Conditions: Rhinoconjunctivitis
Keywords: Cat allergy Rhinoconjunctivitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 715
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the treatment effect of three treatment regimens of HDM-SPIRE vs placebo and to evaluates the treatment effect of HDM-SPIRE on symptoms, rescue medication usage, Quality of Life and Sleep Quality

Detailed description:

Arms:
arm 1: 4 x 12 nmol HDM-SPIRE followed by 4 x placebo 4 weeks apart arm 2: 4 x 12 nmol HDM-SPIRE 4 weeks apart followed by a second course of 4 x 12 nmol HDM-SPIRE 4 weeks apart arm 3: 4 x 20 nmol HDM-SPIRE followed by 4 x placebo 4 weeks apart arm 4: 8 x placebo 4 weeks apart

Interventions: intervention 1: HDM-SPIRE intervention 2: Placebo
Intervention descriptions: intervention 1: 1 dose every 4 weeks intervention 2: 1 dose every 4 weeks

Protocol document:
Prot_000.pdf: 
 
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Circassia Ltd 
Clinical Study Protocol 
Protocol Identifier: TH005 
 
 
01 APRIL 2015 
EudraCT Number: 2014-001662-94 
A Double-Blind, Randomised, Placebo-Controlled, Multi-Centre Field 
Study to Assess the Efficacy and Safety of HDM-SPIRE in Subjects 
with a History of House Dust Mite-Induced Rhinoconjunctivitis 
PROTOCOL IDENTIFIER: TH005 
Version: FINAL 4.0 (incorporating Protocol Amendment 3 and Replacing 
Protocol Version 3.0 dated 20 Aug 2014) 


 
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STUDY PERSONNEL 
 
SPONSOR COMPANY 
Circassia Ltd 
The Magdalen Centre 
Oxford Science Park 
Oxford 
OX4 4GA 
+44 (0) 1865 598078 (Phone) 
+44 (0) 7092 987560 (Fax) 
 
 
COORDINATING INVESTIGATORS 
Global: 
Dr Paul Ratner 
Sylvana Research 101508 
7711 Louis Pasteur Dr 
San Antonio, Texas. 78229. USA 
+1 210 614 6673209 (Phone) 
 
Europe Regional: 
Dr Victoria Cardona 
Hospital Universitari Vall d’Hebron 
Passeig Vall d’Hebron 119-129 
Barcelona. 08035. Spain 
+34 9 327 46169 (Phone) 
 
 
STUDY MONITOR 
Quintiles Inc., 
4820 Emperor Blvd,  
Durham, NC 27703.  USA 
 
 
SPONSOR’S MEDICAL 
REPRESENTATIVE 
Dr Stephen Pawsey 
Chief Medical Officer 
Circassia Limited 
 
 
 


 
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EMERGENCY NUMBERS 
 
Icon plc (formerly Akos Limited) 
SAE Reporting 
 +44 (0)1628 496300 (Phone for Rest of 
World ) 
+1 888 723 9952 (Phone for North 
America) 
 +44 (0)1865 595595 (Fax for Rest of 
World) 
+1 800 540 1863 (Fax for North America) 
f2m-eastleigh-medical@iconplc.com  
(email) 
Circassia Medical Representative 
+44 (0) 1865 573737 (Phone) 
 
 
 
 
 
 
 
This study will be conducted in compliance with: 
 This protocol  
 ICH E6 GCP guidelines 
 The applicable regulatory requirement(s)  
 The principles of the Declaration of Helsinki 
 




 
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PRINCIPAL INVESTIGATOR’S AGREEMENT 
I agree to conduct this study in accordance with: 
 This protocol 
 ICH E6 GCP guidelines 
 The applicable regulatory requirement(s) 
 The principles of the Declaration of Helsinki 
 
 
 
 
Signature 
 
Date 
dd mmm yyyy 
Name:  
 
 
Principal Investigator 


 
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PROTOCOL SYNOPSIS 
Protocol Identifier 
TH005 
Study Title 
A Double-Blind, Randomised, Placebo-Controlled, Multi-Centre Field Study to 
Assess the Efficacy and Safety of HDM-SPIRE in Subjects with a History of House 
Dust Mite-Induced Rhinoconjunctivitis 
Protocol Version 
FINAL 4.0 
Sponsor 
Circassia Ltd 
Phase 
II 
Indication 
House dust mite (HDM)-induced rhinoconjunctivitis in subjects with clinically 
relevant symptoms. 
Objectives 
Primary Objective: 
 
To evaluate the efficacy of HDM Synthetic Peptide Immuno-Regulatory 
Epitopes (HDM-SPIRE) in the reduction of symptoms and the use of allergy 
rescue medication associated with HDM allergy in subjects with clinically 
relevant symptoms. 
Secondary Objectives: 
 
To evaluate the safety and tolerability of HDM-SPIRE. 
 
To evaluate the effect of HDM-SPIRE on rhinoconjunctivitis specific quality of 
life. 
 
To evaluate the effect of HDM-SPIRE on sleep quality.  
Study Design  
The study will be a randomised, double-blind, placebo-controlled, parallel group, 
multi-centre field assessment of 3 dose regimens of HDM-SPIRE administered at 4 
weekly intervals for 28 weeks. 
Subjects will attend the investigative site for screening and administration of study 
medication and for periodic assessments of safety and efficacy. Subjects will also 
complete an electronic diary (eDiary) during four 3-week periods. These diaries will 
capture the primary efficacy variable data (symptom scores and medication use) as 
well as other patient reported data. 
Sample Size 
A total of approximately 660 subjects will be randomised into the study, with 
approximately 165 subjects in each of the 3 HDM-SPIRE treatment groups and 165 
in the placebo group. A 10% drop-out rate is assumed with the expectation that ~150 
subjects per group will complete the study. Randomisation will be stratified 
according to severity of rhinoconjunctivitis symptoms at baseline and the presence 
of asthma.  
Study Population 
Subjects aged 18-70 years with a documented history of moderate to severe  
HDM-induced rhinoconjunctivitis (without asthma or with controlled Step 1 or 
Step 2 asthma according to the Global Initiative for Asthma (GINA) Guidance). 
Inclusion/Exclusion 
Criteria 
Inclusion Criteria  
1. Male or female, aged 18-70 years. 
2. A reliable history consistent with moderate to severe rhinoconjunctivitis 
(sneezing, rhinorrhoea, itchy nose, nasal blockage and/or itchy eyes, red eyes, 
watering eyes and/or itchy ear/palate) on exposure to HDM for at least 1 year 
and which has required symptomatic treatment on at least one occasion during 
the last year. 
3. Mean Total Rhinoconjunctivitis Symptom Score (TRSS) ≥10 from 4 nasal 
symptoms and 4 non-nasal symptoms over a consecutive 7 day period before 


 
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the Screening Visit 1B/C. 
4. Either Dermatophagoides pteronyssinus (Der p) or Dermatophagoides farinae 
(Der f) 
specific 
Immunoglobulin 
E 
(IgE) ≥0.35 kU/L 
measured 
by 
ImmunoCAP®. 
5. Positive skin prick test (preferably using the ALK-Abello Allergen Extract test) 
to either Der p or Der f with a wheal diameter at least 5 mm (average of longest 
and orthogonal) larger than that produced by the negative control. The negative 
control must be <2 mm for the test to be valid. 
6. Provide written informed consent. 
7. Willing and able to comply with the study requirements. 
8. If female and of childbearing potential, must practice a form of contraception 
with a failure rate of <1% when used correctly and produce a negative urine 
pregnancy test at the Screening Visit 1B/C. 
 
Additional Inclusion Criteria at end of the Baseline Evaluation (BAE) Period 
9. Mean TRSS ≥12 from 4 nasal symptoms and 4 non-nasal symptoms during the 
BAE period (3 week period before randomisation). 
10. Completed the eDiary during the BAE on at least 16 days (>75% of occasions)  
 
Exclusion Criteria 
1. Diagnosis of asthma requiring Global Initiative for Asthma (GINA) Step 3 
(www.ginasthma.org)or higher treatment. 
2. If asthmatic, experienced a deterioration of asthma that resulted in emergency 
treatment or hospitalisation in the 12 months before randomisation, or 
experienced a life-threatening asthma attack (e.g. one requiring intubation and 
mechanical ventilation) at any time in the past. 
3. Used any oral or parenteral corticosteroid at any time within 1 month prior to 
Screening Visit 1B/C.  
4. Asthma requiring high-dose inhaled corticosteroids (ICS) or anti-IgE therapy 
within 6 months prior to Screening Visit 1B/C. 
5. Forced expiratory volume in 1 second (FEV1) <80% of predicted, or other 
evidence of partly controlled or uncontrolled asthma. 
6. Clinically significant confounding symptoms of allergy to relevant local 
seasonal allergens (e.g. ragweed, mugwort, tree, grass or mould) and cannot 
complete the BAE and the final post-administration collection (PAC) period at 
50-52 weeks (PAC3) outside the respective allergy seasons. 
7. IgE ≥0.35 kU/L to other perennial allergens (e.g. animal dander, cockroach, 
mould) which cannot be avoided during the study or where sampling for these 
allergens demonstrates significant levels within the subject’s home from dust 
and/or vacuum cleaner samples, analysed using Indoor biotechnologies 
Allergen Analysis Service. 
8. Intends to be away for 7 days or more during the final PAC period at  
50-52 weeks (PAC3), or whose lifestyle means that there is a high likelihood of 
them being away from home for more than 7 days during the PAC3 period. 
9. Received an immunosuppressive treatment within 3 months prior to Visit 1B/C 
(except steroids for allergic and asthma symptoms).  
10. Previous immunotherapy treatment with any HDM allergen product for more 
than 1 month within 5 years prior to screening. 


 
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11. Receiving ongoing treatment with any specific immunotherapy at screening. 
12. Administration of epinephrine is contraindicated (e.g. subjects with acute or 
chronic symptomatic coronary heart disease or severe hypertension). 
13. Use of beta-blockers, alpha-adrenoceptor blockers or monoamine oxidase 
inhibitors within 14 days before the Screening Visit 1B/C. 
14. History of significant recurrent acute sinusitis, defined as 2 episodes per year 
for the last 2 years, all of which required antibiotic treatment, or a history of 
chronic sinusitis, defined as sinus symptoms lasting greater than 12 weeks that 
include 2 or more major factors or 1 major factor and 2 minor factors. Major 
factors are defined as facial pain or pressure, nasal obstruction or blockage, 
nasal discharge or purulence or discoloured postnasal discharge, purulence in 
nasal cavity, or impaired or loss of smell. Minor factors are defined as 
headache, fever, halitosis, fatigue, dental pain, cough, and ear pain, pressure, or 
fullness. 
15. Females who are pregnant, lactating or planning to become pregnant, or donate 
ova for in vitro fertilisation during the study period or within 30 days following 
the study period. Female subjects unwilling to employ appropriate contraceptive 
measures to ensure that pregnancy will not occur either during or for 30 days 
following the completion of study period. 
16. Significant history of alcohol or drug abuse. 
17. Previously been treated in this or another HDM-SPIRE (ToleroMune-HDM) 
study. 
18. Any history of severe drug allergy, severe angioedema or anaphylactic reaction. 
19. Received treatment with an investigational drug within 30 days prior to the 
study. 
20. Are unable to communicate or to understand the requirements of the study, or 
exhibit any psychiatric disorder, which would impair communication between 
the subject and the Investigator thereby interfering with the informed consent 
procedure or the gathering of study data. 
21. History or findings on physical examination of any significant disease or 
disorder (e.g. cardiovascular, pulmonary, gastrointestinal, liver, renal, 
neurological, immunopathological, musculoskeletal, endocrine, metabolic, 
malignant, psychiatric, major physical impairment) which, in the opinion of the 
Investigator, may either put the subject at risk because of participation in the 
study, influence the results of the study or the subject’s ability to participate in 
the study. 
22. Dependent on the Investigator/site either for employment or education or are 
first degree relatives or partners of the Investigator/study staff. 
23. Institutionalised because of a legal or regulatory order. 
24. Active tuberculosis, auto-immune disorders, vaccination within 2 weeks before 
start of immunotherapy as well as subjects with hypersensitivity to excipients of 
HDM-SPIRE. 
 
Additional Exclusion Criteria at end of BAE 
25. Used any oral or parenteral corticosteroid during the BAE period. 
Investigational Product 
HDM-SPIRE 
Route of 
Administration 
Intradermal injection (100 μL) 


 
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Treatment Regimen(s) 
 
8 x placebo 4 weeks apart 
 
4 x 12 nmol HDM-SPIRE followed by 4 x placebo 4 weeks apart 
 
4 x 12 nmol HDM-SPIRE 4 weeks apart followed by a second course of  
4 x 12 nmol HDM-SPIRE 4 weeks apart 
 
4 x 20 nmol HDM-SPIRE followed by 4 x placebo 4 weeks apart 
Efficacy Parameters 
The following efficacy parameters will be measured in the study: 
 
Combined Score [CS] (TRSS/8 plus Rescue Medication Score [RMS]) 
 
Rhinoconjunctivitis symptom scores (4 point categorical scale and visual 
analogue scale) 
 
RMS 
 
Nasal and non-nasal components of TRSS 
 
Number of days subjects have no moderate or severe rhinoconjunctivitis 
symptoms score (RSS) symptoms without rescue medication usage 
 
Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) 
 
Asthma Control Test (ACT) in subjects with asthma 
 
Home environment (exposure to allergen) 
 
Pittsburgh Sleep Quality Index (PSQI)  
 
Clinical Global Impression of Change in Rhinoconjunctivitis Symptoms 
Safety Parameters 
The safety and tolerability of HDM-SPIRE will be assessed by recording of: 
 
Adverse Events (AEs) 
 
Physical examination 
 
Vital signs 
 
Laboratory values (haematology, serum biochemistry, urine tests) 
 
FEV1 
 
Local reactions at the injection site 
Pharmacokinetic 
Parameters 
None 
Statistical Analysis 
A detailed Statistical Analysis Plan (including dictionaries for coding and software 
used) will be approved by the Sponsor prior to unblinding the study. 
If not otherwise specified, statistical significance is defined as p<0.05 and is 2-tailed 
when appropriate. 
Data will be summarised with respect to demographic and baseline characteristics, 
efficacy variables and safety variables. Summary statistics will include the mean, N, 
standard deviation, median, minimum and maximum values for continuous variables 
and frequencies and percentages for categorical variables. 
The primary efficacy variable will be the CS. This is derived from symptom scores 
and medication use recorded by subjects in an eDiary diary over a 3-week period on 
4 occasions during the study. The primary endpoint for this study is the mean daily 
CS during the PAC3 period in HDM-SPIRE treated subjects compared with mean 
daily CS during the PAC3 in placebo treated subjects.  
The primary analysis will be the comparison between the HDM-SPIRE treatment 
groups and placebo for the Intent-to-Treat (ITT) population using Mixed Model 
Repeated Measurement analysis for the PAC1, PAC2 and PAC3 mean CS 
assessments per subject. The model will include treatment, period and pooled centre 
as main effects, gender, asthma status and Baseline Allergy Evaluation CS as 
covariate and treatment by period interaction. An unstructured covariance matrix 
will be used to assess within-subject dependence of the 3 observations of mean CS. 
A point estimate of the adjusted mean and two-sided 95% confidence interval for the 


 
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difference in adjusted means between the active treatment groups and placebo will 
be calculated, with the treatment contrast corresponding to the mean CS of the 
PAC3 period. A hierarchical (step-down) approach will be used to control the 
overall type 1 error rate at 5%.  
Other endpoints will be analysed appropriately. Supportive analysis will include 
non-parametric methods, as appropriate. 
Safety data will be analysed descriptively. The primary safety endpoint will be a 
comparison of the number of adverse events, and subjects with adverse events, in 
the HDM-SPIRE groups compared to placebo.  
Study Sites 
To be determined. 
Planned Study Dates 
Start of clinical phase 
End of clinical phase 
 
Q4 2014 
Q4 2016 
Duration of the Study  
The duration of the study for each subject will be approximately 62 weeks. 
 


