable benefit in 
people who are non-atopic20.  
 
Better prescribing algorithms are needed. 
 
A significant limitation of the clinical studies proving safety and efficacy of these targeted 
biologicals was that they were designed to satisfy international regulatory requirements principally 
by demonstrating superiority over placebo, thereby limiting the eligible pool of patients that could 
receive treatment, and further by focussing on relatively short-term outcomes that acted as a 
surrogate for long term effectiveness. Study design for both agents, was not concerned with 
identifying factors that predicted responsiveness. Subsequent investigator-initiated trials have 

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shown interesting effects of Omalizumab on immune regulation in difficult to control asthma. For 
example, investigators compared the treatment of Omalizumab in children with a history of asthma 
and found Omalizumab improved asthma control and substantially reduced acute exacerbations 21. 
However, when the investigators compared Omalizumab to increasing the dose of ICS in the at-risk 
period, a benefit was only seen in those children who had a history of recent exacerbation and was 
most beneficial in those who were exacerbating with virus infections. In a subset of children they 
also demonstrated improved antiviral responses, following treatment with Omalizumab 22. These 
findings suggest that there may be subsets of patients more likely to respond to treatment, via 
mechanisms not identified in the original regulatory trial designs.  
 
Exacerbations are an important defining feature of severe asthma. One third of total annual asthma-
related health care expenditure may be attributable to asthma-related hospitalisations23,24. 
Exacerbation risk is greatest in those with more severe disease, poor symptom control and persistent 
eosinophilic airway inflammation despite treatment25,26. The most common trigger for 
exacerbations in both children and adults are viral respiratory tract infections27 which we and others 
have shown also to be linked to impaired antiviral interferon (IFN) responses28-31.  The pathogenesis 
of virus-induced asthma exacerbations is complex and whilst only partially understood, it is evident 
there is an interaction between active type 2 airway inflammation in asthma and dysregulated 
antiviral responses. Type-2 biased immune responses are directed by a subset of TH2 effector 
lymphocytes that release signature cytokines IL-4, 5 and 13. These cells are not the exclusive 
source of these cytokines and a recently discovered subset of innate lymphoid cells (ILC-2) have 
been shown to play a crucial role in innate immune responses, with these cells releasing type 2 
cytokines 32. ILC-2 cells are directly activated by IL-25 and IL-33 released by airway epithelial 
cells and play a crucial role in perpetuating type-2 immune responses in asthma 33. Viral infections 
however are usually associated with type I immune responses that should suppress allergic 
inflammation, but paradoxically the reverse appears to be the case in asthma. Allergic sensitisation 
and viral detection increase the odds of being admitted to the hospital with an asthma exacerbation 
34 . Further, persistent eosinophilic airway inflammation has been associated with an increased 
intensity of symptoms following rhinovirus (RV) infection 35.  In the case of both Omalizumab and 
Mepolizumab, the greatest clinical benefit is their ability to reduce exacerbation frequency, yet 
relatively little is known about the mechanism(s) that leads to this outcome.  
 
The literature currently fails to clearly differentiate between these two monoclonal therapies that 
target severe asthma (i.e. those with evidence of refractory type 2 airway inflammation) in terms of 
either efficacy or how to predict a favourable clinical response. Peripheral blood  eosinophils do 

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appear to predict a response to Mepolizumab 36, and, whereas a similar single biomarker is not 
evident for Omalizumab, higher blood eosinophils at baseline are associated with a better response 
to Omalizumab19.  
 
We were able to study “real world experience” for the use of Omalizumab in Australia. Data from 
patients with poor asthma control despite optimised treatment, evidence of atopy and who had 
received Omalizumab prescribed by specialists, was entered into the Australian Xolair Registry 
(AXR). These data demonstrated that of 180 participants in the registry, after 6 months treatment, 
150 (83%) were judged to have improved and continued Omalizumab treatment whereas 30 people 
discontinued due to either adverse events or treatment failure 37. Treatment responders were shown 
to more likely have worse asthma symptoms with a higher asthma control questionnaire (ACQ) 
score at baseline and the analysis showed that a positive response to treatment with Omalizumab 
was not influenced by co-morbidities. Beyond these metrics no other factors predicted treatment 
success. Further interrogation of the AXR registry demonstrated that a large number of subjects 
would have been eligible for therapy with either Omalizumab or Mepolizumab based on Australian 
Pharmaceutical Benefits Scheme (PBS) criteria (Table 1). 
 
Table 1: Serum IgE and blood eosinophils in severe asthma patients included in the SAWD 
registry (measurements at baseline or within 3 years prior to baseline) 
 
 
Blood 
Eosinophils 
0-150 
Blood 
Eosinophils 
150-300 
Blood 
Eosinophils 
>300 
IgE <30 
13 
8 
5 
IgE  ≥ 30 
65 
58 
71 
 
This raises the critical question of which drug should be chosen for individuals who present with 
both raised IgE and high blood eosinophils. 
 
There are no clinical studies that offer a head-to-head comparison between these agents to see 
if one is superior to the other in cases where either may be applicable.  Indeed, it remains 
unclear if clinical or biological markers of disease can be used to identify responders, beyond 
the current prescribing recommendations that have been derived from the selection criteria 
used in regulatory clinical trials.  
 

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If the current circumstance remains it is likely that selection of treatment will default to personal 
physician preference, with the agent chosen being that which is easiest to administer or that which 
is easiest to apply for. This is clearly unsatisfactory for a disease such as severe asthma with these 
biological therapies being both long-term and expensive. Rather, the choice should be based on the 
agent that is best suited to control the disease process in an individual and one that will result in the 
greatest clinical efficacy. Failure to target an appropriate treatment may also have major clinical 
implications and could result in patients at risk of severe exacerbation and death from asthma not 
receiving efficacious treatment in a timely manner.  Current restrictions of the Australian PBS also 
require a six month window between trials of monoclonal antibody therapies, further putting 
patients at risk if the more efficacious treatment is not chosen in the first place. The results of the 
study proposed here will be immediately translatable to the Australian and New Zealand health 
environments and provide clear direction for a change in policy for this important chronic 
condition. 
  
HYPOTHESIS 
We propose that: 
“In patients with the dual phenotypes of severe allergic and eosinophilic asthma, Mepolizumab is as 
effective as Omalizumab”.  
 
In testing this hypothesis experimental analyses will be undertaken to identify key clinical 
biomarkers that may determine a clinical profile which responds best to each of these interventions 
if equivalence is not apparent (inferiority outcome). 
 
AIMS 
 
Aim 1: To determine if Mepolizumab is as effective as Omalizumab in adults with severe 
refractory asthma who exhibit a dual allergic/eosinophilic phenotype in terms of improvement 
in asthma control. 
Aim 2: To determine those with severe refractory eosinophilic and allergic asthma if 
peripheral blood gene expression, immune cell subset analysis, exhaled volatile 
compounds and induced sputum provides novel information that will identify patients 
who are more likely to response to omalizumab or mepolizumab. 
 
 

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INVESTIGATIONAL PROCEDURES 
CLINICAL 
Aim 1: To determine if Mepolizumab is as effective as Omalizumab in adults with severe 
refractory asthma who exhibit a dual allergic/eosinophilic phenotype in terms of improvement 
in asthma control. 
Participants  
 
A non-inferiority un-blinded “pragmatic” randomised control trial (RCT) will be carried out. 190 
participants will be recruited from patients who have been assessed by respiratory or immunology 
specialists in Australia and New Zealand and who dually qualify for treatment of severe asthma 
with either Mepolizumab or Omalizumab according to Australian PBS criteria or New Zealand 
Pharmac criteria (for Omalizumab). As Mepolizumab is currently unfunded in NZ, 
GlaxoSmithKline (GSK) has agreed to provide Mepolizumab on compassionate grounds to up to 
six patients recruited into this study. To qualify for PBS-subsidised provision of these drugs, the 
following criteria need to be satisfied and these criteria will be used to determine inclusion in this 
study.  
 
INCLUSION CRITERIA 
 
Treatment criteria 
 
• Must be treated by a respiratory physician, clinical immunologist, allergist or general 
physician experienced in the management of patients with severe asthma. 
 