 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................................6 
TABLE OF CONTENTS ......................................................................................................11 
1.0 
INTRODUCTION......................................................................................................15 
1.1 
Allergy to House Dust Mites .........................................................................15 
1.2 
House Dust Mite-SPIRE ................................................................................16 
1.3 
Justification for Key Elements of the Study Design ...................................18 
1.3.1 
Dose Selection ...................................................................................18 
1.3.2 
Combined Score, components of Total 
Rhinoconjunctivitis Symptom Score and weighting of 
TRSS and Rescue Medication Score .................................................19 
2.0 
OBJECTIVES ............................................................................................................20 
2.1 
Primary Objectives ........................................................................................20 
2.2 
Secondary Objectives.....................................................................................20 
3.0 
STUDY DESIGN ........................................................................................................21 
3.1 
Overall Study Design .....................................................................................21 
3.2 
Efficacy Endpoints .........................................................................................23 
3.2.1 
Primary Efficacy Variables ...............................................................23 
3.2.2 
Secondary Efficacy Variables ...........................................................23 
3.2.3 
Exploratory Endpoints .......................................................................24 
4.0 
STUDY POPULATION ............................................................................................25 
4.1 
Number of Subjects........................................................................................25 
4.2 
Inclusion Criteria ...........................................................................................25 
4.3 
Exclusion Criteria ..........................................................................................26 
4.4 
Women of Childbearing Potential ................................................................28 
4.5 
Rescreening of Subjects .................................................................................28 
4.5.1 
Subjects from cold climate sites ........................................................29 
4.5.2 
Subjects with Previously Non-Qualifying Specific IgE 
Levels and/or Skin Prick Test ............................................................29 
4.6 
Withdrawal of Subjects from the Study ......................................................29 
4.7 
Criteria for Stopping the Study ....................................................................31 
4.8 
End of the Study .............................................................................................31 
5.0 
STUDY MEDICATION ............................................................................................32 
5.1 
Investigational Product .................................................................................32 
5.2 
Placebo ............................................................................................................32 
5.3 
Packaging and Labelling ...............................................................................33 
5.4 
Supply, Storage and Reconstitution .............................................................33 
5.5 
Administration of the Study Medication .....................................................34 
5.5.1 
Dose Reduction .................................................................................34 
5.5.2 
Missed Dose ......................................................................................35 


 
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5.6 
Blinding ...........................................................................................................35 
5.7 
Randomisation................................................................................................35 
5.8 
Concomitant Medication and Dietary Supplements ...................................36 
5.8.1 
Rescue Medication ............................................................................36 
5.8.2 
Treatment of Suspected Anaphylactic Reactions ..............................37 
5.8.3 
Asthma Medication ...........................................................................37 
5.8.4 
Other Medication ...............................................................................38 
5.8.5 
Contraindicated Medication, Devices and Dietary 
Supplements ......................................................................................38 
6.0 
STUDY CONDUCT ...................................................................................................39 
6.1 
Schedule of Assessments ................................................................................39 
6.2 
Study Visit Procedures ..................................................................................43 
6.2.1 
Period 1: Screening and Baseline Allergy Evaluation ......................43 
6.2.2 
Period 2: Study Medication Administration (Visits 3A-
3H) and End of Dosing Assessment (Visit 3I) ..................................49 
6.2.3 
Period 3: Post-Administration Collection (Visits 4A-4F) 
and Period 3 Follow-Up (Visit 5) ......................................................52 
6.3 
Assessment of Efficacy ...................................................................................55 
6.3.1 
Measurement of RSS, ASS and Allergy Rescue 
Medication Use ..................................................................................55 
6.3.2 
Rhinoconjunctivitis Quality-of-Life Questionnaire ..........................55 
6.3.3 
Asthma Control Test ..........................................................................55 
6.3.4 
Clinical Global Impression of Change in 
Rhinoconjunctivitis Symptoms .........................................................55 
6.3.5 
Home Environment (Exposure to Allergen) ......................................56 
6.3.6 
Pittsburgh Sleep Quality Index ..........................................................56 
6.4 
Assessment of Safety and Tolerability .........................................................56 
6.4.1 
Adverse Events ..................................................................................56 
6.4.2 
Serious Adverse Events .....................................................................59 
6.4.3 
Reporting of Pregnancy .....................................................................61 
6.4.4 
Safety Evaluations .............................................................................62 
7.0 
STATISTICAL CONSIDERATIONS .....................................................................66 
7.1 
Data Management and Quality Assurance ..................................................66 
7.1.1 
Rescreening Data ...............................................................................66 
7.2 
Sample Size .....................................................................................................67 
7.3 
Interim Analysis .............................................................................................67 
7.4 
Analysis Populations ......................................................................................67 
7.4.1 
Intent-to-Treat Population .................................................................67 
7.4.2 
Per Protocol Population .....................................................................67 
7.4.3 
Safety Population ...............................................................................68 
7.5 
Statistical Analysis .........................................................................................68 
7.5.1 
Hypothesis Testing ............................................................................68 
7.5.2 
Demographic and Baseline Characteristics .......................................69 
7.5.3 
Efficacy Analysis ...............................................................................69 
7.5.4 
Safety Analysis ..................................................................................74 


 
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8.0 
INVESTIGATOR RESPONSIBILITIES ................................................................76 
8.1 
Investigator Performance ..............................................................................76 
8.2 
Ethical Considerations...................................................................................76 
8.2.1 
Ethics Committee Review and Approval ..........................................76 
8.2.2 
Written Informed Consent .................................................................76 
8.2.3 
Information for Subject’s General Practitioner/Primary 
Care Physician ...................................................................................77 
8.3 
Confidentiality ................................................................................................77 
8.3.1 
Subject Confidentiality ......................................................................77 
8.3.2 
Sponsor Confidentiality .....................................................................78 
8.4 
Study Documentation ....................................................................................78 
8.4.1 
Case Report Forms ............................................................................78 
8.4.2 
Investigator Site File ..........................................................................78 
8.4.3 
Study Drug Accountability Records ..................................................79 
8.4.4 
Record Retention ...............................................................................79 
8.4.5 
Source Documentation ......................................................................79 
8.5 
Publication ......................................................................................................79 
8.6 
Non-Protocol Research ..................................................................................80 
9.0 
SPONSOR RESPONSIBILITIES ............................................................................81 
9.1 
General ............................................................................................................81 
9.2 
No Fault Compensation and Indemnity .......................................................81 
9.3 
Monitoring ......................................................................................................81 
9.4 
Confidentiality ................................................................................................81 
9.5 
Finance ............................................................................................................82 
9.6 
Audit ................................................................................................................82 
10.0 
DATA SAFETY MONITORING COMMITTEE ..................................................83 
11.0 
WARNINGS, PRECAUTIONS AND CONTRA-INDICATIONS .......................84 
12.0 
REFERENCES ...........................................................................................................85 
13.0 
APPENDICES ............................................................................................................87 
 
List of Tables 
Table 1  
Study TH002: Summary of the Primary Efficacy Endpoint 
Analysis (ITT population) .............................................................................17 
Table 2 
Dosing Schedule .............................................................................................22 
Table 3 
Reconstitution of Study Medication and Volume to be 
Administered ..................................................................................................32 
Table 4 
Nominal Composition of the Vehicle ............................................................32 
Table 5 
Schedule of Assessments ................................................................................40 
Table 6 
Schedule of Assessments on Dosing Days ....................................................43 
Table 7 
Grading of Injection Site Reactions .............................................................50 
 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ACT 
Asthma Control Test 
ANCOVA 
Analysis of Covariance 
ASS 
Asthma Symptom Score 
BAE 
Baseline Allergy Evaluation 
CRO 
Clinical Research Organisation 
CS 
Combined Score 
Der f 
Dermatophagoides farinae allergen 
Der p 
Dermatophagoides pteronyssinus allergen 
DSMC 
Data Safety Monitoring Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eDiary 
Electronic Diary 
EEC 
Environmental Exposure Chamber 
EU 
Europe 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in 1 Second 
FOCBP 
Female of Child-bearing Potential 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
HDM 
House dust mite 
HDM-SPIRE 
House Dust Mite-SPIRE 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICS 
Inhaled Corticosteroid 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ISO 
International Standards Organisation 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measurements 
PAC 
Post-Administration Collection 
pDiary 
Paper Diary 
PP 
Per Protocol 
PSQI 
Pittsburgh Sleep Quality Index 
QoL 
Quality-of-Life 
RMS 
Rescue Medication Score 
RQLQ 
Rhinoconjunctivitis Quality-of-Life Questionnaire 
RSS 
Rhinoconjunctivitis symptom scores 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
SPIRE 
Synthetic Peptide Immuno-Regulatory Epitopes 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TRSS 
Total Rhinoconjunctivitis Symptom Score 
UK 
United Kingdom 
USA 
United States  
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell 
WFI 
Water for Injection 
 
 


 
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1.0 INTRODUCTION 
1.1 
Allergy to House Dust Mites 
House Dust Mites (HDM) are small translucent organisms belonging to the Arachnid class. 
They are found globally in mattresses or pillows of beds, sofas and carpets where they can 
reach a constant source of food (human skin scales) and where humidity is high enough to 
permit their survival. Throughout their lifetime of approximately 3 months, HDM produce 
around 2000 faecal pellets, each containing digestive enzymes and other proteins to which 
some people are allergic. The allergens found in the faecal pellets play a major part in the 
development of allergic asthma, rhinoconjunctivitis and eczema. There are two predominant 
‘allergenic’ 
species 
of 
HDM, 
Dermatophagoides 
pteronyssinus 
(Der 
p) 
and 
Dermatophagoides farinae (Der f) with Euroglyphus maynei also being a recognised indoor 
dust mite. The major allergenic proteins from these two species are very similar and there is a 
high degree of cross-reactivity of Immunoglobulin E (IgE) to proteins from both species. 
Clinical manifestations of HDM allergy include rhinoconjunctivitis, asthma and eczema. 
Allergic rhinitis affects between 10% and 30% of all adults and up to 40% of children, 400 
million people in the world. The Centers for Disease Control and Prevention report that in the 
United States of America, 30 to 60 million individuals are affected annually. In Europe, the 
European Community Respiratory Health Survey established the prevalence of allergic 
rhinitis as being from 4% to 32%. Epidemiological studies show that the prevalence of 
allergic rhinitis is increasing worldwide (World Allergy Organization White Book. 2011). In 
the third National Health and Nutrition Examination Surveys, 54.3% of the US population 
had positive skin prick test responses to one or more allergens; the prevalence for HDM was 
27.4% (Arbes 2005). In a study on inner city children with asthma, aged from 5 to 11 years in 
the US, 62% of children had a positive skin prick test to HDM. This was as high as 84% in 
Dallas and 78% in Seattle (Gruchalla 2005). A study of 6 to 11 year olds in the UK showed 
that 37% were atopic and 68% of these had a positive HDM skin prick test (Linehan 2006). 
In Europe, the prevalence of HDM allergy varies according to geographical region but an 
increase in the prevalence of sensitisation to HDM is occurring across Europe correlating 
with the increase in allergic diseases. 
The management of HDM-induced rhinoconjunctivitis, asthma and eczema includes allergen 
avoidance and medication. However, it can be difficult to avoid indoor allergens and there is 
no medication available that provides a definitive treatment for the symptoms of 
rhinoconjunctivitis, asthma or eczema. 


 
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1.2 
House Dust Mite-SPIRE 
HDM Synthetic Peptide Immuno-Regulatory Epitopes (HDM-SPIRE) is being developed for 
the treatment of HDM allergy. It has been designed on the basis of the selection of a set of 
seven peptides that on the one hand interact with T cells to induce tolerance but, on the other, 
are too short to cross-link IgE on mast cells and basophils, thereby greatly reducing the 
unwanted side effects of traditional immunotherapy using whole allergen extracts. 
HDM-SPIRE has been investigated in two clinical trials, both conducted in Canada. These 
studies have recruited about 200 subjects (more than 150 exposed to relevant active doses) in 
total. A dose escalation study (Circassia TH001) evaluated 4 administrations of HDM-SPIRE 
(0.03-12 nmol) 4 weeks apart and demonstrated that all doses up to and including 12 nmol 
were well tolerated with no safety concerns identified. A second study (Circassia TH002), 
involving exposure to HDM allergen in an Environmental Exposure Chamber (EEC), found 
that a unit dose of 12 nmol HDM-SPIRE was effective in treating rhinoconjunctivitis 
symptoms and appeared to be more effective than lower doses (3 or 6 nmol unit doses). The 
study evaluated both 4 and 11 administration regimens of the 12 nmol unit dose and whereas 
the 4 administration regimen was significantly more effective than placebo, the 11 
administration regimen did not appear to be (Table 1). Post-hoc analyses suggested that the 
lack of effect with 11 administrations may have been due to differential responses according 
to symptom severity at baseline, together with greater than expected data variability, and that 
while 11 administrations does not have any incremental benefit compared with four 
administrations, it also does not appear to have any detrimental effect. 
All doses and regimens evaluated in this study were well tolerated and no safety concerns 
were raised.  
 
 
 
 
 
 
 


 
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Table 1  
Study TH002: Summary of the Primary Efficacy Endpoint Analysis (ITT 
population) 
 
 
 
 
 
 
Difference between Active and Placebo 
Population 
n 
Mean 
SD 
Median 
LS Means 
LS Means 
95% CI 
p-value 
Baseline TRSS 
Placebo 
31 
15.46 
3.80 
16.36 
 
HDM-SPIRE 4 x 12 
nmol 
33 
16.21 
5.03 
15.64 
HDM-SPIRE 11 x 12 
nmol 
33 
16.39 
4.31 
15.21 
HDM-SPIRE 11 x 3 
nmol 
15 
15.47 
3.67 
15.29 
HDM-SPIRE 11 x 6 
nmol 
16 
15.97 
3.55 
16.71 
Change from Baseline to EEC3 Challenge at 49-50 weeks 
Placebo 
31 
-3.04 
4.53 
-3.21 
-2.969 
 
HDM-SPIRE 4 x 12 
nmol 
33 
-5.82 
4.37 
-5.43 
-5.879 
-2.910 
-5.396, -0.424 
0.0223 
HDM-SPIRE 11 x 12 
nmol 
33 
-3.30 
5.96 
-2.86 
-3.282 
-0.313 
-2.792, 2.167 
0.8029 
HDM-SPIRE 11 x 3 
nmol 
15 
-3.17 
5.92 
-1.00 
-3.656 
-0.342 
-3.569, 2.885 
0.8328 
HDM-SPIRE 11 x 6 
nmol 
16 
-2.92 
5.80 
-2.61 
-2.723 
0.592 
-2.593, 3.777 
0.7112 
Baseline is defined as the average of symptom scores at 1-4 hours on Days 2-3 at Baseline Challenge. 
Environmental Exposure Chamber 3 (EEC3) Challenge is defined as the average of symptom scores at 1-4 h on Days 2-3 
of EEC3 Challenge at 49-50 weeks. 
SD – standard deviation; TRSS – Total Rhinoconjunctivitis Symptom Scores 
Least Square Means (LSMeans), 95% confidence intervals (CI) and p-values are based on analysis of covariance 
(ANCOVA) with change from baseline as dependent variable, treatment as fixed effect and baseline and responder as 
covariate. P-values are from two-sided test at 5 %-level. 
Note: Two separate ANCOVAs were performed, one for Placebo, 4 x 12 nmol and 11 x 12 nmol and another for Placebo, 
11 x 3 nmol and 11 x 6 nmol. 
Source: Table 10 in clinical study report TH002 
 
As neither of the completed studies included subjects with asthma, a study is currently 
underway to evaluate the tolerability of HDM-SPIRE in subjects with Global Initiative for 


 
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Asthma (GINA) Step 1 or GINA Step 2 controlled asthma (Circassia TH004) and the results 
are expected to be available for evaluation prior to the start of dosing in this present study.  
Further information on the safety and efficacy findings from the completed clinical studies, as 
well as a comprehensive summary of the non-clinical safety and biology data, may be found 
in the Investigator’s Brochure.  
1.3 
Justification for Key Elements of the Study Design  
1.3.1 
Dose Selection 
Three active dose regimes will be evaluated in this study. The doses have been selected on 
the basis of data from Study TH002 (see Section 1.2). In this study a unit dose of 12 nmol 
was found to be more effective than unit doses of 3 and 6 nmol whilst being equally well 
tolerated with no safety concerns. However, the data on the 12 nmol unit dose was not 
unequivocal in that subjects who received 4 administrations responded well, as did subjects in 
Phase 1 of the study who received 11 administrations of this dose. However, subjects in 
Phase 2 of the study who received 11 administrations of 12 nmol did not respond better than 
subjects who received placebo. Post-hoc analyses suggested that this lack of effect may have 
been due to differential responses according to symptom severity at baseline, together with 
greater than expected data variability, however it was not possible to refute conclusively the 
hypothesis that additional doses (over and above 4 doses) negated the beneficial effects of the 
4 dose regimen.  
The highest unit dose of HDM-SPIRE evaluated in any study is 12 nmol and in Study TH002 
a regimen of four administrations of this dose was found to be effective. It is not known 
whether higher unit doses will be more effective and/or safe and well tolerated.  
The rationale for each dose regimen of HDM-SPIRE in the TH005 study is, therefore, as 
follows: 
Dose 
Group 
Dose Regimen 
Rationale 
1 
8 x placebo 4 weeks apart 
Control group 
 
2 
4 x 12 nmol HDM-SPIRE followed 
by 4 x placebo 4 weeks apart 
To confirm the efficacy of this dosing regimen that 
was observed in study TH002 
 
3 
4 x 12 nmol HDM-SPIRE 4 weeks 
apart followed by a second course of 
4 x 12 nmol HDM-SPIRE 4 weeks 
apart 
To determine whether a second course of 4 doses of 
HDM-SPIRE negates the efficacy of the first course, 
and 
To determine whether two courses of HDM-SPIRE 
are more effective than one course 
 


 
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4 
4 x 20 nmol HDM-SPIRE followed 
by 4 x placebo 4 weeks apart 
To determine whether a higher (than 12 nmol) unit 
dose has greater efficacy and equivalent 
safety/tolerability 
 
1.3.2 
Combined Score, components of Total Rhinoconjunctivitis Symptom 
Score and weighting of TRSS and Rescue Medication Score 
The primary efficacy variable in this study will be the Combined Score (CS) which is derived 
by combining the total rhinoconjunctivitis symptom score (TRSS) and the rescue medication 
score (RMS).  Eight symptoms are defined in the TRSS, 4 nasal symptoms: runny nose, 
sneezing, blocked nose, and itchy nose and 4 non-nasal symptoms: itchy eyes, watery eyes, 
red eyes and itchy ear/palate.  Each TRSS symptom and RMS score will be rated in severity 
(0-3) as described in Section 6.2.1.2.1 and the TRSS will be divided by the number of 
symptoms (8) to provide an average score per symptom of 0-3. The RMS score is not 
additive and therefore the maximum RMS is 3 and the maximum CS is 6. 
The primary efficacy endpoint will be a comparison of the CS during the Post Administration 
Collection (PAC) Period 3 (PAC3) in the HDM-SPIRE treatment groups compared with the 
mean CS in the placebo group during PAC3 (CS = TRSS [0-24]/8 + Rescue Medication 
Score (RMS) [0-3]).   
Relevant regulatory guidance identifies that the scoring of rescue medications is related to the 
approximated relief of symptoms, as well as magnitude and duration of effect and to the kind 
of symptoms affected, and that the primary efficacy endpoint should reflect both symptom 
scores and rescue medication use (CHMP/EWP/18504/2006).  A categorical scoring system 
consistent with ARIA Guidelines (2010) and published by Didier et al (Didier 2009) is 
included in this protocol.  The use of rescue medications will be scored as detailed in Section 
6.2.1.2.1. 
The proposed equal weighting for nasal and non-nasal symptoms is consistent with the 
findings from Circassia studies TH002 and TH003. In both studies nasal and non-nasal 
symptoms contributed in approximately equal measure to the symptom score. Equal 
weighting of the symptom scores and rescue medication use scores to derive the CS is 
supported by the findings from a study by Clark and colleagues (Clark 2007) which showed 
that equal weighting had the highest precision and discriminatory power, and by the World 
Allergy Organization Taskforce Guidelines (Canonica 2007). The US Food and Drug 
Administration (FDA) has also recently adopted a combined score with equal weighting in its 
reviews of Oralair® grass sub-lingual immunotherapy.  


 
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2.0 OBJECTIVES 
The purpose of the proposed study is to evaluate the efficacy, safety, tolerability and effect on 
quality of life of administration of a range of doses/regimens of HDM-SPIRE compared with 
placebo in HDM allergic subjects and thereby identify an appropriate dose and regimen to 
take forward into a confirmatory Phase 3 study.  
 
2.1 
Primary Objectives 
To evaluate the efficacy of HDM-SPIRE in the reduction of symptoms and the use of allergy 
rescue medication associated with HDM allergy in subjects with clinically relevant 
symptoms. 
 
2.2 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the safety and tolerability of HDM-SPIRE 
 To evaluate the effect of HDM-SPIRE on rhinoconjunctivitis specific quality of life  
 To evaluate the effect of HDM-SPIRE on sleep quality 


 
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3.0 STUDY DESIGN 
3.1 
Overall Study Design 
The study will be a randomised, double-blind, placebo-controlled, parallel group, multi-
centre field assessment of three dose regimens of HDM-SPIRE administered at 4 weekly 
intervals for 28 weeks. 
Subjects will attend the investigative site for screening and administration of study drug and 
for periodic assessments of safety and efficacy (see Table 5). Subjects will also complete an 
electronic diary (eDiary) during four 3-week periods. These diaries will capture the primary 
efficacy variable data (symptom scores and medication use) as well as other subject reported 
data. 
The study is designed to have Baseline Allergy Evaluation (BAE) for 3 weeks and collection 
of data for the primary efficacy endpoint, measured at 50-52 weeks after the initiation of 
treatment (PAC3), outside of any seasonal allergen pollen periods for which the subject has 
clinically significant symptoms. For each individual subject, the BAE must commence only 
after the relevant Autumn/Fall seasonal allergy pollen period is over, and it must complete at 
least 1 week before the anticipated start of the relevant next Spring seasonal allergy pollen 
period. The intermediate data collection times (PAC1 and PAC2 periods, collected at 18-20 
and 37-39 weeks after the initiation of treatment respectively) may overlap seasonal allergy 
pollen periods. For each individual subject the PAC3 period will, ordinarily, occur only after 
the relevant Autumn/Fall seasonal allergy pollen period has ended and should finish at least 
one week before the relevant next Spring seasonal allergy pollen period commences. 
Period 1, Consent, Screening and Baseline Allergy Evaluation: Rhinoconjunctivitis scores 
and allergy rescue medication usage will be collected. After consent has been obtained, 
screening will be conducted in a staged approach to minimise the number of investigations 
that a potentially ineligible subject undertakes. Firstly, a blood sample will be taken for 
measurement of IgE to Der f, Der p and relevant perennial allergens. This visit (visit 1A) may 
be performed during a seasonal allergen period and before the start of additional screening 
activities.  Potential subjects with IgE above the required levels will complete, between visits 
1A and visit 1B/C, a paper diary (pDiary) of symptoms for 1 week before additional 
screening activities are performed.  Subjects found to be eligible based on these two steps 
will undergo screening up to a maximum of 8 weeks before randomisation which may consist 
of 1 or 2 visits to the clinic, at the Investigator’s discretion. In exceptional circumstances, due 
to reasons beyond the control of the Investigator and/or subject (for example extreme 
weather), this 8 week period may be exceeded; however this requires documented approval 
by the Sponsor.    Suitable subjects will record Baseline rhinoconjunctivitis symptom scores 


 
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(RSS) using a 4-point categorical scale and RMS for a 3-week period in an eDiary before 
randomisation. The completion of the p Diary over 7 days, allergy screening and the BAE 
period will take place outside of any and all relevant seasonal allergy periods for each 
individual subject. 
Period 2, Study Medication Administration: Subjects meeting the inclusion/exclusion criteria 
will be randomised to either one of the 3 active treatment groups or the placebo group in 
equal proportions.  
A total of 8 doses of HDM-SPIRE or placebo will be administered, one dose every 4 weeks 
(±2 days), for a total duration of 28 weeks as shown in Table 2. 
 
Table 2 
Dosing Schedule 
Visit 
3A 
3B 
3C 
3D 
3E 
3F 
3G 
3H 
Week (± 2 days) 
0 
4 
8 
12 
16 
20 
24 
28 
Treatment Groups 
 
 
 
 
 
 
 
 
Placebo 
P 
P 
P 
P 
P 
P 
P 
P 
HDM-SPIRE 4 x 12 nmol 
X 
X 
X 
X 
P 
P 
P 
P 
HDM-SPIRE 4 x 12 nmol, two 
courses 
X 
X 
X 
X 
X 
X 
X 
X 
HDM-SPIRE 4 x 20 nmol 
X 
X 
X 
X 
P 
P 
P 
P 
X = Active doses; P = Placebo doses 
 
Period 3, Post-Administration Collection (PAC): The RSS and RMS for efficacy evaluation 
will be collected during Period 3. There will be 3 PAC periods: PAC1 (Weeks 18-20), PAC2 
(Weeks 37-39) and PAC3 (Weeks 50-52). The primary efficacy evaluation period will be 
PAC3, commencing 50 weeks after randomisation and outside of any and all relevant 
seasonal allergy periods for the subject. The use of allergy rescue medication during the PAC 
periods will be according to a pre-specified Rescue Medication Plan (see Appendix 3). Data 
collected in the periods commencing at 18 weeks (PAC1) and 37 weeks (PAC2) after 
randomisation will be used for exploratory efficacy analyses.  
At the Period 3 Follow-Up Visit 5, 52 weeks from first dosing, subjects will undergo a final 
safety assessment. 
The duration of the study for each subject will be approximately 62 weeks. 


 
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3.2 
Efficacy Endpoints 
3.2.1 
Primary Efficacy Variables 
The primary efficacy variable will be the mean CS during the PAC3 period (Weeks 50-52 
after randomisation) in the HDM-SPIRE treatment groups compared with the mean CS in the 
placebo group. Analysis of this endpoint is described in further detail in Section 7.5.3.1.1. 
The CS is a composite measurement of symptoms as measured by the TRSS and RMS, as 
measured using a pre-defined rating system that takes into account the different potency of 
available rescue medication.  
The TRSS comprises assessment of 8 symptoms that are given a score of between 0 and 3 
giving a range of potential scores of 0 to 24.    
Allergy rescue medications will be provided to subjects to be used according to a pre-
specified Rescue Medication Plan (See Appendix 3). Subjects will be requested to use 
antihistamine eye drops as first line allergy rescue medication for troublesome ocular 
symptoms; with oral antihistamines and/or intranasal corticosteroids to be added or 
substituted if subjects have unacceptable nasal symptoms or ocular antihistamines do not 
provide adequate symptom relief (see Section 5.8.1). Oral corticosteroids may be prescribed 
at the Investigator’s discretion. The use of allergy rescue medications will be scored based on 
Didier et al (Didier 2009) as follows: 
 RMS = 0; no allergy rescue medication used per day 
 RMS = 0.5; at least one dose of antihistamine eye drops used per day 
 RMS = 1; at least one dose of oral antihistamine used per day 
 RMS = 2; at least one dose of intranasal corticosteroid used per day 
 RMS = 3; at least one dose of systemic corticosteroid used per day 
The RMS score is not additive, and therefore the maximum RMS is 3. The TRSS (0-24) and 
the RMS (0-3) will be combined for analysis of the primary endpoint as follows: 
CS = TRSS/8 + RMS 
The maximum Combined Score is therefore 6. 
3.2.2 
Secondary Efficacy Variables 
The secondary efficacy variables are  
 Clinical Global Impression of Change in Rhinoconjunctivitis Symptoms for the 
HDM-SPIRE treatment groups compared with placebo at the end of study. 
 
Mean TRSS in the HDM-SPIRE treatment groups compared with placebo during the 


 
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PAC3 period. 
 
Mean component scores of the TRSS (nasal and non-nasal) in the HDM-SPIRE 
treatment groups compared with placebo during the PAC3 period. 
 
Mean RMS in the HDM-SPIRE treatment groups compared with placebo during the 
PAC3 period. 
 
Mean Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score in the HDM-
SPIRE treatment groups compared with placebo at the end of the PAC3 period. 
 
Number of days subjects in the HDM-SPIRE treatment groups have no moderate or 
severe RSS symptoms without rescue medication usage compared with placebo 
during the PAC3 period. 
3.2.3 
Exploratory Endpoints 
 
Rhinoconjunctivitis symptom scores measured using a visual analogue scale (VAS) 
during the BAE and each PAC period 
 
Mean CS in the HDM-SPIRE treatment groups compared with placebo during PAC1 
and PAC2 periods. 
 
Mean TRSS in the HDM-SPIRE treatment groups compared with placebo during 
PAC1 and PAC2 periods. 
 
Mean RMS in the HDM-SPIRE treatment groups compared with placebo during 
PAC1 and PAC2 periods. 
 
Mean component scores of the TRSS (nasal and non-nasal) in the HDM-SPIRE 
treatment groups compared with placebo during the PAC1 and PAC2 periods. 
 
Overall RQLQ score in the HDM-SPIRE treatment groups compared with placebo at 
the end of the PAC1 and PAC2 periods. 
 
Sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI) for the 
HDM-SPIRE treatment groups compared with placebo at the end of each PAC and 
PAC period. 


 
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4.0 STUDY POPULATION 
The study population will consist of subjects aged from 18 to 70 years, with a documented 
history of moderate to severe allergic rhinoconjunctivitis on exposure to HDM allergen for at 
least 1 year. This history is expected to include experiencing nasal and/or ocular symptoms 
on performing one or more of the following daily activities: 
 Changing the bed linen 
 Dusting 
 Vacuum cleaning 
Subjects must have required symptomatic treatment of their allergic rhinoconjunctivitis on at 
least one occasion during the last year. Asthmatic subjects will be permitted to participate 
provided that their symptoms are well controlled by GINA Step 1 or Step 2 therapy. 
In both stages of the study, subjects will be stratified in each of the treatment groups 
according to presence or absence of asthma and by severity of their symptoms at baseline 
(TRSS <16, TRSS >16). 
 
4.1 
Number of Subjects 
A total of approximately 660 subjects will be randomised into the study, with approximately 
165 subjects in each of the three HDM-SPIRE treatment groups and 165 in the placebo 
group. A 10% drop-out rate is assumed with the expectation that ~150 subjects per group will 
complete the study. Randomisation will be stratified according to severity of 
rhinoconjunctivitis symptoms at baseline and the presence of asthma.   
4.2 
Inclusion Criteria 
1. Male or female, aged 18-70 years. 
2. A reliable history consistent with moderate to severe rhinoconjunctivitis (sneezing, 
rhinorrhoea, itchy nose, nasal blockage and/or itchy eyes, red eyes, watering eyes and/or 
itchy ear/palate) on exposure to HDM for at least 1 year and which has required 
symptomatic treatment on at least one occasion during the last year. 
3. Mean TRSS ≥10 from 4 nasal and 4 non-nasal symptoms over a consecutive 7 day period 
before the Screening Visit 1B/C. 
4. Either Der p or Der f specific IgE ≥0.35 kU/L measured by ImmunoCAP®. 


 
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5. Positive skin prick test (preferably using the ALK-Abello Allergen Extract test) to either 
Der p or Der f with a wheal diameter at least 5 mm (average of longest and orthogonal) 
larger than that produced by the negative control. The negative control must be <2 mm 
for the test to be valid.  
6. Provide written informed consent. 
7. Willing and able to comply with the study requirements. 
8. If female of childbearing potential (FOCBP), must practice a form of contraception with a 
failure rate of <1% when used correctly and produce a negative urine pregnancy test at 
the Screening Visit 1B/C. 
Additional Inclusion Criteria at End of BAE 
9. Mean TRSS ≥12 from 4 nasal and 4 non-nasal symptoms during the BAE period (3-week 
period before randomisation). 
10. Completed the eDiary during the BAE on at least 16 days (>75% of occasions).  
4.3 
Exclusion Criteria 
1. Diagnosis of asthma requiring GINA Step 3 or higher treatment. 
2. If asthmatic, experienced a deterioration of asthma that resulted in emergency treatment 
or hospitalisation in the 12 months before randomisation, or experienced a life-
threatening asthma attack (e.g. one requiring intubation and mechanical ventilation) at 
any time in the past. 
3. Used any oral or parenteral corticosteroids at any time within 1 month prior to Screening 
Visit 1B/C.  
4. Asthma requiring high-dose inhaled corticosteroids (ICS) or anti-IgE therapy within 
6 months prior to Screening Visit 1B/C. 
5. Forced expiratory volume in 1 second (FEV1) <80% of predicted, or other evidence of 
partly controlled or uncontrolled asthma. 
6. Clinically significant confounding symptoms of allergy to relevant local seasonal 
allergens (e.g. ragweed, mugwort, tree, grass or mould) and cannot complete the BAE and 
the final PAC period at 50-52 weeks (PAC3) outside the respective allergy seasons. 
7. IgE >0.35 kU/l to other perennial allergens (e.g. animal dander, cockroach, mould) which 
cannot be avoided during the study or where sampling for these allergens demonstrates 
significant levels within the subject’s home from dust and/or vacuum cleaner samples, 
analysed using Indoor Biotechnologies Allergen Analysis Service. 


 
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8. Intends to be away for 7 days or more during the final PAC period at  
50-52 weeks (PAC3), or whose lifestyle means that there is a high likelihood of them 
being away from home for more than 7 days during the PAC3 period. 
9. Received an immunosuppressive treatment within 3 months prior to screening (except 
steroids for allergic and asthma symptoms). 
10. Previous immunotherapy treatment with any HDM allergen for more than 1 month within 
5 years prior to screening. 
11. Receiving ongoing treatment with any specific immunotherapy at screening. 
12. Administration of epinephrine is contraindicated (e.g. subjects with acute or chronic 
symptomatic coronary heart disease or severe hypertension). 
13. Use of beta-blockers, alpha-adrenoceptor blockers or monoamine oxidase inhibitors 
within 14 days before the Screening Visit 1B/C. 
14. History of significant recurrent acute sinusitis, defined as 2 episodes per year for the last 2 
years, all of which required antibiotic treatment, or a history of chronic sinusitis, defined 
as sinus symptoms lasting greater than 12 weeks that include 2 or more major factors or 1 
major factor and 2 minor factors. Major factors are defined as facial pain or pressure, 
nasal obstruction or blockage, nasal discharge or purulence or discoloured postnasal 
discharge, purulence in nasal cavity, or impaired or loss of smell. Minor factors are 
defined as headache, fever, halitosis, fatigue, dental pain, cough, and ear pain, pressure, 
or fullness. 
15. Females who are pregnant, lactating or planning to become pregnant, or donate ova for in 
vitro fertilisation during the study period or within 30 days following the study period. 
Female subjects unwilling to employ appropriate contraceptive measures to ensure that 
pregnancy will not occur either during or for 30 days following the completion of study 
period. 
16. Significant history of alcohol or drug abuse. 
17. Previously been treated in this or another HDM-SPIRE (ToleroMune-HDM) study. 
18. Any history of severe drug allergy, severe angioedema or anaphylactic reaction. 
19. Received treatment with an investigational drug within 30 days prior to the study. 
20. Are unable to communicate or to understand the requirements of the study, or exhibit any 
psychiatric disorder, which would impair communication between the subject and the 
Investigator thereby interfering with the informed consent procedure or the gathering of 
study data. 


 
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21. History or findings on physical examination of any significant disease or disorder (e.g. 
cardiovascular, 
pulmonary, 
gastrointestinal, 
liver, 
renal, 
neurological, 
immunopathological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, 
major physical impairment) which, in the opinion of the Investigator, may either put the 
subject at risk because of participation in the study, influence the results of the study or 
the subject’s ability to participate in the study. 
22. Dependent on the Investigator/site either for employment or education or are first degree 
relatives or partners of the Investigator/study staff. 
23. Institutionalised because of a legal or regulatory order. 
24. Active tuberculosis, auto-immune disorders, vaccination within 2 weeks before start of 
immunotherapy as well as subjects with hypersensitivity to excipients of HDM-SPIRE. 
 
Additional Exclusion Criteria at end of BAE 
25. Used any oral or parenteral corticosteroid during the BAE period. 
4.4 
Women of Childbearing Potential 
A female is considered to be of childbearing potential (FOCBP) if she has experienced 
menarche and has not undergone successful sterilisation (e.g. hysterectomy, bilateral tubal 
ligation or bilateral oophorectomy) or is not postmenopausal. A female is considered to be 
postmenopausal if amenorrheal for >2 consecutive years. 
An effective method of birth control (one with a failure rate of <1% when used correctly) 
must be used by FOCBP during the course of the study, in a manner such that risk of failure 
is minimised.  
A negative urine pregnancy test is required for all females at Screening Visit 1B/C and prior 
to each administration of study drug. A pregnancy test will also be conducted at the end of 
dosing assessment visit (Visit 3I) and at the Follow-Up Visit 5. 
Female subjects should be instructed to contact the Investigator immediately if they suspect 
they might be pregnant. 
4.5 
Rescreening of Subjects  
Rescreening of subjects is permitted in a limited number of circumstances for subjects who 
only failed to qualify for the study because of a criteria which is no longer applicable. The 
handling of the original and re-screen data for these subjects is described in Section 7.1.1. 


 
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Subjects who are rescreened will be given a new screening number and will be required to 
sign a new information sheet and consent form.  
4.5.1 
Subjects from cold climate sites  
Subjects from cold climate sites (Northerly latitudes) whose second dust sample failed to 
meet the required criteria (see Section 6.2.1.2) but for which all other eligibility criteria were 
met, may be rescreened and enrolled once the mean average outdoor temperature at the site is 
above zero degrees Celsius.  
Subjects will restart the study at Visit 1A but will only need to repeat certain screening 
assessments. The assessments to be repeated are shown in Section 6.1. For those assessments 
that are not repeated, the original data will be used and will need to be transcribed to the new 
eCRF.  
4.5.2 
Subjects with Previously Non-Qualifying Specific IgE Levels and/or 
Skin Prick Test 
Versions 1.0 to 3.0, inclusive, of the protocol required subjects to have positive skin prick 
tests and specific IgE levels of ≥0.7 kU/L to both Der p and Der f. Version 4.0 of the protocol 
amends this to be a requirement for these assessments to be positive for either Der p or Der f 
and for a minimum IgE concentration of ≥0.35 kU/L. Subjects who previously failed to 
qualify for the study because of the original criteria but who now qualify based on the revised 
criteria may be rescreened and will restart the study at Visit 1A. The blood sample for 
specific IgE does not need to be repeated; the result from the previous Visit 1A can be 
entered into the eCRF. There is no time limit for this rescreening for this criteria.   
4.6 
Withdrawal of Subjects from the Study 
The subjects will be informed that they have the right to withdraw from the study on their 
own accord at any time, for any reason and without having to state their reason and that this 
will not affect their future management and treatment. When a subject chooses to withdraw 
from the study, where possible, the Investigator will record a reason according to the 
following:  
 Recovery/no longer experiencing symptoms of HDM allergic rhinoconjunctivitis.  
 Lack of therapeutic response.  
 Treatment related side effects.  
 Unpleasant study procedures.  
 Another disease or condition intervenes and prevents continuation in the study.  
 External factors unrelated to the study.  