AND 
 
• Patient must be under the care of the same physician for at least 6 months; OR 
Patient must have been diagnosed by a multidisciplinary severe asthma clinic team,  
 
AND 
 

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• Patient must have a diagnosis of asthma confirmed and documented by a respiratory 
physician, clinical immunologist, allergist or general physician experienced in the 
management of patients with severe asthma, defined by the following standard clinical 
features; (i) forced expiratory volume (FEV1) reversibility greater than or equal to 12% and 
greater than or equal to 200mL at baseline within 30 minutes after administration of 
salbutamol (200 to 400 micrograms) or (ii) airway hyper-responsiveness defined as a greater 
than 20% decline in FEV1 during a direct bronchial provocation test or greater than 15% 
decline during an indirect bronchial provocation test, (iii) peak expiratory flow (PEF) 
variability of greater than 15% between the two highest and two lowest peak expiratory flow 
rates during 14 days; OR 
 
• Patient must have a diagnosis of asthma from at least two physicians experience in the 
management of patients with severe asthma, 
 
AND 
 
• Patient must have a duration of asthma of a least 1 year, 
 
AND 
 
• Patient must have past or current evidence of atopy, documented by skin prick testing or an 
in vitro measure of specific IgE, that is no more than 1 year old, 
AND 
 
• Patient must have total serum human immunoglobulin E greater than or equal to 30 IU/mL, 
 
AND  
 
• Patient must have blood eosinophil count greater than or equal to 300 cells per microliter in 
the last 12 months; OR 
Patient must have blood eosinophil count greater than or equal to 150 cells per micolitre 
while receiving treatment with oral corticosteroids in the last 12 months. 
 
AND 
 

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• The treatment must not be used in combination with and within 4 weeks of another PBS-
subsidised biological medicine prescribed for severe asthma. 
AND 
 
• 
Must be aged 12 years or older. 
 
Optimised asthma therapy: 
 
 (i) Adherence to maximal inhaled therapy, including high dose inhaled corticosteroid (ICS) plus 
long-acting beta-2 agonist (LABA) therapy for at least 12 months, unless contraindicated or not 
tolerated; 
AND 
(ii) treatment with oral corticosteroids, either daily oral corticosteroids for at least 6 weeks, OR a 
cumulative dose of oral corticosteroids of at least 500 mg prednisolone equivalent in the previous 
12 months, unless contraindicated or not tolerated. 
The following criteria indicate failure to achieve adequate control and must be demonstrated: 
• 
an Asthma Control Questionnaire (ACQ-5) score of at least 2.0, as assessed in the previous 
month, AND 
• 
while receiving optimised asthma therapy in the past 12 months, experienced at least 1 
admission to hospital for a severe asthma exacerbation, OR 1 severe asthma exacerbation, 
requiring documented use of systemic corticosteroids (oral corticosteroids initiated or increased 
for at least 3 days, or parenteral corticosteroids) prescribed/supervised by a physician. 
 
NZ specific criteria: 
 
Participants recruited in New Zealand must meet the main inclusion criteria listed above. In 
addition they must be eligible for both Pharmac funded Omalizumab and Mepolizumab therapy in 
NZ. Participants in NZ will therefore represent a subset of all possible participants and will meet all 
of the following additional inclusion criteria: 
 
1. Total serum IgE between 76 IU/mL and 1300 IU/ml at baseline 
2. Proven adherence with optimal inhaled therapy including high dose inhaled corticosteroid 
(budesonide 1,600 mcg per day or fluticasone propionate 1,000 mcg per day or equivalent), 
plus long-acting beta-2 agonist therapy (at least salmeterol 50 mcg bd or eformoterol 12 mcg 
bd) for at least 12 months, unless contraindicated or not tolerated 

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3. Asthma Control Test (ACT) score of 10 or less 
4. Systemic corticosteroids: 
a. Patient has received courses of systemic corticosteroids equivalent to at least 28 days 
treatment in the past 12 months, unless contraindicated or not tolerated OR 
b. Or patient has had at least 4 exacerbations needing systemic corticosteroids in the 
previous 12 months, where an exacerbation is defined as either documented use of 
oral corticosteroids for at least 3 days or parenteral steroids 
 
Exclusion Criteria 
 
1. Unwilling to provide consent 
2. Other conditions likely to compromise participant safety or impact on the feasibility of results, at the 
discretion of the investigator (examples include pregnancy and malignancy). 
 