 
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The subject may also be withdrawn by the Investigator for the following reasons: 
 Adverse events (AEs), which in the opinion of the Investigator compromises the 
subject’s participation in the study. 
 Non-compliance with study procedures. 
 Lost to follow-up. 
 Withdrawal of consent. 
 Protocol violation. 
 Termination of the study. 
 Pregnancy prior to completion of administration of study medication. 
 Deterioration in the subject’s signs/symptoms and/or the subject develops a disease or 
condition prior to completion of administration of study medication that, in the 
opinion of the Investigator, would compromise the subject’s safety in continuing in 
the study. 
 Use of any of the prohibited therapies. 
 
In addition to this list of general criteria for withdrawing subjects from the study dosing 
should immediately be discontinued (and not restarted) in the event of one or more of the 
following events: 
 A grade 3 or 4 systemic allergic reaction (see Appendix 4) 
 Two consecutive doses result in a grade 3 or 4 injection site reaction despite reduction 
of the dose (See Section 5.5.1) 
 A serious adverse event that in the opinion of the Investigator is treatment related 
 Medical necessity for a subject to use any of the contraindicated medications (see 
Section 5.8.5) during the treatment period. 
 
Treatment discontinuation will not necessarily result in withdrawal of the subject from the 
study. For the subjects who withdraw from the study, all safety assessments scheduled for the 
Period 3 Follow-Up (Visit 5) (see Section 6.2.3.2) will be requested and observations will be 
recorded as far as is possible. Reasons for omission of tests will be documented. The date and 
reason(s), if provided, for withdrawal from the study will also be recorded in the electronic 
Case Report Form (eCRF). 
If the subject withdraws due to an AE, all of the Period 3 Follow-Up (Visit 5) assessments 
will be requested and the event followed until resolution or care is transferred to the subject’s 
primary care physician or a specialist. 


 
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Subjects who are withdrawn may be replaced. 
4.7 
Criteria for Stopping the Study 
If, in the opinion of an Investigator, the clinical observations in the study suggest that it may 
be unwise to continue, the Investigator may terminate his or her involvement in the study 
after consultation with Circassia Ltd.   
For the study as a whole, Circassia Ltd may terminate the study for safety or administrative 
reasons. 
A Data Safety Monitoring Committee (DSMC) will be convened to provide independent 
oversight of the trial from a safety perspective (see Section 10.0). The DSMC may 
recommend stopping of the study for safety reasons and detailed guidance to the DSMC will 
be provided in the DSMC Charter.  
4.8 
End of the Study 
The end of the study is when the last subject completes the Period 3 Follow-Up (Visit 5). 


 
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5.0 STUDY MEDICATION 
5.1 
Investigational Product 
The investigational product for this study will be HDM-SPIRE, an equimolar mixture of 
seven peptides whose individual sequences are derived from Der p1, Der p2 and Der p7, 
supplied as a lyophilisate. Further details of the peptides are provided in the Investigator’s 
Brochure for HDM-SPIRE. Two concentrations of HDM-SPIRE will be used in the study: 
 A 120 μM product which will be used for administration of the 12 nmol doses 
 A 200 μM product which will be used for administration of the 20 nmol dose 
The blinded lyophilisate will be reconstituted with water for injection (WFI) as shown in 
Table 3. 
The peptides have been synthesised by Bachem AG (Switzerland) and formulated, filled and 
finished by Patheon (Italy).  All manufacturing processes have been performed according to 
current Good Manufacturing Practice. 
Table 3 Reconstitution of Study Medication and Volume to be Administered 
Study Medication 
Volume of Water for Injection 
for Reconstitution 
Volume Administered  
Lyophilisate 
300 µL 
100 μL 
5.2 
Placebo 
The placebo product is supplied as a lyophilisate with an appearance identical to that of the 
HDM-SPIRE product. When reconstituted it comprises the vehicle used (see Table 4) to 
formulate the HDM-SPIRE peptides and its appearance is identical to the reconstituted 
HDM-SPIRE lyophilisate. The injection volume will also be the same (100 µL). 
Table 4 Nominal Composition of the Vehicle 
Raw Material 
Function 
Nominal Concentration 
L-Methionine 
Antioxidant 
5 mM 
D-Trehalose dihydrate 
Tonicity agent 
260 mM 
Hydrochloric acid  
pH adjustment 
as needed to pH 4 
Ammonia 


 
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5.3 
Packaging and Labelling 
Individual study packs containing blinded vials of lyophilisate of either HDM-SPIRE or 
placebo will be provided for each subject. Individual study medication vials and study packs 
will be labelled in accordance with local regulations and will include subject randomisation 
numbers. The outer packaging of each study pack will also be labelled in accordance with 
local regulations and will include a product description or identifier; a product lot number, 
storage conditions and expiry date; protocol details; sponsor name and address; and subject 
randomisation numbers. 
5.4 
Supply, Storage and Reconstitution 
The Investigator has overall responsibility for all study medication issued to the 
Investigator’s centre. The Investigator may delegate the management of the study medication 
to a Pharmacist or other qualified team member. 
The randomised subject study packs will be shipped to the Investigator together with spares. 
Medication will be shipped under controlled conditions and a temperature logger will be 
included. The temperature logger must be returned following the instructions provided. The 
Investigator or designee will confirm receipt and disposition of the study medication in 
writing. 
The study medication must be kept in an appropriate, limited access, secure storage area at 
2 to 25°C until its use or return to Circassia Ltd or its designee for destruction. The 
temperature in the storage areas will be monitored and recorded daily (minimum and 
maximum temperature). Copies of temperature logs must be kept in the site study file. 
Reconstitution should ideally be performed in an International Organisation for Standardization 
(ISO) Class 5 (or better), temperature-controlled area on a clean surface and with limited 
access. Only the required vial of lyophilisate for a single subject dose must be present in the 
preparation area during reconstitution to avoid any errors.  Reconstitution will be achieved by 
injecting 300μL of sterile WFI into the study medication vial. 
Warning: Study medication does not contain a preservative.  Consequently, 
reconstitution more than a few hours prior to administration carries the risk of 
microbial contamination.  
Following reconstitution, sufficient time (typically 3-5 minutes) should be allowed for any 
foaming of the solution to subside. The Investigator or designee should withdraw the 
necessary volume into the syringe to allow the administration of 100 μL; in practice this will 
be 180-250 μL to account for the dead volumes of the needle and syringe. This must not be 


 
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more than 6 hours after reconstitution is completed. If administration will not be performed 
within 1 hour after reconstitution, the reconstituted doses must be transferred to and kept at 5 
± 3ºC in injection vials until the point of administration.  
Where an ISO Class 5 environment is not available, reconstitution should be performed in a 
temperature-controlled area on a clean surface and with limited access. In this situation the 
study medication must be administered within 1 hour of reconstitution. 
Unused/excess solutions generated during the preparation of individual subject medication 
will be kept for accountability purposes.  At the end of the study, upon written authorisation 
by Circassia Ltd, the Investigator will return unused study medication to Circassia Ltd or 
their designee for destruction. A copy of the completed Drug Accountability Record should 
be included in the shipment. The unused study medication will be destroyed and a certificate 
of destruction generated. 
The study medication supplied for this study is intended for use only by subjects in this study. 
5.5 
Administration of the Study Medication 
The reconstituted study medication will be administered by intradermal injection by the 
Investigator or designee into the flexor (volar) surface of the forearm. The dose to be 
administered is 100 µL.  
5.5.1 
Dose Reduction 
In the event that a subject experiences a grade 3 or 4 injection site reaction (see Section 
6.2.2.1) or a grade 2 systemic allergic reaction (See Appendix 4) the following dose reduction 
scheme should be followed: 
 On first occurrence of a dose reduction trigger reaction the next dose should be 
reduced by half. This is achieved by administering a dose of 50 µL instead of 100 µL.  
 If the reduced dose is well tolerated then the subsequent dose should be escalated 
back to 100 µL. If this is well tolerated then further doses should continue to be 100 
µL.  
 If however the full dose is again not well tolerated and a further trigger reaction 
occurs then the dose should again be reduced to 50 µL and remain at that dose for the 
remainder of the study.  


 
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 If two consecutive half doses are not well tolerated the subject should be withdrawn 
from the study.  
5.5.2 
Missed Dose 
Dosing visits should be scheduled at intervals of 4 weeks from Visit 3A, with a window of ±2 
days. In the event that a visit needs to be rescheduled it may be rearranged such that it falls no 
later than 7 days before or after the original 4 week interval from the prior dose. On 
successful completion of a rearranged dosing visit the next dose should then be scheduled as 
per the original schedule (± 2 days).  
If it is not possible to reschedule within 3-5 weeks of the previous dose then it should be 
considered a missed dose and the next dose should be scheduled in accordance with the 
original schedule (± 2 days) provided that this does not result in an interval between any two 
doses of less than 3 or greater than 5 weeks. 
5.6 
Blinding 
This is a double-blind study and the active treatments and placebo are identical in appearance 
both before and after reconstitution and administration. During the conduct of the study, the 
subject, Investigator/study staff, Circassia Ltd and the Clinical Research Organisation (CRO) 
staff directly involved in the clinical study will remain blind to the treatment group. 
Wherever possible, and considering the best interests of the study subject, once study 
medication has been administered, management of any subsequent AE should not be 
predicated upon knowledge of a subject’s treatment assignment. 
Where the Investigator believes that unblinding is required, they should document and 
explain the reasons for any unblinding of the study (e.g., due to a Serious Adverse Event 
(SAE)). The Investigator may discuss the decision to unblind with the Sponsor’s medical 
monitor should time permit.  
5.7 
Randomisation 
Subjects who successfully complete Period 1 Screening and continue to meet the study entry 
criteria at the end of the BAE, will be randomised to receive placebo or one of the HDM-
SPIRE regimens. The Randomisation Schedule will be produced by a computer-generated 
algorithm by HMD Clinical.  
Subjects will be randomised on an equal basis (i.e. 1:1:1:1) to placebo and each of the 3 
HDM-SPIRE treatment groups.  


 
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Randomisation will be stratified according to the following criteria: 
 Current history of asthma (present or absent) 
 Mean TRSS during BAE (<16, >16)   
Study medication packs will be assembled in accordance with the Randomisation Schedule. 
An interactive response technology (IRT) system will be used to allocate study medication 
packs to subjects, according to the randomisation and stratification schema. The Investigator 
or designee will also record the Subject Screening Number against the allocated randomised 
study pack on the Drug Accountability Record. 
5.8 
Concomitant Medication and Dietary Supplements 
5.8.1 
Rescue Medication 
Subjects may, at any time during the study, take allergy medication. During the BAE and 
PAC periods subjects will be asked to use only allergy rescue medication provided to the 
subject in the Rescue Medication Package according to the defined Rescue Medication Plan 
(Appendix 3).   
The following allergy rescue medications will be provided to subjects and their use will be 
documented in their eDiaries during the BAE and PAC periods: 
 Antihistamine eye drops 
 Oral antihistamines 
 Intranasal corticosteroids 
If a subject finds that he or she is not able to obtain a comfortable level of relief from 
symptoms with the allergy rescue medications provided during the BAE, the Investigator and 
subject may agree to use alternative allergy rescue medications in the same categories as 
above. Alternative allergy rescue medications will be scored on the same RMS scale as the 
equivalent category of allergy rescue medication from the Rescue Medication Package.  The 
Investigator may also prescribe oral corticosteroids, if required and their use will be 
documented in the subjects’ eDiaries during the PAC periods. 
A subject who uses any other category of allergy medications than those included in the 
Rescue Medication Package during the BAE Period will not be randomised.  Use of any other 
category of allergy medications during the PAC periods will be considered a protocol 
deviation. 


 
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Subjects will be instructed to record all allergy medications other than those provided in the 
Rescue Medication Package in the pDiary. 
The recorded allergy rescue medication usage data in the eDiary will be transferred into the 
study database directly. No duplication of recording in eCRF is required. 
All allergy rescue medications dispensed or prescribed to subjects as part of the Rescue 
Medication Package will be recorded in the eCRFs. 
5.8.2 
Treatment of Suspected Anaphylactic Reactions 
Anaphylactic reactions may be life-threatening and any suspected anaphylactic reaction must 
be treated immediately. 
All medications and medical equipment for the treatment of suspected anaphylactic 
reactions must be immediately available at the study centre. 
Appendix 2 presents an example of algorithms for the management of suspected anaphylactic 
reactions (Resuscitation Council United Kingdom [UK], 2008 and Anaphylaxis Emergency 
Action Plan). The Investigator may follow their own national guidelines or Standard 
Operating Procedure (SOP) for treating suspected anaphylactic reactions, but a copy of the 
Guideline or SOP must be placed in the Investigator Site File and have been verified to be 
suitable by the CRO managing the study. 
For all but the mildest cases of anaphylaxis, subjects should be hospitalised overnight or 
monitored for at least 12 hours. 
All cases of anaphylaxis or suspected anaphylaxis must be recorded as an AE of Special 
Interest and should be reported in an expedited manner to the Sponsor in the same way as an 
SAE (See Section 6.4.2.1). The report must include a grading of the event using the World 
Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System (See 
Appendix 4). 
5.8.3 
Asthma Medication 
Subjects with asthma should be controlled and compliant with Treatment Step 1 or Step 2 
(see GINA, Appendix 1). Treatment for asthma must have been stable (drug(s), dose, 
frequency) for at least 3 months prior to screening. 
Short acting bronchodilator should not be used for a minimum of 4 hours before each 
spirometry assessment. 


 
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Full details of the subject’s asthma medications will be entered into the eCRF. Use of short-
acting inhaled ß2 agonist and inhaled corticosteroid medications during the BAE Period and 
each PAC period will be recorded in the eDiary. 
5.8.4 
Other Medication 
The Investigator should record the use of all concomitant medications, both prescribed and 
over-the-counter, into the eCRF and subject’s medical records. This includes medications 
used on both a chronic and an as-needed basis. Subjects should be discouraged from starting 
any new medication, both prescribed and over-the-counter, without consulting the 
Investigator, unless the new medication is required for emergency use. 
Hormonal contraceptives may be used by FOCBP. The peptides used in treatment are 
designed to induce immunological tolerance via binding to major histocompatibility complex 
Class II on antigen-presenting cells and are therefore not anticipated to interact with 
hormonal contraceptives. 
5.8.5 
Contraindicated Medication, Devices and Dietary Supplements 
The following medications are not permitted during Periods 1 and 2 of the study.  A 
minimum washout period of 14 days is required before Screening visit 1B/C. 
 beta-blockers 
 alpha-adrenoceptor blockers 
 monoamine oxidase inhibitors 
Subjects using any of the above during Period 1 will not be randomised and during Period 2 
will be withdrawn from the study. 
Subjects are prohibited from starting any other form of immunotherapy during the study. 


 
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6.0 STUDY CONDUCT 
6.1 
Schedule of Assessments 
The study procedures, efficacy and safety assessments will be made as shown in Table 5.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 5 
 
Schedule of Assessments 
 
Study Periods 
Period 1 
Period 2 
Period 3 
 
Consent 
Visit 
Screening  Baseline Allergy 
Evaluation 
Dose Administration 
(every 4 wks ±2 
days)q 
End of Dosing 
Assessment 
Post-Administration Collection 
Follow-Up 
PAC1a 
PAC2 
PAC3 
Visit 
1A 
1B/C 
2A 
2B 
3A-3H 
3I 
4A-4Bb 
4C-4Db 
4E-4Fb 
5 
Schedule (Week) 
 
-8 wks 
(max) 
-3 wks 
0 
0-28 wks 
32 wks 
(±2days) 
18-20 wks 
(±2 days) 
37-39 wks 
(±2 days) 
50-52 wks 
(±2 days) 
52 wks 
(±5 days) 
Duration 
 
1-2 days 
3 weeks 
 
1 day 
3 weeks 
3 weeks 
3 weeks 
1 day 
*Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion Criteria 
 
X 
 
X 
 
 
 
 
 
 
Demography 
 
X 
 
 
 
 
 
 
 
 
Medical history including allergy history 
 
X 
 
 
 
 
 
 
 
 
Smoking history 
 
X 
 
 
 
 
 
 
 
 
History of asthma 
 
X 
 
 
 
 
 
 
 
` 
Physical examination 
 
X 
 
 
 
X 
 
 
 
X 
Urine dipstick 
 
X 
 
 
 
X 
 
 
 
X 
*Spirometry (FEV1) c 
 
X 
 
 
Xd 
X 
Xe 
Xe 
Xe 
 
*Vital signs 
 
X 
 
 
Xd 
X 
X 
X 
X 
X 
Skin prick testingf 
 
X 
 
 
 
 
 
 
 
 
Issue dust collection pack 
X 
 
 
 
 
 
 
 
Xe 
 
*Blood sample for 
haematology/biochemistry 
 
X 
 
 
 
X 
 
 
 
X 
Blood sample for specific IgE 
X 
 
 
 
 
X 
 
 
 
X 
Blood sample for Der p allergen analysis 
X 
 
 
 
 
 
 
 
 
 
Biomarker sampleg [OPTIONAL substudy] 
 
 
 
 
X 
 
 
 
 
X 
Blood sample for tryptase 
 
 
 
 
Xh 
 
 
 
 
 
*Pregnancy test (FOCBP) 
 
X 
 
 
Xi 
X 
 
 
 
X 
Daily eDiary recording for 3wks: 
 RSS on a 4 point categorical scale 
 Asthma Symptom Score 
 Allergy rescue medication use 
 
 
X 
 
 
 
X 
X 
X 
 


 
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Study Periods 
Period 1 
Period 2 
Period 3 
 
Consent 
Visit 
Screening  Baseline Allergy 
Evaluation 
Dose Administration 
(every 4 wks ±2 
days)q 
End of Dosing 
Assessment 
Post-Administration Collection 
Follow-Up 
PAC1a 
PAC2 
PAC3 
Visit 
1A 
1B/C 
2A 
2B 
3A-3H 
3I 
4A-4Bb 
4C-4Db 
4E-4Fb 
5 
Schedule (Week) 
 
-8 wks 
(max) 
-3 wks 
0 
0-28 wks 
32 wks 
(±2days) 
18-20 wks 
(±2 days) 
37-39 wks 
(±2 days) 
50-52 wks 
(±2 days) 
52 wks 
(±5 days) 
Duration 
 
1-2 days 
3 weeks 
 
1 day 
3 weeks 
3 weeks 
3 weeks 
1 day 
For footnotes and abbreviations, please see end of table 
 
Visual analogue scales for allergy 
symptomsj 
 
 
X 
 
 
X 
X 
X 
 
Eligibility TRSS (from eDiary) 
 
 
 
X 
 
 
 
 
 
 
HDM control measuresk  
 
 
 
X 
 
 
X 
X 
X 
 
*pDiaryl (dispense) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
*pDiaryl (review/collect) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense rescue medicationm 
 
 
X 
 
 
 
X 
X 
X 
 
ACT (asthmatics only) 
 
 
 
X 
 
 
Xe 
Xe 
Xe 
 
RQLQ 
 
 
 
Xn 
 
 
Xe 
Xe 
Xe 
 
PSQI  
 
 
 
Xn 
 
 
Xe 
Xe 
Xe 
 
Clinical Global Impression of Change  
 
 
 
 
 
 
 
 
 
X 
Dosing 
 
 
 
 
X 
 
 
 
 
 
Examination of injection site 
 
 
 
 
X 
X 
 
 
 
 
*Concomitant medicationo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Adverse Eventsp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
For footnotes and abbreviations, please see end of table 
 
 


 
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a Study Visit 4B will take place at the same time as dosing Visit 3F. 
b Study visit will occur on the first and last day of the PAC (±2 days). 
c Asthmatic subjects should not take their asthma medication for a minimum of 4 hours prior to spirometry. 
d Pre-dose and 30 min post-dose.  
e Measured on Visits 4B, 4D and 4F only. For dust collection - the kit will be issued on 4E and returned on 4F 
f Skin prick testing to Der p, Der f and a battery of standard allergen extracts. (Antihistamines should not be taken three days prior to skin prick test) 
g Biomarker samples will ONLY be collected from Canadian and US sites for this OPTIONAL sub- study – and only at Visit 3A and follow up.  
h Measured only in the event of a suspected anaphylactic response, in which case blood sample taken approximately 1 hr and 3 hr after the suspected reaction and then repeated every 3 
hr until discharge. 
i Pre-dose. 
j Visual Analogue Scales assessed once at the start of BAE visit 2A and at start of PAC periods. 
k HDM control measures (e.g. humidity, regular washing, regular vacuuming and installation of mattress and pillow casings). 
l Including RSS over 7 days at Visit 1 only, recording of AEs, recording of concomitant medications. 
mAllergy rescue medication dispensed at the start of the BAE Period (Visit 2A) and the start of each PAC period (Visits 4A, 4C, 4E). 
n After subject eligibility confirmed based on TRSS (from eDiary). 
o Including all concomitant medications described in Sections 5.8.1-5.8.5. 
p Investigator will ask non-leading questions. 
qVisits may be rescheduled within + 1 week of the scheduled date if required 
 
*Rescreening assessments to be performed (See Section 4.5): informed consent, spirometry, vital signs, blood sample for haematology/biochemistry and pregnancy test (if applicable). A 
pDiary will also be issued. For concomitant medication and adverse events collect any new information since previous screening. 
 
Abbreviations: AE = Adverse events; ACT = Asthma Control Test; BAE – baseline allergy evaluation Der f = Dermatophagoides farinae allergen; Der p -=Dermatophagoides 
pteronyssinus allergen; FEV1 = forced expiratory volume in 1 second; FOCBP = female of child bearing potential; HDM = house dust mite; IgE = Immunoglobulin E; eDiary = 
electronic diary; PAC = Post-Administration Collection; pDiary = paper diary; PSQI = Pittsburgh Sleep Quality Questionnaire; RQLQ = Rhinoconjunctivitis Quality-of-Life 
Questionnaire; RMS = Rescue Medication Score; (T)RSS = (Total) Rhinoconjunctivitis Symptom Scores.  
 


 
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The schedule of assessments on dosing days (Visits 3A-3H) is stated in Table 6. 
Table 6 
 Schedule of Assessments on Dosing Days 
 
Pre-dosing 
TREATMENT 
30 min Post-dosing 
Urine pregnancy test for FOCBP 
X 
 
FEV1 
X 
X 
Vital signsa 
Xb 
X 
Examination of injection site  
Xc 
X 
Adverse Events 
X 
X 
a Vital signs to be measured after spirometry assessment. 
b Short acting bronchodilators should not be used for a minimum of 4 hours before each spirometry assessment. 
c At Visits 3B-3H, to include examination of the injection site where administration was made 4 weeks previously. 
Note: FOCBP = Female of Child Bearing Potential; FEV1= Forced Expiratory Volume in 1 second 
 
6.2 
Study Visit Procedures 
6.2.1 
Period 1: Screening and Baseline Allergy Evaluation 
6.2.1.1 Visits 1A and 1B/C: Consent and Screening 
At Visit 1A, prior to any study procedures starting, information about the study will be given 
to the subject both verbally and in writing, and written informed consent must be obtained 
from the subject. The study information sheet will explain the objectives of the study, its 
potential risks and benefits. If a subject agrees to participate, he/she will be asked to sign and 
date an Informed Consent Form (ICF).  
After informed consent has been obtained the following procedures will take place at the 
Consent Visit (Visit 1A): 
 A blood sample will be taken for IgE measurement of Der f, Der p and other perennial 
allergens by ImmunoCAP®. 
 A blood sample will be taken for measurement of levels of IgE antibodies to a fixed 
panel of Der p allergens, using an immune-affinity based analysis technology such as 
ImmunoCAP®. 
 Subjects will be issued with a dust collection pack for assessment of exposure in the 
home to perennial allergens. Subjects with evidence of exposure (in dust samples or 
via lifestyle) and sensitivity (positive IgE and skin prick test) to other perennial 
allergens (e.g. cockroach) will be excluded from further participation. Every 
reasonable effort should be made to collect dust samples but subjects in South Africa 
who do not have ready access to a vacuum cleaner will not be required to collect dust 


 
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samples and will be excluded if they have IgE ≥0.35 kU/L to any other perennial 
allergen.  
 Subjects will be given a pDiary and asked to record their RSS for 4 nasal and 4 non-
nasal symptoms on a scale of 0-3 each over the last 24 hours and concomitant 
medication use over a 7 day consecutive period. The timing of the completion of this 
diary card should be outside of any seasonal allergy periods to which the subject has 
clinically significant symptoms and completed for 1 week immediately before the 
start of formal Screening commences at Visit 1B/C. If more than 7 days are recorded 
then the last 7 days before Visit 1B/C will be used to assess their RSS symptoms. 
The subject will return to the clinic after the diary has been completed and once the IgE and 
dust sample analysis results are available and provided their average TRSS meets Inclusion  
Criterion 3 and their Der p and Der f specific IgE meets Inclusion Criterion 4, the following 
procedures will take place at the Screening Visit (Visit 1B/C): 
 The subject will be assessed for compliance with the inclusion and exclusion criteria. 
 Demographic data (date of birth, gender, ethnicity, height and weight) will be 
obtained. 
 A detailed medical history will be taken, including a detailed allergy history and a 
detailed history of asthma and details of exposure to HDM. 
 A smoking history will be taken, including if the subject is a non-smoker, an ex-
smoker or a current smoker and the number of cigarettes smoked each day. 
 The subject will undergo a physical examination. 
 The subject’s FEV1 will be measured using a spirometer.  Short acting 
bronchodilators should not have been taken for a minimum of 4 hours before 
spirometry. 
 Vital signs (sitting or semi-recumbent) will be measured. 
 Skin prick testing with Der p, Der f, a battery of standard allergen extracts (e.g. 
mould, ragweed, grass, tree mix, animal danders, seasonal allergens appropriate for 
the local geography) and diluent control (performed on the flexor aspect of the 
forearm) after a suitable wash-out period (>3 days) from last use of oral 
antihistamines. The orthogonal diameter will be measured at the mid-point of the 
longest axis and the average of the longest and the orthogonal diameter must be 
calculated. Pseudopodia will not be assessed.  The negative control must be <2 mm 
for the test to be considered valid. If the negative control is >2 mm the test should be 
repeated on another day. 
 Blood samples for routine haematology and biochemistry will be taken. 
 A dipstick urinalysis will be performed on the subject’s urine. 


 
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 Urine pregnancy test for FOCBP. 
 Concomitant medications will be fully recorded. 
 Recording of any AEs. 
 Each subject will be provided with a pDiary to record AEs and concomitant 
medications. 
Subjects who successfully complete Screening will undergo BAE. 
6.2.1.2 Visits 2A and 2B: Baseline Allergy Evaluation 
The Baseline Allergy Evaluation will take place during a 3-week period before randomisation 
and subjects will attend the clinic at the start and end of the BAE period, Visits 2A and 2B, 
respectively. The BAE must start after the end of the pollen period for all relevant seasonal 
allergens to which the subject has clinically significant symptoms and must complete at least 
1 week before the anticipated start date of the Spring pollen season for any allergen to which 
the subject has clinically significant symptoms. The requirement to complete the BAE at least 
1 week before the anticipated start date of the relevant Spring pollen season is intended to 
ensure the PAC3 period can also complete before the start date of the relevant Spring pollen 
season, 50-52 weeks after randomisation. This is illustrated schematically below.  
For sites in the most Northerly latitudes with cold and dry winters the BAE should also 
generally take place before the onset of winter. Sites may be permitted to continue the BAE 
during winter months with the agreement of the Sponsor and where sampling of dust shows 
the presence of house dust mite allergen in the home at a suitable level.  
 
Fall (Autumn) 
pollen season 
Winter period - no 
relevant pollen in air 
Spring/ Summer/ Fall (Autumn) pollen 
season 
Winter period - no 
relevant pollen in air
Screening may 
occur 
Baseline Allergy 
Evaluation occurs 
PAC 1 and PAC 2 periods may occur 
during pollen periods 
PAC3 period occurs
 
Must complete at least 1 
week before anticipated 
start date of relevant 
spring allergen to which 
subject has clinically 
significant symptoms
Must complete at least 
1 week before anticipated 
start date of relevant  
spring allergen to which  
subject has clinically  
significant symptoms 


 
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6.2.1.2.1 
Visit 2A 
The following procedures will take place at Visit 2A: 
 Each subject will be provided with an eDiary to record RSS, Asthma Symptom Scores 
(ASS) and allergy rescue medication use. 
 Recording of any changes to concomitant medication since last visit. 
 Recording of any AEs. 
 Dispense a pDiary to record AEs and concomitant medications. 
 Subjects will be requested to discontinue their current allergy medication. Subjects 
will be trained on how to follow the study-specific Rescue Medication (Appendix 3) 
and will be asked to only use medications from the Rescue Medication Package for 
the duration of the BAE. 
 Dispense allergy rescue medication. 
The following information will be recorded in the eDiary on a daily basis first thing in the 
morning for a period of 3 weeks: 
 RSS on a 4 point categorical scale 
 Allergy rescue medication use 
 ASS 
If a subject’s allergic rhinoconjunctivitis symptoms become unacceptable to them, they may 
take allergy rescue medications from the Rescue Medication Package provided in accordance 
with the Rescue Medication Plan (Appendix 3). Subjects will be instructed to inform the 
Investigator if they have taken any allergy medication other than those prescribed from the 
Rescue Medication Package. The Investigator must record these allergy medications as 
concomitant medications in the eCRF. 
For each symptom, the subject will rate the severity over the last 24 hours as follows: 
0 = absent 
1 = mild, barely noticeable 
2 = moderate, annoying/troublesome 
3 = severe, very annoying/ very troublesome 
RSS symptoms will be captured as follows: 
Nasal Symptoms 
 Runny nose 
 Sneezing 
 
 Blocked nose 
 Itchy nose 


 
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Non nasal Symptoms 
 Itchy eyes 
 Watery eyes 
 
 Red eyes 
 Itchy ear/palate
 
The use of rhinoconjunctivitis rescue medications will be scored based on Didier et al  
(Didier 2009) as follows: 
 
 RMS = 0; no rescue medication used per day; 
 RMS = 0.5; at least one dose of antihistamine eye drops used per day; 
 RMS = 1; at least one dose of oral antihistamine used per day; 
 RMS = 2; at least one dose of intranasal corticosteroid used per day; 
 RMS = 3; at least one dose of systemic corticosteroid used per day. 
Where a subject finds that he or she is not able to obtain a suitable level of relief from 
symptoms with the provided allergy rescue medications, the Investigator and subject should 
discuss the use of alternative allergy rescue medications in the same categories as above. 
Alternative allergy rescue medications will be scored on the same RMS scale as the 
equivalent category of allergy rescue medication from the Rescue Medication Package. 
Asthma Symptom Scores (ASS) will be captured as follows for all subjects using the same 4 
point (0-3) grading scale described above: 
Asthma Symptoms 
 Cough 
 Wheezing 
 Shortness of breath 
In addition, ASS will be captured as follows for subjects with asthma: 
 Limitations of activities  
Over the last 24 hours, how limited have your activities been because of asthma? 
0: Not limited 
1: Very slightly limited 
2: Slightly limited 
3: Moderately limited or worse 
 Nocturnal symptoms or awakenings due to asthma 
Overnight (last night) how has your asthma affected you? 
0: Not at all 
1: Hardly at all 
2: A few minutes disturbance 


 
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3: Several times or more 
 Need for short-acting inhaled 2 agonist treatment 
Over the last 24 hours, how many puffs of reliever medication (e.g. albuterol or 
salbutamol) have you used? 
0: None 
1: One 
2: Two 
3: Three or more 
Study site personnel should contact subjects at the end of the first and second weeks of the 
BAE by telephone or text message to remind and encourage them to complete the eDiary on a 
daily basis. 
VAS for allergy symptoms 
In addition, at the start of the BAE period, subjects will record their RSS using a VAS. This 
assessment will be based on the subject’s assessments of their symptoms over the preceding 
week. Subjects will be asked to rate their allergy symptoms on a visual scale where 0 = no 
symptoms and 10 = worst symptoms possible. This assessment will be recorded on the 
eDiary.  
6.2.1.2.2 
Visit 2B 
Following completion of the Baseline Allergy Evaluation, subjects will attend the study 
centre for Visit 2B and will be eligible for randomisation provided they comply with 
Inclusion Criteria 9 and 10 and continue to comply with the Exclusion Criteria (particularly 
those related to asthma). The following procedures will take place at this visit: 
 Recording of any change to concomitant medications, and any allergy medication 
other than those recorded in eDiary. 
 Recording of any AEs. 
 Completion of RQLQ. 
 Completion of ACT (asthmatic subjects only). 
 Completion of PSQI. 
 Review pDiary and  issue new pDiary 


 
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6.2.2 
Period 2: Study Medication Administration (Visits 3A-3H) and End of 
Dosing Assessment (Visit 3I) 
6.2.2.1 Visits 3A-3H: Study Medication Administration 
Subjects will be randomised when they attend Visit 3A [note: Visit 3A should immediately 
follow completion of Visit 2B, or if this is not convenient may occur within 7 days of  
Visit 2B]. Study medication, HDM-SPIRE or placebo, will be administered at 8 visits 
(Visits 3A-3H) for each subject (see also Section 3.1). The 8 visits will take place at intervals 
of 4 weeks (±2 days). If the subject has a significant systemic or local illness that includes a 
fever (oral or aural temperature >38oC), the dosing visit should be rescheduled for 5 days 
later; there is no need to reschedule dosing for subjects with an upper respiratory tract 
infection without any significant associated fever.  If the subject’s pre-dose FEV1 is <70% of 
predicted the dosing visit should be rescheduled. Subjects will be permitted to leave the clinic 
after a minimum of 30 minutes based on the Investigator’s assessment of their clinical 
condition. Intradermal injections of HDM-SPIRE or placebo (100 μL) will be made into the 
flexor (volar) surface of the forearm by the Investigator or designee. Standards for practical 
allergen-specific immunotherapy are described in Alvarez-Cuesta et al (Alvarez-Cuesta 
2006). 
Emergency treatment must be available and immediately accessible for treatment of 
suspected anaphylactic reactions (see Section 5.8.2 and Appendix 2) 
The following procedures and assessments will take place at each of the study medication 
administration visits (Visits 3A-3H): 
Pre-dose assessments: 
 Recording of any AEs. 
 Recording of any changes to concomitant medication since last visit. 
 Urine pregnancy test (for females and which must be negative for the subject to 
continue in the study). 
 Examination of the injection site from previous administration (not relevant for Visit 
3A) with recording of any injection site reaction on the following scale (FDA 
Guidance for Industry 2007) (Table 7): 


 
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Table 7 
Grading of Injection Site Reactions 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. ** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
 Spirometry (FEV1) [asthmatic subjects should not take their β agonist asthma 
medication for a minimum of 4 hours prior to spirometry]. FEV1 must be ≥70% of 
predicted for a subject to be dosed.  
 In the event that the FEV1 is less than 70% of predicted the subject’s asthma 
medication use should be reviewed and any appropriate adjustments made. The 
dosing visit should then be rescheduled within 5 days. A dosing visit may only be 
rescheduled once, after which time it becomes a missed visit. 
 Vital signs (seated or semi-recumbent). 
 Blood sample for biomarker analysis (OPTIONAL sub-study ONLY at Visit 3A – see 
Section 6.4.4.7) 
Study medication administration: 
 Intradermal injection of 100 µL of HDM-SPIRE or placebo. 
Post-dose assessments: 
 Spirometry (FEV1) will be performed 30 minutes after injection.  Asthmatic subjects 
should not take their asthma medication for a minimum of 4 hours prior to spirometry. 
 Vital signs measured 30 minutes after injection (seated or semi-recumbent). 
 Examination of the injection site between 30 minutes after injection, with findings 
recorded using the scale above. 
 Blood sample for tryptase will be taken only in the event of a suspected anaphylactic 
response. The initial sample should be taken approximately 1 hour after the attack, 
with a further sample at approximately 3 hours and then repeated every 3 hours until 
the Investigator is satisfied that the subject may be discharged. Note: blood sampling 
 