RANDOMISATION AND DRUG PROVISION 
 
Participants who are suitable for study inclusion and who have provided Informed Consent will be 
randomised (1:1) using the CReDITSS Online Randomisation Engine (CORE) at the HMRI to 
receive either open label Mepolizumab or Omalizumab for 6 months. 
 
Site personnel will be unblinded to the randomisation process. 
 
In Australia, Treatments will be sourced by the treating physician after successful application to the 
PBS authority. 
 
In New Zealand, Omalizumab and Mepolizumab will be sourced by the treating physician after 
successful application to Pharmac.  
 
CLINICAL ASSESSMENTS 
 
Baseline data will be collected at Visit 0 by the local site at the time of randomisation and 
participant data forwarded electronically for collation by the central coordinating site.  
 
Study-specific clinical data collected at baseline V0, by the site and sent electronically to the central 
site. This will include: 
 
 
Evidence of asthma (as defined in the inclusion criteria 4). 

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Evidence of poor asthma control in the past 12 months (as defined inclusion criteria 8)  
 
Exhaled nitric oxide (FeNO), if available. The preferred device for use will be the Niox 
Vero, however an alternative device may be used by sites after review of its speciifcations. 
 
Post-bronchodilator spirometry  
 
Blood samples for measurement of:  
I.blood eosinophils,  
II.C reactive protein (CRP)  
III.total IgE 
IV.allergen specific IgE for mixed fungi, house dust mite, Australian grass mix, and 
animal dander (dog and cat) mix.  
 
Sputum induction (selected sites only) 
 
eNose 
 
Optional blood samples (included in visit blood sampling if consent provided) 
 
Telephone contacts by the central coordinating site 
 
The central site will telephone each  randomised participant within 48hrs following the  
randomisation visit (Visit 0). The central site will take a standard asthma history. They will take a 
standard history of co-morbid conditions. They will determine current medications being used. 
They will assess asthma symptoms and calculate the ACQ5.  This ACQ5 score will be used as the 
baseline metric to determine the primary outcome of the study.  
The central site will then enter this data into the study database. They will generate a brief summary 
report for the referring site. They will generate the Australian PBS initial application form for the 
site and return this electronically to the site, together with the ACQ5 form.  
 
The reffering clinican will need to sign the PBS initial application form and ACQ5 form 
acknowledging that both are correct. They will then submit these forms together with a prescription 
to the PBS. 
 
Upon approval and receipt of the prescription the referring site will invite the patient to return to 
receive for their first dose (V1). 
 
Those who elect to take part in the substudies defined in Aim 2, will have the following done: 
• Blood taken for transcriptomics (x1 9ml EDTA tube) 
• Blood taken for isolation of peripheral blood monocytes (1-2 9ml EDTA tube) 
• Spirometry 
• FeNO 
• Measurement by the eNOSE 
  
The central site will contact participants monthly by phone (P1, P2, P3, P4, P5 and P6 – see Time 
and Events table – Table 2) to determine if there has been change in clinical condition of asthma or 
otherwise or  if any adverse event has occurred. In regard to asthma, this telephone call will involve 
the collection of:  
 
 
ACQ5  
 
ACQ6 
 
details of any exacerbations 
 
unplanned hospital or primary care visits 
 
use of prednisone 
 
adherence to asthma therapy  
 

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Those who elect to take part in the substudies defined in Aim 2, will have one or more of the 
following done, 4 weeks after starting treatment, 12 weeks and at the conclusion of treatment: 
• Blood taken for transcriptomics (x1 9ml Paxgene tube) 
• Blood taken for isolation of peripheral blood monocytes (1-2 9ml EDTA tube) 
• Spirometry 
• FeNO 
• Measurement by the eNOSE 
 
 
End of treatment trial visit (Visit 2) 
The subject will be contacted by the central site 2 weeks before Visit 2 (P6). Data required for possible 
reapplication for their monoclonal therapy will be obtained. A report including this data will be sent 
to the referring local clinician. This report will included ACQ5 results, prednisone dose, number of 
asthma exacerbations in the last 6 months and an assessment indicating if the subject meets PBS 
criteria for continuation, together with a completed PBS continuation form and ACQ5 form. At Visit 
2 the referring clinician will determine if the subject has experienced clinical success and should 
reapply for the treatment. The subject will be determined as a treatment success or failure. Subjects 
may also at this time elect to discontinue treatment or may elect to trial the alternative monoclonal 
antibody therapy.  
 