Grade 0 
Grade 1 
Grade 2  
Grade 3  
Grade 4  
Pain  
None 
Does not 
interfere  
with activity  
Repeated use 
of non-narcotic 
pain reliever 
>24 hours or 
interferes with 
activity  
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity  
Emergency room 
visit or  
hospitalization  
Tenderness  
None 
Mild 
discomfort to 
touch  
Discomfort 
with movement  
Significant 
discomfort at 
rest  
Emergency room 
visit or 
hospitalization  
Erythema/ 
Redness *  
None 
2.5 – 5 cm  
5.1 – 10 cm  
>10 cm  
Necrosis or 
exfoliative 
dermatitis  
Induration/ 
Swelling**  
None 
2.5 – 5 cm and 
does not 
interfere with 
activity  
5.1 – 10 cm or 
interferes with 
activity  
>10 cm or 
prevents daily 
activity  
Necrosis  


 
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for tryptase must not delay initial resuscitation. Any subject that experiences a 
suspected anaphylactic reaction must also have a sample collected for assay of 
tryptase at the next dosing visit or the end of study visit.  
 Recording of any AEs prior to discharge. 
 Issue new pDiary prior to discharge and instruct subjects to record details of injection 
site reactions in the 7 days after each dose. 
Post-treatment assessments made within ±5 minutes of the nominal times will not be 
regarded as a protocol deviation. Where more than one assessment is scheduled at a nominal 
time, the assessments will be conducted in the following order: 
1. Vital signs  
2. Spirometry (FEV1) 
3. Examination of injection site 
Subjects will be asked to complete a pDiary from Visit 3A to Visit 3I of AEs and 
concomitant medications. The pDiary will be checked at all visits and information entered 
into the eCRF.  The pDiary must then be retained in the Investigator Site File. 
The Investigator will assess the need for any asthmatic subject to be provided with a 
salbutamol/albuterol inhaler and/or peak flow meter at Visit 3A before leaving the clinic. 
6.2.2.2 Visit 3I: End of Dosing Assessment 
An End of Dosing Assessment (Visit 3I) will take place 4 weeks (±2 days) after the subject 
received the last dose of study medication. Subjects who are withdrawn from the study prior 
to receiving the final dose for any reason will proceed directly to a Period 3 Follow-Up 
(Visit 5). 
At Visit 3I the following procedures and assessments will take place: 
 Targeted Physical Examination (guided by findings at screening and emerging AEs). 
 Examination of the injection site from Visit 3H. 
 Spirometry (FEV1) [asthmatic subjects should not take their short acting 
bronchodilator for a minimum of 4 hours prior to spirometry]. 
 Vital Signs (seated or semi-recumbent). 
 Clinical laboratory assessments including dipstick urinalysis and blood samples for 
clinical chemistry and haematology. 
 Blood sample will be taken for Der p and Der f specific IgE by ImmunoCAP®. 
 Urine pregnancy test (for FOCBP). 
 Transfer information from pDiary to eCRF, i.e.: 
o Home environment changes (see Section 6.3.5). 


 
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o Concomitant Medications. 
o AEs. 
 
Issue new pDiary. 
6.2.3 
Period 3: Post-Administration Collection (Visits 4A-4F) and Period 3 
Follow-Up (Visit 5) 
Investigators should ensure that subjects are contacted at least once per month by telephone 
or text message after Visit 3I to ensure subjects remain motivated to participate in the study 
and continue to complete their pDiary as well as to ensure the subject is available for their 
PAC2 and PAC3 periods. 
6.2.3.1 Visits 4A-4F: Post-Administration Collection 
Subjects will participate in three post-administration data collection (PAC) periods.  
Each PAC will take place over a 3-week period and will consist of 1 clinic visit at the start of 
the PAC period to provide the eDiary and Rescue Medication Package to the subject and 
1 visit at the end of each PAC period to collect the eDiary. Subjects will record symptom 
scores, rescue medication use and ASS (where relevant) daily (in the morning) in the eDiary 
in the intervening 3-week period.  
Investigators should contact subjects at the end of the first and second week of each PAC 
period by telephone or text message to remind and encourage subjects to complete the eDiary 
on a daily basis. 
Investigators must review completion of eDiary data through the web portal and immediately 
contact any subject who has not completed the eDiary during a PAC period and seek to 
encourage the subject to resume completing the eDiary as soon as possible. 
The PAC periods are: 
 PAC1: Weeks 18-20 (±2 days) Visits 4A and 4B will occur on the first and last day, 
respectively. Visit 4B will take place at the same time as the Dosing Visit 3F.  PAC1 
may occur during a pollen period to which the subject has clinically significant 
symptoms. 
 PAC2: Weeks 37-39 (±2 days), Visits 4C and 4D will occur on the first and last day, 
respectively. PAC2 may occur during a pollen period to which the subject has 
clinically significant symptoms. 
 PAC3: Weeks 50-52 (±2 days), Visits 4E and 4F will occur on the first and last day, 
respectively. The PAC3 period must start after the end of the pollen period for all 
relevant seasonal allergens to which the subject has clinically significant symptoms 


 
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and must complete at least 1 week before the anticipated start date of the Spring 
pollen season for any allergen to which the subject has clinically significant 
symptoms. 
If a subject requires medication for allergy symptoms during a PAC period they may take 
allergy rescue medications from the Rescue Medication Package provided in accordance with 
the Rescue Medication Plan (Appendix 3). 
At the start of each PAC (Visits 4A, 4C and 4E), the following assessments will be 
performed: 
 Vital Signs (sitting or semi-recumbent) 
 Recording of AEs. 
 Recording any changes in concomitant medications since last visit. 
 The subject must be retrained on how to follow the Rescue Medication Plan 
(Appendix 3). 
 Allergy rescue medication will be dispensed. 
 Subjects will be reminded to check with the Investigator before they start any new 
medications other than their allergy rescue medication. 
 A new pDiary will be issued. 
 At the end of the visit, subject will be provided with their eDiary to record the 
following information on a daily basis, first thing in the morning, for the next 3 
weeks: 
o RSS using a 4 point categorical scale 
o ASS 
o Allergy rescue medication use 
 
In addition, at the start of each PAC period, subjects will record their RSS using a VAS. This 
assessment will be based on the subject’s assessments of their symptoms over the preceding 
week. Subjects will be asked to rate their allergy symptoms on a visual scale where 0 = no 
allergy symptom and 10 = my allergy symptom is the worst it could possibly be. This 
assessment will be recorded on the eDiary. 
 
Note: Visit 4B at the end of PAC1 and the Dosing Visit 3F will take place at the same time 
and assessments that are duplicated at these two visits need to be made only once.  
At the end of each PAC (Visits 4B, 4D and 4F), the following assessment will be performed: 
 Vital Signs (sitting or semi-recumbent). 
 Recording of AEs. 


 
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 Recording any changes in Concomitant Medication since the last visit, and any other 
allergy medication not recorded in the eDiary. 
 Collect eDiary. 
 Collect pDiary and transfer to eCRF: 
o Home environment changes (see Section 6.3.5). 
o Concomitant medications. 
o AEs. 
 Issue new pDiary at Visits 4B and 4D. 
In addition, at Visits 4B, 4D and 4F the subject will complete the following assessments: 
o RQLQ (see Section 6.3.2). 
o Spirometry (FEV1) [asthmatic subjects should not take their asthma 
medication for a minimum of 4 hours prior to spirometry]. 
o ACT for asthmatic subjects. 
o PSQI  
 
6.2.3.2 Period 3 Follow-Up (Visit 5) 
A Period 3 Follow-up (Visit 5) visit will be conducted either at the same time as Visit 4F or 
as a separate visit no later than 10 days after the PAC3 period is completed.  The following 
procedures will be conducted: 
 Vital signs (sitting or semi-recumbent). 
 Targeted physical examination (guided by findings at screening and emerging AEs). 
 Blood samples for routine haematology and biochemistry. 
 Blood sample for Der p and Der f specific IgE. 
 Blood sample for biomarker analysis (OPTIONAL sub-study – see Section 6.4.4.7) 
 Blood sample for tryptase in any subject who has had a suspected anaphylactic 
response and is being withdrawn from the study. 
 A dipstick urinalysis will be performed on the subject’s urine. 
 Urine pregnancy test (for FOCBP). 
  Recording of any changes to concomitant medication since last visit. 
 Recording of any AEs. 
 Subjects will be asked to complete a Clinical Global Impression of Change in 
Rhinoconjunctivitis Symptoms. 


 
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6.3 
Assessment of Efficacy 
6.3.1 
Measurement of RSS, ASS and Allergy Rescue Medication Use   
Subjects will record their RSS using the 4 point categorical scale (reflective over last 24 
hours), ASS and allergy rescue medication use on a daily basis, first thing in the morning, in 
an eDiary during the Baseline Allergy Evaluation, PAC1, PAC2 and PAC3. 
Symptoms will be divided into nasal, non-nasal and asthma symptoms and rated for severity 
as described in Section 6.2.1.2. 
Subjects will also record their RSS using the VAS (reflective over the past week) once at the 
beginning of the BAE and each PAC period. 
6.3.2 
Rhinoconjunctivitis Quality-of-Life Questionnaire 
Subjects will complete the RQLQ at the end of the BAE and at the clinic visits at the end of 
PAC1, PAC2 and PAC3. 
6.3.3 
Asthma Control Test  
 
The ACT will be completed by asthmatic subjects at the end of the BAE and at the clinic 
visits at the end of PAC1, PAC2 and PAC3. 
6.3.4 
Clinical Global Impression of Change in Rhinoconjunctivitis 
Symptoms 
Subjects will complete a Clinical Global Impression of Change in Rhinoconjunctivitis 
Symptoms at the Period 3 Follow-up visit (Visit 5). Subjects will rate their overall allergy 
symptoms at the end of the study relative to Baseline on a 7 point scale as follows: 
 Very much better (0) 
 Moderately better (1) 
 A little better (2) 
 Unchanged (3) 
 A little worse (4) 
 Moderately worse (5) 
 Very much worse (6) 


 
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6.3.5 
Home Environment (Exposure to Allergen) 
Subjects will be asked to record any changes to their home environment in the pDiary. This 
will include changes to HDM control measures, such as, humidity, regular washing, regular 
vacuuming, installation of mattress and pillow encasings and significant changes to their 
home furnishing (e.g. removal of carpets).  The Investigator will transfer this information into 
the eCRF. At the start of the BAE and at the end of the final PAC period, subjects will 
provide dust samples from their homes for analysis to confirm domestic HDM exposure and 
to measure levels of other perennial allergens such as cockroach and moulds. (Subjects in 
South Africa who do not have ready access to a vacuum cleaner will not be required to 
collect dust samples). 
6.3.6 
Pittsburgh Sleep Quality Index 
The PSQI will be completed by subjects at the end of the BAE and at the clinic visits at the 
end of PAC1, PAC2 and PAC3. 
6.4 
Assessment of Safety and Tolerability 
6.4.1 
Adverse Events 
At each study visit, the Investigator will determine whether any AEs have occurred by asking 
non-leading questions. Adverse Event reporting begins from signed informed consent and 
ends at Visit 5. 
An AE is any untoward medical occurrence. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom or disease. An adverse 
drug reaction is defined as any noxious and unintended responses to a medicinal product 
related to any dose. The phrase “responses to a medicinal product” means that a causal 
relationship between a medicinal product and the AE is at least a reasonable possibility, i.e., 
the relationship cannot be ruled out.  Treatment and placebo will be blinded in this study, so a 
causal relationship between treatment and an AE cannot be established before the data are 
unblinded. 
All AEs must be fully recorded in the eCRF, from the time that a subject has provided signed 
informed consent to the time of their final study visit (although continued monitoring may be 
required for AEs ongoing at this visit).  
When recording an AE, the following details should be given: 
 Event observed (brief description using medical terminology); 
 Start and stop dates and times; 
 Severity (see below); 


 
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 Relationship to study medication (see below); 
 Action taken (brief description); 
 Outcome (see below); 
 Serious (Yes/No). 
An AE does include: 
 Exacerbation of a pre-existing illness; 
 Increase in frequency or severity of a pre-existing episodic condition; 
 A condition detected or diagnosed after study start even though it may have been 
present prior to the start of the study. 
An AE does not include: 
 Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion); the condition that led to the procedure is an AE. 
 Pre-existing disease or conditions documented prior to the start of the study, which 
does not worsen. 
 Elective surgery, social and/or convenience admissions previously arranged or 
anticipated before the start of the study and reported to the Investigator. 
 Disease or disorder being studied or associated signs or symptoms provided these do 
not worsen/appear during treatment. 
 Overdose of either study or concomitant medication without any signs or symptoms. 
 Uncomplicated pregnancy 
Adverse events will be recorded as they are reported, whether spontaneously volunteered by a 
subject or in response to questioning about well-being at each study visit. The subject will be 
questioned in a general way and no specific symptoms will be suggested. The questioning 
about AEs will cover the current visit and the period of time between the previous and current 
visit although subjects may report AEs occurring at any other time during the study. Follow-
up of all AEs will continue until the overall clinical outcome is definitive. If any AEs have 
occurred, they will be recorded in the subject’s medical record and transcribed to the eCRF. 
The Investigator must detail the symptom of the event, the onset of the event, the measures 
taken and the outcome, the date of disappearance or stabilisation. If known, the diagnosis 
should be recorded, in addition to the listing of individual signs and symptoms. The 
Investigator will assess each AE in terms of severity and relationship to study medication as 
indicated in the sections that follow. 
 
 


 
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Severity 
Mild 
Noticeable to the subject, but does not interfere with their usual 
activities. Usually does not require additional therapy, dose 
reduction or discontinuation of medicinal product. 
Moderate 
Interferes with usual activities, possibly requires additional therapy, 
but usually does not require discontinuation of medicinal product. 
Severe 
Incapacitating with inability to perform usual activities. May require 
medical intervention and treatment and may require discontinuation 
of medicinal product. 
The Investigator will make a judgement regarding whether or not the AE was related to the 
study medication. The Investigator will evaluate any changes in laboratory values (including 
vital signs and 12-lead electrocardiogram and make a determination as to whether or not the 
change is clinically important and whether or not the changes were related to study 
medication. However, even if the Investigator feels there is no relationship to the study 
medication, the AEs MUST be recorded in the eCRF and the rationale for the judgement 
should be recorded in the medical notes. 
Causality 
Related: 
Any event that follows a reasonable temporal sequence from 
administration of study treatment OR that follows a known response 
pattern to the investigational drug. 
(Any event that does not meet the criteria for unlikely or not related should 
be classified as related) 
Unlikely to be 
related 
Any event that does not follow a reasonable temporal sequence from 
administration of study treatment AND does not follow a known response 
pattern to the suspected drug. 
Not related 
Any event that starts before administration of study medication AND/OR 
for which there is a clear alternative explanation. 
Outcome 
For each event, the following outcomes are possible: 
 Recovered; 
 Recovered with sequelae; 
 Ongoing; 
 Death; 


 
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 Unknown (appropriate follow-up to determine the outcome of all AEs will be 
undertaken and therefore “Unknown” should only be used as a last resort). 
Follow-Up of Adverse Events 
If any AEs are present when a subject completes the study or if a subject is withdrawn from 
the study, the subject will be followed up by telephone in 3-7 days. If the AE has still not 
resolved, additional follow-up will be performed as appropriate. Every effort will be made by 
the Investigator or delegate to contact the subject until the AE has resolved or stabilised. This 
should be documented in the subject’s medical records. All AEs must be followed until 
resolution, until the condition stabilises, until the subject dies or is lost to follow-up. The 
Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations that may be indicated, including (but not limited to) additional laboratory tests, 
histopathology or consultation with other health care professionals. 
6.4.2 
Serious Adverse Events 
A SAE is any untoward medical occurrence that: 
 Results in death; 
 Is life-threatening (subject is at immediate risk of death in the judgement of the 
Principal Investigator at the time of the event); 
 Results in persistent or significant disability or incapacity; 
 Requires hospitalisation or prolongation of an existing hospitalisation; 
 Is a congenital abnormality or birth defect; 
 Is a medically significant event; 
Medical and scientific judgement should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation, but may jeopardise the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also be considered to be SAEs. 
6.4.2.1 Adverse events of Special Interest 
Systemic Allergic Reaction (as defined by World Allergy Organization (WAO) Subcutaneous 
Immunotherapy Systemic Reaction Grading System, Appendix 4 [Cox et al., 2010]) are 
considered Adverse Events of Special Interest and should be reported expeditiously to the 
Sponsor in the same way as Serious Adverse Events.  
If a systemic allergic reaction also meets any of the definitions of serious then it will also be 


 
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classified as a serious event and will be managed in the same way as any other serious event.  
6.4.2.2 Life-Threatening Adverse Event 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
6.4.2.3 Hospitalisation 
This is defined as the subject being hospitalised overnight. Any pre-planned or anticipated in-
hospital visits should be documented in advance of the start of study medication 
administration and will be excluded from this category. 
6.4.2.4 Subject Withdrawal 
If the subject discontinues study medication administration due to a SAE and withdraws from 
the study, this should be reported using the SAE forms provided. 
6.4.2.5 Unexpected Adverse Event 
An unexpected AE is defined as an AE, the nature or severity of which is not consistent with 
the applicable product information (i.e., the Investigator’s Brochure). 
6.4.2.6 Reporting Serious Adverse Events/Expeditable Adverse Events 
Investigators are obliged to notify, by fax, the contract Pharmacovigilance CRO, Icon plc 
(formerly Akos Ltd.), of all SAEs immediately (within 24 hours of the Investigator becoming 
aware of the event). 
SERIOUS ADVERSE EVENTS MUST BE REPORTED BY PHONE, FAX OR 
EMAIL TO ICON IMMEDIATELY 
(NO LATER THAN 24 HOURS OF THE INVESTIGATOR BEING NOTIFIED) 
+44 1628 496300 (Phone for Rest of World) 
+1 888 723 9952 (Phone for North America) 
+44 1865 595595 (Fax for Rest of World) 
+1 800 540 1863 (Fax for North America) 
f2m-eastleigh-medical@iconplc.com (email) 
 
 
 


 
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The minimum information required on the SAE report is: 
 Protocol number; 
 Centre number or Investigator name; 
 Subject number; 
 An AE or outcome that can be identified as serious; 
 A suspected investigational product; 
 Investigator’s or Co-Investigator’s assessment of relationship to the investigational 
product; 
 Name and signature of reporter. 
Follow-up information must be actively sought and submitted as soon as it becomes 
available. 
All serious, unexpected and related AEs (SUSARs) must also be reported to the reviewing 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) according to local 
and national requirements. Circassia Ltd will provide details to other Investigators of such 
AEs for this purpose. 
Reports relating to the subject’s subsequent medical course must be submitted to the Sponsor 
until the event has subsided or, in the case of permanent impairment, until it stabilises and the 
overall clinical outcome has been ascertained. The Investigator will also provide additional 
information, including a copy of the following documents (where applicable): 
 Copies of all test results; 
 Hospital discharge summary (as soon as it is available to the Investigator); 
 Autopsy report (as soon as it is available to the Investigator). 
SAEs that come to the attention of the Investigator at any time up until the end of the study 
(Visit 5) must be reported to the Sponsor in the same manner as a SAE occurring during the 
dosing period. 
The Investigator will notify the IRB/IEC of all SAEs that occur during this study, if required 
by local or national laws and regulations. 
The appropriate regulatory authority will be notified of all SUSARS within the required 
reporting timelines. 
6.4.3 
Reporting of Pregnancy 
Subjects who become pregnant before the start of dosing (from consent to Visit 3A) must be 
withdrawn from study immediately after the pregnancy is confirmed. Subjects who become 


 
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pregnant during the dosing period must receive no further study treatment and the pregnancy 
must be reported using the same procedure as for SAEs (see Section 6.4.2). Subjects who 
become pregnant once dosing has completed may remain in the study and the pregnancy must 
be reported using the same procedure as for SAEs. Pregnancy will be recorded in the 
subject’s medical files.  A Pregnancy Notification Form must be completed and is reported 
using the same procedure as for the SAEs (see Section 6.4.2). The outcome of the pregnancy 
will be followed-up until term end, full or premature termination. A Pregnancy Outcome 
Form, to assess the health of the mother and any infants, will be completed and reported 
following the same procedure as the notification form. 
6.4.4 
Safety Evaluations 
6.4.4.1 Demographic and Medical History 
The demographic data and a complete medical history with an emphasis on allergy including 
rhinoconjunctivitis and asthma will be recorded at Screening (Visit 1B/C). This will include 
skin prick testing to HDM. 
6.4.4.2 Physical Examination 
A physical examination will be conducted at Screening (Visit 1B/C), at the End of Dosing 
Assessment (Visit 3I) and at the Period 3 Follow-Up (Visit 5). At Screening this will be a full 
examination comprising: 
 Eye, ears, nose, throat, neck, including a check for nasal polyps; 
 Respiratory system; 
 Central and peripheral nervous system; 
 Cardiovascular system; 
 Gastrointestinal system (including the mouth); 
 Musculoskeletal system; 
 Skin; 
 Lymph node palpation; 
 Other systems if abnormality is suspected. 
At visits 3I and 5 the physical examination will be a targeted exam, with organ systems 
examined if the medical history or AEs indicate a reason for examination. 
6.4.4.3 Vital Signs 
Blood pressure, pulse rate, respiratory rate and body temperature will be recorded at 
Screening (Visit 1B/C), prior to and 30 minutes after Study Medication Administration 


 
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(Visits 3A-3H), at the End of Dosing Assessment (Visit 3I), at each PAC visit and at Period 3 
Follow-Up (Visit 5). Measurements will be made with the subjects rested and in the sitting or 
semi-recumbent position. 
6.4.4.4 Laboratory Assessments 
Blood samples using the Vacutainer® system for haematology and biochemistry tests and 
urine samples for urine dipstick tests will be obtained at Screening (Visit 1B/C), at the End of 
Dosing Assessment (Visit 3I) and at the Period 3 Follow-Up (Visit 5). 
Blood samples for Der p, Der f and perennial allergen specific IgE will be obtained at 
Screening (Visit 1A) and will be measured by ImmunoCAP®. At the End of Dosing 
Assessment (Visit 3I) and at Period 3 Follow-Up (Visit 5) blood samples for Der p and Der f 
specific IgE, measured by ImmunoCAP®, will be obtained. 
A blood sample will be taken at screening only for measurement of a fixed panel of Der p 
allergens using an immune-affinity based analysis technology such as ImmunoCAP®. 
Urine samples for pregnancy tests will be collected from FOCBP and analysed immediately 
at Screening (Visit 1B/C), before dosing at Study Medication Administration Visits 
(Visits 3A-3H), at the End of Dosing Assessment (Visit 3I) and at Period 3 Follow-Up 
(Visit 5). 
The following parameters will be measured: 
Haematology:  
haematocrit, haemoglobin, red blood cells, white blood cells (WBC), 
WBC differentials (neutrophils, eosinophils, basophils, lymphocytes, 
monocytes) and platelets. 
Biochemistry: 
sodium, potassium, chloride, urea, creatinine, calcium, phosphorus, 
total protein, albumin, uric acid, total bilirubin, glucose (random), 
lactate dehydrogenase, creatine phosphokinase, alanine transaminase, 
aspartate transaminase, gamma glutamyltransferase, and alkaline 
phosphatase ;  
Blood samples will be collected for assay of tryptase in the case of a 
suspected anaphylactic response [see Section 6.2.2]). 
Urine dipstick: 
pH, protein, ketones, blood and glucose. 
Immunology: 
Der p, Der f and relevant perennial allergen specific IgE (measured by 
ImmunoCAP®). 


 
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Additional tests may be performed if clinically warranted. Abnormal values should be 
followed up they have returned to normal or an adequate explanation has been established.  
All laboratory test reports must be reviewed, signed and dated by the Investigator or 
delegated physician. Reports will then be filed with the subject’s medical record. The 
Investigator will comment on all abnormal results and determine whether it is clinically 
significant. These assessments will be recorded in the eCRF. 
Any clinically significant abnormal laboratory value constitutes an AE and must be recorded 
as an AE in the eCRF. For grading an abnormal value or result of a clinical or laboratory 
evaluation, Investigators are encouraged to consult National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0. A value that increases by 
one grade from baseline or from the last post-baseline value that does not meet grading 
criteria should ordinarily be considered clinically relevant and hence reported as an adverse 
event. A CTCAE grade increase of one in clinical or laboratory evaluation will translate to 
‘mild’ in the above grading, an increase of two will be ‘moderate’ and an increase of three or 
more will be ‘severe’. For additional information and a printable version of the manual, 
consult the NCI-CTCAE web site: http://ctep.cancer.gov/reporting/ctc.html. 
6.4.4.5 FEV1 
The FEV1 will be measured at Screening (Visit 1B/C), prior to and 30 minutes after Study 
Medication Administration (Visits 3A-3H), at the End of Dosing Assessment (Visit 3I), and 
at the end of PAC1, PAC2 and PAC3 (Visits 4B, 4D and 4F). Asthmatic subjects should not 
use their asthma medication for a minimum of 4 hours prior to the spirometry assessment. 
At each assessment FEV1 will be measured according to the American Thoracic Society 
guidelines with the subject sitting and the highest reading will be recorded in the eCRF. 
6.4.4.6 Injection Site Reactions 
At each study medication administration (Visits 3A-3H), the injection site will be examined 
immediately prior to and 30 minutes after the administration of study drug for signs of 
reaction. Reactions should be graded on a 5 point (0-4) scale for each of the following 
parameters, as shown in Section 6.2.2.1: pain, tenderness, redness, swelling.   
At Visits 3B-3H and at the End of Dosing Assessment (Visit 3I), this will include 
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6.4.4.7 OPTIONAL Biomarker Analysis 
Blood samples for biomarker analysis will be obtained at Visit 3A and at Follow-Up (Visit 
5). These samples will ONLY be taken from subjects at participating sites in Canada and US. 
Subjects will be required to sign a separate consent form to participate in this optional sub-
study. 
A blood sample (20 mL) will be collected and stored for future analysis. A biomarker 
analysis plan will be on file prior to the start of the biomarker analysis.  


 
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7.0 STATISTICAL CONSIDERATIONS 
7.1 
Data Management and Quality Assurance 
All data in the study will be captured and maintained in a secure, validated electronic data 
capture (EDC) system.  Study site staff will enter the data for each subject on an eCRF.  The 
laboratory data and eDiary card data will be transferred electronically to Data Management 
and reconciled with the data entered at site.  The subjects will enter their RSS, ASS and use 
of Rescue Medication directly into the study eDiary. 
Additionally a pDiary Card will be used to aid the collection of AEs, concomitant 
medications and home environment changes.  The Investigator will review the pDiary Card at 
each study visit and the data will be transcribed onto the eCRF. 
The eCRF and eDiaries will contain automated edit checks to ensure the quality, integrity, 
accuracy and completeness of the data entered. The Study Monitor will periodically review 
the eCRF input and source document verify eCRF data. The medical monitor may examine 
eCRF and diary card data for preliminary medical review. 
The eCRF data will be maintained in a validated study database with an audit trail of all 
changes that are made to the database, including the reason for the data change. Adverse 
events will be coded using a standard dictionary (Medical Dictionary for Regulatory 
Activities [MedDRA]), while concomitant medications will be categorised using the World 
Health Organisation drug dictionary. 
Creation and validation of the EDC system and management of the data will be conducted in 
accordance with title 21 of the Code of Federal Regulations Part 11 and the US FDA 
Guidance for Industry on Computerised Systems used in Clinical Investigations. Methods 
used to ensure the quality and integrity of the data will be documented in the Data 
Management Plan, which will be approved by the Sponsor. 
7.1.1 
Rescreening Data 
In a limited set of circumstances, subjects will be permitted to be rescreened for the study 
(See Section 4.5). All data from these subjects, both the original and repeat assessments, will 
be entered into the study database. For those parameters where repeat assessments are made, 
the repeat assessment will be used in data summaries. The original assessments will be listed 
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7.2 
Sample Size 
The study will recruit approximately 660 subjects (approximately 165 per group). Based on 
the data from observational study TH003, if a mean CS of 1.6 is observed for the placebo 
group, and a mean CS of 1.28 for the active group, the expected treatment difference of 0.32 
will be a 20% improvement from placebo. The statistical model will include the baseline CS 
as a covariate, taking this into account a standard deviation of 0.986 is assumed, so that a 
sample of 150 patients will have 80% power to detect a statistically significant difference in 
treatment. 
Other data sources result in sample size estimates that range from 103/group (based on the 
TRSS data from Study TH002) through to 200/group (based on symptom scores adjusted for 
medication use in a study of sublingual HDM immunotherapy [Bergmann et al, 2013]).  
These data support the assumptions from Study TH003 and indicate that a difference of 20% 
between placebo and active treatment will be observed with a sample size of 150 subjects per 
group. It is estimated that up to 10% of subjects may drop-out before PAC3 or have missing 
data during PAC3. Consequently, approximately 660 subjects in total will be randomised. 
7.3 
Interim Analysis 
No interim analysis is planned for this study.  
7.4 
Analysis Populations 
7.4.1 
Intent-to-Treat Population 
The population for the efficacy analyses will be the Intent-to-Treat (ITT) population 
consisting of all subjects who are randomised, who have received at least one dose of study 
medication. Subjects will be reported by the treatment they were randomised to. This is the 
primary population for the study, and all the primary and secondary efficacy analyses will be 
based on the ITT population. 
7.4.2 
Per Protocol Population 
Subjects who are part of the ITT population, have no major protocol deviations likely to 
affect the integrity of the study and complete the entire study will constitute the Per Protocol 
(PP) population. The PP population will be evaluated for the primary endpoint to confirm 
results from the ITT population. 


 
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7.4.3 
Safety Population 
All subjects receiving at least 1 dose of study medication (HDM-SPIRE or placebo) and with 
at least one safety assessment will be included in the safety population. Subjects will be 
reported by the treatment they actually received. The safety population will be used for all of 
the safety endpoints.   
7.5 
Statistical Analysis 
Further detail of the statistical analyses and data presentations to be used in reporting the 
study, including dictionaries used for coding and software used, will be provided in the 
Statistical Analysis Plan (SAP), which will be finalised prior to breaking the blind. 
If not otherwise specified, statistical significance is defined as p<0.05 and is 2-sided. 
Data will be summarised with respect to demographic and baseline characteristics, efficacy 
variables and safety variables. Summary statistics will include the mean, N, standard 
deviation (SD), median, minimum and maximum values for continuous variables and 
frequencies and percentages for categorical variables. 
The primary efficacy analysis will utilize a Mixed Model Repeated Measures (MMRM) 
model. To assess the effect of missing data on the primary analysis, a sensitivity analysis 
using different imputation methods will be performed. The imputation method(s) to be 
applied will be defined in the SAP. 
If any parametric analyses are found to be inappropriate and/or fail their assumptions then 
supportive analysis will include non-parametric methods, as appropriate. 
7.5.1 
Hypothesis Testing 
The null (H0) and alternative (H1) hypotheses for the primary efficacy analysis are: 
 H0: there is no difference between the HDM-SPIRE treatment group(s) and the 
placebo group. 
 H1: there is a difference between the HDM-SPIRE treatment group(s) and the placebo 
group. 
Such that: 
H0  μA = μp 
H1 μA ≠ μp 


 
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where, μA is estimated by the mean daily CS during the PAC3 period in the HDM-
SPIRE treatment group and μP by the mean daily CS during the PAC3 period in the 
placebo group. 
7.5.2 
Demographic and Baseline Characteristics 
Data will be summarised with respect to demographic and baseline characteristics by study 
treatment group. 
7.5.3 
Efficacy Analysis 
7.5.3.1 Primary Analysis 
7.5.3.1.1 
Combined Score (TRSS and RMS) 
The primary endpoint for this study is the mean daily CS during the PAC3 period in 
HDM-SPIRE treated subjects compared with mean daily CS during the PAC3 period in 
placebo treated subjects. The CS is a composite measurement of symptoms as measured by 
the TRSS and RMS, as measured using a pre-defined rating system that takes into account the 
different potency of available rescue medication.  
The TRSS comprises assessment of 8 symptoms (4 nasal and 4 non-nasal symptoms) that are 
given a score of between 0 (absent) and 3 (severe) giving a range of potential scores of 0 to 
24. Subjects are asked to record the average intensity of their symptoms over the last 
24 hours once each morning for 3 weeks in the baseline and PAC periods.  
Subjects also record their use of any of the provided rescue medications in the previous 
24 hours. These are assigned a score as follows: 
• 
RMS = 0; no allergy rescue medication used per day 
• 
RMS = 0.5; at least one dose of antihistamine eye drops used per day 
• 
RMS = 1; at least one dose of oral antihistamine used per day 
• 
RMS = 2; at least one dose of intranasal corticosteroid used per day 
• 
RMS = 3; at least one dose of systemic corticosteroid used per day 
The RMS score is not additive, and therefore the maximum RMS is 3.  
The TRSS (0-24) and the RMS (0-3) will be combined for analysis of the primary endpoint as 
follows: 
CS = TRSS/8 + RMS 


 
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The maximum Combined Score is therefore 6. 
The primary analysis will be the comparison between the HDM-SPIRE treatment groups and 
placebo for the ITT population using MMRM analysis for the PAC1, PAC2 and PAC3 mean 
CS assessments per subject. The model will include treatment, period and pooled centre as 
main effects, gender, asthma status and Baseline Allergy Evaluations CS as covariate, and 
treatment by period interaction. An unstructured covariance matrix will be used to assess 
within-subject dependence of the 3 observations of mean CS. A point estimate of the adjusted 
mean and two-sided 95% confidence interval for the difference in adjusted means between 
the active treatment groups and placebo will be calculated, with the treatment contrast 
corresponding to the mean CS of the PAC3 period. The Baseline Allergy Evaluation CS is 
defined as the mean of daily CS during the BAE period, as defined in Section 6.2.1.2. A 
hierarchical (step-down) approach will be used to control the overall type 1 error rate at 5%.  
For declaring statistical significance, a step-down approach (first 4 x 12 nmol versus placebo, 
then 4 x 20 nmol versus placebo and then 8 x 12 nmol versus placebo) will be used to control 
the overall type I error at 0.05. Thus: 
 Step 1: If 4 x 12 nmol versus placebo is significantly different at the 0.05 significance 
level, move to Step 2. If there is no significance, no further statistical significance will be 
declared.  
 Step 2: If 4 x 20 nmol versus placebo is significantly different at the 0.05 significance 
level, move to Step 3. If there is no significance, no further statistical significance will be 
declared. 
 Step 3: If 8 x 12 nmol versus placebo is significantly different at the 0.05 significance 
level, declare statistical significance. 
The above analysis will be performed using all available data on the assumption that the 
probability of missing observations is independent of unobserved measurements (missing at 
random). Therefore the missing values will not be imputed for the primary analysis.  
A sensitivity analysis will be performed to check the robustness of the primary results, 
assuming a missing not at random process. A Patter-mixture model based on control-based 
imputation will be utilized for the sensitivity analysis. 
Additional sensitivity analyses may be defined in the SAP as appropriate. 