Clinical assessments and blood samples will be collected from all participants at the end of the 6 
month treatment trial and study-specific data recorded by the local site. As described for Visit 0, a 
phone assessment by the central site will be made within 48 hours of the 6 month visit taking place. 
 
Extra study visits for sub-study participants (optional) 
 
Extra study visits can take place 4 and/or 12 weeks after treatment initiation (see Table 2). These 
study visits will be for those subjects who provide consent to participate in the sub-studies. If these 
visits are completed a phone assessment will be made within one week of each extra visit by the 
central site. 
 
Treatment failure and treatment with the alternate treatment 
 
If a randomised participant is deemed a treatment failure i.e. no change in ACQ5 of at least -0.5 
from baseline or an inability to reduce either regular prednisone dose or intermittent prednisone 
dose usage by at least 15%, they will undergo an 8 week washout and then be reassessed at the 
study site as for Visit 0 of the first treatment period. If it is judged to be clinically appropriate by 

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their treating physician the participant will be asked if they are willing to continue in the study. 
Those subjects that agree to continue their involvement in the study will treated with the alternate 
monoclonal antibody for a further period of 6 months. All study assessments described for the 
initial randomised treatment period will be repeated for this second treatment period. 
 
Participants who decline to continue in the study after initial treatment failure will be managed 
according to standard clinical practice at their clinical centre which may include trial of the alternate 
monoclonal antibody treatment. 
 
 

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Table 2: Schedule of Time and Events  
 
 
V0 
1 
V1 
Treatment 
start 
Optional 
visits  
Weeks 4 
& 12d 
2 
3 
4 
5 
6 V2 
Week 
-4 to 
-2 
≤48 
hours 
post-
V0 
0 
4 
4 
8 
12 
16 
22 
24 
Asthma History 
X 
 
 
 
 
 
 
 
 
 
Comorbidities 
X 
 
 
 
 
 
 
 
 
 
ACQ5 & ACQ6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Exacerbation 
occurrence 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Asthma meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
OCS dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Spirometrya,  
X 
 
X 
X 
 
 
 
 
 
X 
FeNO b 
X 
 
X 
X 
 
 
 
 
 
X 
Paxgene b 
 
 
X 
X 
 
 
 
 
 
X 
FBC 
X 
 
 
X 
 
 
 
 
 
X 
EDTA blood 
samples 
 
 
X 
X 
 
 
 
 
 
X 
CRP 
X 
 
 
X 
 
 
 
 
 
X 
IgE & RAST 
X 
 
 
 
 
 
 
 
 
Xe 
Sputum induction b 
 
 
X 
X 
 
 
 
 
 
X 
eNOSE b 
X 
 
X 
X 
 
 
 
 
 
X 
mAb treatment 
randomisation 
X 
 
 
 
 
 
 
 
 
 
 
a. Post-bronchodilator 
b. will be done by selected sites only 
d. Sub-study sample collection visit  
e. IgE only 
 
 
 
 
 

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STUDY ENDPOINTS 
 
Primary Outcome 
• Change in ACQ5 after 6 months of treatment, adjusted for baseline ACQ5. Mean ACQ5 in the 
Mepolizumab group will be compared to that in the Omalizumab group using a pre-specified 
non-inferiority margin (Δ) of 0.35. 
 
Secondary outcomes 
• 
Number of Exacerbations, requiring change in oral corticosteroids, with either a course of 
prednisone for at least 3 days or, for those subjects on maintenance OCS, an increase in 
dose of at least 50% for at least 3 days. 
• 
Time to first exacerbation 
• 
Number of admissions to hospital and /or ED presentations 
• 
Reduction in dose of regular OCS 
• 
Reduction in total OCS use during the 6 month treatment period 
• 
Changes in spirometry (FEV1 or FVC) 
• 
Change in blood eosinophil count 
• 
Proportion continuing on randomisation assigned medication after 6 months (successful 
treatment) 
• 
Adverse events 
 
Treatment Failure 
 
After 6 months of treatment subjects will be clinically assessed to determine if the treatment has 
succeeded or failed.  The following criteria will be used be regarded as the treatment having failed: 
 
1. No improvement in ACQ5 of at least 0.5 (minimum clinically important difference) from 
baseline, and 
 
2. No reduction in regular prednisone dose or intermittent prednisone usage by at least 15% 
and 
 
3. An intolerance to the agent or the emergence of clinically significant side-effects. 
 

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In New Zealand participants will be considered to have treatment failure if they do not meet the 
following additional criteria: 
1. An increase in the Asthma Control Test (ACT) score of at least 5 from baseline AND 
2. A reduction in the maintenance oral corticosteroid dose or number of exacerbations of at 
least 50% from baseline. 
 
Alternate treatment challenge 
 
Those participants who are deemed to have failed initial therapy will then undergo a 4 week 
washout period. At the end of this time they will then be offered therapy with the alternative 
monoclonal antibody for 6 months where the same visit schedule will be followed as was done for 
the initial randomised treatment period. 
 
In Australia, the supply of the alternate medication will be provided on compassionate grounds 
from either GSK (mepolizumab) or Novartis (omalizumab) for 6 months. In New Zealand, use of 
omalizumab as an alternate medication will be funded by Pharmac whereas mepolizumab will be 
provided by GSK under compassionate access. If Pharmac fund Mepolizumab during the study, 
participants randomised after this point will be placed on Pharmac funded mepolizumab if they 
meet the Pharmac criteria in place at that time. 
 
If the alternate treatment is successful, an application will be made for continuation of the treatment 
from the PBS, for Australian participants, or Pharmac, for New Zealand participants. If 
mepolizumab is not funded by Pharmac at that time GSK will supply ongoing mepolizumab on a 
compassionate basis up to a maximum of 6 participants. 
 
Based on the experience gained from the Australian Xolair data registry, a 16% failure rate with the 
first agent is anticipated. This expectation suggests treatment with either Mepolizumab or 
Omalizumab as an alternate may be required for approximately 30 participants of the initial cohort 
of 190 randomised subjects. ` 
 
DATA COLLECTION 
 
Data will be collected by the sites recruiting participants on a clinical record form, with data 
forwarded to the central site for data entry. The data will be entered into the secure Severe Asthma 
Network database, ‘SAWD’ that works on a Research Electronic Data Capture (REDCap) platform. 

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The central site will conduct all phone assessments and will enter this data directly into the 
database. 
 
All data will stored in password protected secure electronic format, with access limited to those 
with database administrator rights.  Access to the database is managed by the Data Custodian and 
individual user rights within the database are controlled according to the specific role/access 
permission of the user.  All users require individual log-in details which remain confidential. 
 
The SAWD REDCap database is stored and run from the HMRI data centre with all data both 
physically and virtually secured. The application security provides role based access and uses 256 
bit grade encryption to protect the authentication details and all communication between clients and 
the servers will utilise HTTPS via SSL. The HMRI data centre offers cold disaster recovery – if the 
infrastructure housing the application fails, HMRI provide an offsite fully operational replica of the 
system within the University of Newcastle Callaghan Campus data centre that can be turned on 
within moments. Backups are taken at 30 minute increments, stored to disk and tape and are housed 
onsite and offsite. Access to the server physically and virtually is limited to HMRI IT Services staff 
only. 
 
STATISTICAL PLAN FOR AIM 1 
 
The hypothesis of this study aim is that Mepolizumab is as effective as Omalizumab in improving 
asthma symptom control. 
 
Web-based randomisation 
The Clinical Research Design, IT and Statistical Support (CReDITSS) unit at the Hunter Medical 
Research Institute is a consulting unit that provides statistical services to researchers. 
Randomisation will be performed using the CReDITSS Online Randomisation Engine (CORE): a 
web-based randomisation and data entry system deployed as a standalone application for individual 
research projects. We will use permuted block randomisation, with block sizes of 4 or 6, stratified 
by baseline eosinophil count (using a median split). 
 
Blinding 
Owing to the pragmatic nature of the trial, neither participants, treating clinicians nor site staff will 
be blinded. However, research staff recording outcomes by phone will be blinded. In addition, data 
managers and statisticians will be blinded. 

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Sample Labelling 
All subjects, questionnaires and phone interview records and laboratory samples will be labelled 
using a code in the format CAM – site number – subject number: CAM-XXX-XXX. 
 
A list will be maintained at each site by the study coordinator and a master identification list 
maintained at the central site. This coding is to allow the blinding of data managers and statisticians. 
 
Sample size/power 
The sample size has been selected to provide 80% power to test the one-sided null hypothesis H0: 
µM - µO ≥ Δ where µM is the mean 6 month ACQ5 in the Mepolizumab group, µO is the mean 6 
month ACQ5 in the Omalizumab group and Δ is the non-inferiority margin, which we have 
specified as 0.35. The corresponding alternative hypothesis is HA: µM - µO < Δ. 
 
The non-inferiority margin has been selected as a proportion (slightly less than half) of the effect 
size observed in two of the largest superiority trials comparing Omalizumab to placebo 39. 
Using pilot data, we estimated a standard deviation (SD) of 1.05 for the mean ACQ5 and a 
correlation of 0.4 between baseline and 6 month ACQ5 for patients treated with Omalizumab and 
Mepolizumab. To test the non-inferiority of Mepolizumab compared to Omalizumab will require 95 
participants per group (1:1 allocation ratio). This will provide 80% power to estimate a one-sided 
95% confidence interval (alpha=0.05) for the baseline-adjusted group difference in mean ACQ that 
excludes the 0.35-point non-inferiority margin, assuming a SD of 0.962 for the baseline-adjusted 6 
month mean ACQ5 (based on the ACQ5 SD of 1.05 and a correlation of 0.4 between baseline and 
follow-up ACQ5). Allowing for a 5% loss to follow-up at the 6 month visit, the study will recruit 
200 subjects.  
 
Statistical analysis 
Efficacy of the intervention: All analyses will be conducted blind to group allocation. The primary 
endpoint will be analysed for the as treated population to minimise type I error inflation by 
treatment failure and subsequent crossover. A sensitivity analysis will be performed for the 
intention-to-treat (ITT) population. 
 
Treatment group differences in six-month ACQ5 will be estimated using a Generalised Linear 
Model (GLM) with a normal response distribution and identity link function. The model will be 

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fitted in an ANCOVA framework (i.e. adjusted for baseline). The model will include fixed effects 
for group and baseline eosinophil count. The treatment effects will be estimated as baseline-
adjusted, least-square mean differences between the two treatment groups at 6 month follow-up. 
Secondary analyses will be assessed using the same GLM approach, with response link function as 
appropriate to the response distribution. 
 
Attrition: The GLM provides unbiased estimates of treatment effect under the assumption that data 
are missing completely at random. Based on previous experience with this patient population, 
attrition is anticipated to be very low. However, sensitivity analyses such as multiple imputation and 
pattern mixture modelling will be used to investigate the robustness of conclusions to different 
missing data mechanisms. 
 
EXPERIMENTAL APPROACH 
LABORATORY-BASED PROCESSES 
Aim 2: To determine those with severe refractory eosinophilic and allergic asthma if peripheral 
blood gene expression, immune cell subset analysis, exhaled volatile compounds and induced 
sputum provides novel information that will identify patients who are more likely to response 
to omalizumab or mepolizumab. 
 
The registration trials for both Mepolizumab and Omalizumab, identified a clinical phenotype, i.e. 
dual atopy and persistent eosinophilia that may potentially respond to both agents. This description 
however may be a superficial means of describing this heterogenous group of patients. A more 
detailed analysis of the pathology present, before and after treatment, would better define whether 
participants will respond to one agent better than the other and may also provide invaluable data for 
future clinical interventions. 
From two subsets of participants we will seek to determine the influence of treatment on immune 
responses in asthma. 
Participants will be asked to provide consent for the additional blood samples required for this 
aspect of the research study. 
Aim 2a: Characterisation of peripheral blood molecular signature to predict response to 
treatment. 

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We will collect blood samples (i.e. 3 x 9ml EDTA tubes & 1 x 2.5 ml PaxGene tube) for storage 
and measurement of biomarkers and gene associations using RNA-Seq to predict response from 80 
participants, 40 assigned to each treatment arm. 
Blood samples will be collected at randomisation (V0) and again after 6 months of treatment (V2). 
In addition, blood samples will be collected from participants who have been deemed treatment 
failures as described above. 
Samples for RNA-Seq will be collected in Paxgene tubes and stored, batched and sent to the central 
lab (HMRI) for processing. The RNA-Seq will be used to perform determine responder gene(s) 
profiles in severe asthma patients to be characterised before and after treatment. This transcriptomic 
profile will be compared to that of our collaborators in the large U-BIOPRED population that 
assessed severe asthma at baseline 40. 
A subgroup of individuals will have systemic and airway immune profiles characterised before and 
after treatment with Mepolizumab. 
Forty (20) participants recruited from the John Hunter Hospital, Newcastle and Princess Alexandra 
Hospital, Brisbane will have blood (1 x 9ml EDTA tubes) taken for isolation of peripheral blood 
monocytes (PBMCs) and also be asked to undergo a sputum induction. 
PBMCs will be characterised by flow cytometry to determine and quantify the presence lymphocyte 
populations; CD3+ CD4+ T helper (TH-1/2/17), T Regulatory cells; CD3+, CD4+, CD25+, CD8+ 
T cells, Plasmacytoid dendritic cells (pDCs), NKT cells; CD3+CD56+, NK cells CD3- CD56+, 
monocyte derived dendritic cells; CD14+, CD11c+ and plasmacytoid dendritic cells; CD3- 
CD304+. Innate lymphoid 2 cells. Total ILCs will be identified as CD45+ cells, negative for 
lineage markers and CD127+; ILC2 are positive for the prostaglandin D2 receptor (CRTH2) or 
IL-33 receptor (ST2). 
 
• 
A subset of PBMCs will be stimulated to assess immune response to important asthma 
triggers. PBMCs will be cultured with Influenza, Rhinovirus, House dust mite extract and LPS. 
Responses will be determined in regard to release of; IFN-, IFN-, IL-1, IL-6, IL-12, IL-10, IL-5, 
IL-4, IL-13. Responses will be assessed at 24hrs and after 7 days, by ELISA or flow cytometry bead 
array. 

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• 
Induced sputum will be collected and processed. Cell count and differential performed on 
selected mucus plugs. Cell count will be determined using microscopy followed by flow cytometry 
to quantify monocyte and lymphocyte populations. 
 
Aim 2b: Characterisation of exhaled molecular signature using an “electronic nose” to predict 
response to treatment. 
The “SpiroNose” is an electronic nose especially designed for medical purposes that can be used as 
add-on to routine lung function testing41. This technology will be supplied through our 
collaboration with AI-Sterk. The “SpiroNose” incorporates e-nose assessment in routine daily 
practice. The SpiroNose consists of 8 separate sensor arrays, each comprising 4 metal oxide 
semiconductor sensors. Four of the sensor arrays are used as reference arrays to detect the ambient 
volatile organic compounds (VOCs) and 4 sensor arrays are used to monitor the VOCs in exhaled 
breath. 
 
Deidentified data (changes in electrical voltage) are transmitted in real-time and stored in the online 
server of “BreathCloud”. “BreathCloud” is a reference database of exhaled biomarker profiles 
linked to a computer programme by a corresponding application to enable point-of-care 
personalized medicine. 
 
This database provides immediate diagnostic answers for the individual patient. For each patient, 
BreathCloud automatically selects the most optimal model, based on patient characteristics and 
differential diagnosis, in order to create a final report. 
 
The “SpiroNose” will be performed on those participants (n=80) who consent to participate in Aim 
2a. This will provide the unique opportunity to combine data from clinical characterisation and a 
systemic molecular signature of disease and relate these data directly to treatment efficacy. 
 
FINAL OUTCOME 
At the conclusion of this study the information gained may provide the opportunity to determine a 
precise clinical profile that can be immediately applied in real world severe asthma clinics. It is 
hoped that these data will enable an accurate predictor of success for treatment with both 
Omalizumab and Mepolizumab in people with severe allergic/eosinophilic asthma. If this outcome 

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is demonstrated it will be a significant improvement on the present situation where imprecision may 
lead to suboptimal selection of treatment. 
 
 

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