 
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7.5.3.1.2 
Supportive Analyses 
The above analysis will be supported by a responder analysis identifying the number of 
subjects who show a reduction from baseline CS during PAC3 at each tenth percentile for the 
percentage change from baseline in CS for each HDM-SPIRE treatment and placebo. In 
terms of significant reductions in allergic rhinoconjunctivitis symptom scores in individual 
subjects, in general ≥20% reduction in baseline scores can be regarded as being clinically 
meaningful and this level, as well as a 10% reduction, will be particularly evaluated in a test 
of proportions analysis between the HDM-SPIRE treatment groups and placebo group. A 
waterfall plot of the clinical response showing change in CS from baseline to PAC3 for each 
individual subject will be plotted for the HDM-SPIRE treatment groups and the placebo 
group. 
The effect of centre on the primary endpoint for the ITT population will be investigated via 
an MMRM with main effects and covariates as specified for the primary analysis together 
with a treatment-by-centre interaction. A significant treatment-by-centre interaction in this 
analysis will be explored further. The pooled centres will be defined in the SAP. 
Sensitivity analysis of differing weightings of TRSS and RMS for CS and the contribution of 
oral corticosteroids to the RMS will be defined in the SAP. 
If any of the model assumptions are not met, further supportive analysis will be defined in the 
SAP. 
7.5.3.1.3 
Handling Missing Data 
The SAP will provide a detailed plan to account for other missing data as a result of blinded 
review(s) prior to breaking the study blind. Examples of reasons for missing data include 
missing score and sub-score data for a visit and/or missing data for whole visits as a result of 
subject drop-outs. However, some forms of missing data have been prospectively accounted 
for and are described below. 
If any of the 8 individual RSS, namely sneezing, runny nose, blocked nose, itchy nose, itchy 
eyes, watery eyes, red eyes or itchy ear/palate for a given day is missing; the TRSS for that 
day will be considered missing. If either the TRSS or the RMS is missing for a particular day 
then the CS will also be considered missing. This will also apply to other symptoms score 
endpoints (e.g. Total nasal symptom score and Total non-nasal symptom score) that use the 
ITT population. 
For each subject in the PAC3 period (Weeks 50-52) the mean of the daily non-missing CS 
during that period will be calculated. 


 
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7.5.3.2 Secondary Analysis 
Secondary endpoints will be prioritised in order of importance as outlined below.  If any of 
the model assumptions of analysis of covariance (ANCOVA) are not met for any of the 
secondary endpoints then more appropriate statistical method will be applied and explained in 
the CSR. 
7.5.3.2.1 
Rhinoconjunctivitis Symptom Scores – Categorical scores 
The mean TRSS and the mean component scores of the TRSS (nasal and non-nasal) during 
the PAC3 period will be summarised by treatment group. The difference in the TRSS and the 
component scores of the TRSS between the HDM-SPIRE treatment groups and the placebo 
group will be calculated and treatment comparisons made using the same methodology as 
described for the primary efficacy analysis. 
7.5.3.2.2 
Rescue Medication Usage 
The mean RMS during the PAC3 period will be summarised by treatment group. The 
difference in the RMS between the HDM-SPIRE treatment groups and the placebo group will 
be calculated and treatment comparisons made using the same methodology as described for 
the primary efficacy analysis. 
7.5.3.2.3 
Clinical Global Impression of Change in Rhinoconjunctivitis 
Symptoms 
An evaluation of the number of subjects in each category of the Clinical Global Impression of 
Change in Rhinoconjunctivitis Symptoms will be presented. Global impression of Change 
will be analysed using the Cochran-Mantel-Haenszel test. 
7.5.3.2.4 
Proportion of Symptom-Free Days 
The difference in proportion of Symptom-Free Days between HDM-SPIRE treatment groups 
compared with the placebo group will be calculated and treatment comparisons made using 
the same model as specified for the primary efficacy analysis. 
7.5.3.2.5 
Rhinoconjunctivitis Quality-of-Life Questionnaire 
The mean RQLQ score and the RQLQ domains at the end of the PAC3 period will be 
summarised by treatment group.  The difference in the RQLQ scores between the HDM-
SPIRE treatment groups compared with the placebo group will be calculated and treatment 
comparisons made using an ANCOVA. 


 
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7.5.3.3 Exploratory Analysis 
The PAC1 and PAC2 periods will be analysed by the same methods as for the PAC3 period.  
These analyses will be considered exploratory, since they may be confounded by seasonal 
allergies. Where appropriate, the same covariates will be included in the exploratory analysis 
statistical models as for the primary efficacy analysis. 
7.5.3.3.1 
Combined Score 
The mean CS during the PAC1 and PAC2 periods will be summarised by treatment group.  
The difference between the HDM-SPIRE treatment groups and the placebo group will be 
calculated and treatment comparisons made using the same methodology as described for the 
primary efficacy analysis, except that the treatment contrast will be specified corresponding 
to the mean CS of the PAC1 and PAC2 periods respectively. 
7.5.3.3.2 
Rhinoconjunctivitis Symptom Scores – Categorical Scores 
The mean component scores of the TRSS (nasal and non-nasal) and the mean TRSS during 
the PAC1 and PAC2 periods will be summarised by treatment group.  The difference in  
component scores of the TRSS and the TRSS between the HDM-SPIRE treatment groups and 
the placebo group will be calculated and treatment comparisons made using the same 
methodology as described for the primary efficacy analysis, except that the treatment contrast 
will be specified corresponding to the mean CS of the PAC1 and PAC2 periods respectively.  
7.5.3.3.3 
Rhinoconjunctivitis Symptom Scores – VAS Scores 
Rhinoconjunctivitis symptom scores recorded using the VAS will be summarised 
descriptively by treatment group.  
7.5.3.3.4 
Rescue Medication Usage 
The mean RMS during the PAC1 and PAC2 periods will be summarised by treatment group. 
The difference in RMS between the HDM-SPIRE treatment group and the placebo group will 
be calculated and treatment comparisons made using the same methodology as described for 
the primary efficacy analysis, except that the treatment contrast will be specified 
corresponding to the mean CS of the PAC1 and PAC2 periods respectively. 
7.5.3.3.5 
Rhinoconjunctivitis Quality-of-Life Questionnaire 
The overall RQLQ score and the RQLQ domains at the end of the PAC1 and PAC2 periods 
will be summarised by treatment group.  The difference in the RQLQ scores between the 
HDM-SPIRE treatment groups and the placebo group will be calculated and treatment 
comparisons made using an ANCOVA. 


 
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7.5.3.3.6 
Asthma 
An evaluation of asthma control (ACT score) at the end of the BAE and each PAC period 
will be performed in asthmatic subjects.  
7.5.3.3.7 
Home Environment (Exposure to Allergen) 
Exposure to allergen (extent and variability) at baseline and end of PAC3 based on home 
environment changes will be summarised by treatment group and listed. 
7.5.3.3.8 
Sleep 
The overall and component scores of the PSQI at the end of the BAE and each PAC period 
will be summarised descriptively. 
7.5.3.3.9 
Concomitant Medication Use 
An evaluation of the use of any concomitant medications associated with rhinoconjunctivitis 
or related conditions will be performed. This will not include the use of allergy rescue 
medications defined in the Rescue Medication Plan. 
7.5.4 
Safety Analysis 
Safety will be evaluated by analysis of the following parameters: 
 
AEs; 
 
Physical examination; 
 
Clinical laboratory tests (including immunology); 
 
FEV1; 
 
Vital signs; 
 
Local reactions at the injection site. 
The primary safety endpoint will be a comparison of the number of adverse events, and 
subjects with adverse events, in the HDM-SPIRE groups compared to placebo.  
For safety analysis, descriptive statistics such as N, mean, median, minimum, maximum and 
SD will be summarised by treatment group for continuous variables. Frequency distribution 
will be summarised for categorical variables. No formal inferential tests will be performed on 
safety data. 
The number and percentage of subjects who experience AEs will be presented by treatment 
group. Based on the MedDRA Preferred Term, subjects who experience the same AE on 
multiple occasions will be summarised at the maximum severity and most conservative 
relationship to the study medication. If 2 or more AEs are reported as a single event, the 


 
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individual terms will be reported as separate AEs. 
The total number of AEs will be summarised by MedDRA System Organ Class and Preferred 
Term for each treatment group. Descriptive statistics will be presented for differences 
between the HDM-SPIRE treatment groups and the placebo group, but no hypothesis testing 
is planned. 
Any deaths, SAEs and AEs leading to discontinuation of study medication administration 
will also be summarised by treatment group. 
Local reactions at the injection site will be summarised by type of reaction and visit for each 
treatment group. 
Physical examinations data will be listed only. 
 
Vital signs will be presented as descriptive statistics on absolute values and the change from 
baseline will be summarised for each treatment group by visit. 
 
FEV1 will be presented as descriptive statistics and the absolute change from baseline and 
percentage change from baseline will be summarised for each treatment group by visit. 
 
Clinical laboratory data for individual subjects will be listed and any out of range values will 
be highlighted. Laboratory data will be summarised for each treatment group by visit as 
follows: summary of absolute values and change from baseline and analysis of shifts from 
baseline. 
 
Values for total IgE at Screening and Period 3 Follow-Up (Visit 5) and values for Der p and 
Der f specific IgE at Screening, End of Dosing Assessment (Visit 3I) and Period 3 Follow-Up 
(Visit 5) will be presented separately.  Changes in total IgE and Der p and Der f specific IgE 
will be compared descriptively between the HDM-SPIRE treatment groups and the placebo 
group. Values for tryptase (if analysed) will be listed separately. 


 
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8.0 INVESTIGATOR RESPONSIBILITIES 
 
8.1 
Investigator Performance 
The Principal Investigator and each Investigator will ensure that the study described in this 
protocol will be carried out to the highest standards of medical and clinical research practice. 
Each Investigator will also ensure that all those involved in the conduct of the study, such as, 
Co-Investigators, Pharmacists and Research Nurses, are qualified by experience and training 
to participate in the study, are provided with copies of the protocol and all safety information 
before study start and are fully familiar with their role. 
The study will be performed in full accordance with this protocol, the principals of the 
Declaration of Helsinki, International Conference on Harmonisation (ICH) E6 Good Clinical 
Practice (GCP); and applicable local regulatory requirement(s). 
8.2 
Ethical Considerations 
8.2.1 
Ethics Committee Review and Approval 
IRB/IEC approval for the study will be obtained prior to initiating the study at any study site. 
Documents reviewed by the IEC/IRB will include the protocol, ICF, subject information 
sheet, Investigator’s Brochure, any materials used directly by subjects (diaries, rating scales 
etc.) and any advertisements that are intended to be used in the study. All the required study 
documents must be approved by the IRB/IEC prior to the consent of the first subject. A copy 
of the IRB/IEC written approvals must be submitted to Circassia Ltd before the study may 
start and Investigational Medicinal Product release. Written approval must be obtained from 
the IRB/IEC for all major changes to the protocol, except when necessary to eliminate 
apparent immediate hazard to the subject. In this case, the IRB/IEC should be notified as 
soon as possible and written approval obtained. 
The study protocol will also be reviewed by the appropriate competent authority/authorities. 
The study will not proceed until the appropriate competent authority/authorities has/have 
granted a clinical study authorisation. 
8.2.2 
Written Informed Consent 
Prior to enrolment, the study procedures and any known or likely risks will be explained to 
the subjects in lay language by the Investigator or designee. The study information sheet will 
explain the objectives of the study, its potential risks and benefits. The subject should have 


 
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adequate time to read the information sheet and to ask the Investigator any questions. The 
Investigator must be satisfied that the subject has understood the information provided before 
written consent is obtained. If there is any doubt as to whether the subject has understood the 
written and verbal information, the subject should not enter the study. If a subject agrees to 
participate, he/she will be asked to sign and date an ICF. 
All subjects will receive a copy of the signed ICF, as well as the written information sheet 
about the study. The subjects will be assured that they can withdraw from the study at any 
time and for any reason. Written informed consent must be obtained before any study-related 
procedure is performed. Each subject’s ICF must be signed and dated by both the Investigator 
or designee and the subject. All ICFs will be checked by the Study Monitor, but retained by 
the Investigator. 
The original signed ICFs will be kept in the subject’s medical notes and must be made 
available for inspection by the Study Monitor and/or the regulatory authority. A record 
should also be made in the medical records that the subject voluntarily agreed to participate 
in the study. 
8.2.3 
Information for Subject’s General Practitioner/Primary Care Physician 
If the subject consents, their general practitioner/primary care physician (and any specialist 
the subject might be treated by) will be notified of the subject’s intended involvement in the 
study and will be asked whether or not there is any contraindication to the subject’s 
participation. 
8.3 
Confidentiality 
8.3.1 
Subject Confidentiality 
The Investigator shall reassure subjects that their identity will be kept confidential by third 
parties that conduct audits and inspections of the study centre and its documentation. 
A unique study number assigned to each subject at the start of the study will be used to 
identify the subject in the eCRF, on all study correspondence and in the study database. The 
Investigator will keep an identification code list and enrolment log, which will list the full 
name of each subject alongside the subject number assigned and the date enrolled. This log 
will remain in the Investigator’s Site File at the study centre. 


 
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8.3.2 
Sponsor Confidentiality 
All information concerning the Circassia study medication and the operations of Circassia, 
such as patent applications, formulae, manufacturing processes, basic scientific data or 
formulation information, supplied to the Investigator by Circassia and not previously 
published in the open literature is considered confidential by Circassia and shall remain the 
sole property of the company. The Investigator agrees to use this information only in 
performing this study and will not use it for other purposes without the written consent of the 
company. 
8.4 
Study Documentation 
8.4.1 
Case Report Forms 
Clinical data will be entered onto eCRFs for transmission to the Sponsor. Data on eCRFs 
transmitted via the web-based EDC system must correspond to and be supported by source 
documentation maintained at the study centre. All eCRFs and records transmitted to the 
Sponsor must carry only coded identifiers such that personally identifying information is not 
transmitted. Access to the EDC system is available to authorised users via the study’s Internet 
web site, where an assigned username and password are required for access. 
Any changes made to data after collection will be made through the use of Data Clarification 
Forms.  Data reported on the eCRFs, which are derived from source documents, should be 
consistent with the source documents or the discrepancies should be explained.  Electronic 
case report forms will be considered complete when all missing and/or incorrect data have 
been resolved. An audit trail of all changes that are made to the database, including the reason 
for the data change, will be created and maintained. 
The assessments (RSS, RMS, ASS) captured in the eDiary will be used for efficacy analyses.  
Assessments captured in the pDiary (productivity, lost work/school days, additional 
doctor/clinic visit, home environment changes, recording of AEs, recording of concomitant 
medications) will be entered on the eCRF by the Investigator or designee. The pDiary cards 
must be retained in the Investigator Site File. 
The Investigator will keep a copy of the eCRFs, the Investigator’s Site File and source 
documents until notified otherwise by Circassia. 
8.4.2 
Investigator Site File 
The Investigator Site File must be kept up to date and ready for inspection / audit at any time. 


 
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8.4.3 
Study Drug Accountability Records 
Detailed Drug Accountability Records must be generated and maintained for each shipment 
and subject. 
The Investigator or their designee will be responsible for documenting the use of each pack 
of the study medication, including details of the study packs used for each subject, in the 
Drug Accountability Records. Periodically during the conduct of the study, Drug 
Accountability Records will be inspected by the Study Monitor. 
All Drug Accountability Records and temperature logs must be maintained securely in the 
Pharmacy.  At the end of the study the Pharmacy records must be transferred to the 
Investigator to archive within the Investigator Site File. 
8.4.4 
Record Retention 
Study records and source documents need to be preserved for at least 15 years after the 
completion or discontinuation of the study or 2 years after the last approval of a marketing 
application in an ICH region, whichever is the longer time period.  Records will be retained 
for longer time periods than specified above if required by any regulatory authority. No 
records must be destroyed without the prior permission of Circassia. 
8.4.5 
Source Documentation 
The Investigator agrees to permit study-related monitoring, audits, IRB/IEC review and 
regulatory inspections of the study centre and any source documentation, by clinical research 
and audit personnel from the Sponsor or designee or representatives of regulatory authorities. 
Direct access to the subject’s medical/clinical records (if applicable to the study) is necessary 
to verify and corroborate the data recorded on the eCRFs. This procedure is termed Source 
Document Verification.  These third parties are obligated to maintain confidentiality of the 
subjects’ identities. 
8.5 
Publication 
Circassia intends to publish the results of this study, whether positive or negative, in line with 
the guidance in the Declaration of Helsinki (Part B, No 26). The Investigator and Circassia 
will normally prepare a manuscript together. To avoid disclosures that may affect the 
proprietary rights of the Sponsor, the Investigator agrees to allow Circassia the opportunity to 
review all manuscripts and abstracts 60 days prior to submission for publication. Circassia 
reserves the right to include the report of this study in any regulatory documentation or 
submission or in any informational materials. 


 
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8.6 
Non-Protocol Research 
No investigational research procedures pertaining to this study other than those outlined in 
this protocol may be undertaken on the subjects without the prior written permission of the 
subject, the Sponsor, the IRB/IEC and, when necessary, the appropriate competent authority. 


 
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9.0 SPONSOR RESPONSIBILITIES 
 
9.1 
General 
Circassia agrees to adhere to the most current version of ICH E6 Guidelines on GCP. 
Circassia has a legal responsibility to report fully to regulatory authorities the results of this 
study. 
9.2 
No Fault Compensation and Indemnity 
Circassia will provide “no-fault” compensation insurance against any injury incurred by a 
subject as a result of participation in the study. Circassia adheres to the ABPI “Clinical Trial 
Compensation Guidelines” (1991). The Investigators in this study will be indemnified as 
detailed in a separate document. 
9.3 
Monitoring 
The study staff may not enter any subjects into the study prior to completion of a pre-study 
initiation meeting conducted by a representative of Circassia or designee. 
Monitoring during the study will be undertaken at regular intervals by suitably qualified and 
appropriately trained personnel under contract to Circassia according to SOPs. The purpose 
of monitoring is to ensure: 
 Compliance with the protocol; 
 Adherence to regulatory and GCP obligations; 
 Proper maintenance of all study documentation; 
 The completeness and exactness of the data entered in the eCRFs; 
 Accurate reporting of all AEs; 
 Close liaison with the Investigator and study staff to clarify any problems that may 
arise during the study. 
9.4 
Confidentiality 
Neither Circassia nor its designee(s) will keep any material on file referring to the study 
subject by their full name. The identity of the subject will be respected and maintained as 
confidential at all times. 


 
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9.5 
Finance 
Financial agreements between Circassia and the CRO managing the study and the CRO 
managing the study and the Investigator will be the subject of separate agreements. 
9.6 
Audit 
Circassia may audit or appoint an independent auditor to conduct an audit of this study while 
it is running or after it has been completed. The study may also be inspected by a regulatory 
authority either while it is running or up to several years later. 


 
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10.0 DATA SAFETY MONITORING COMMITTEE 
Circassia will appoint an independent Data Safety Monitoring Committee (DSMC) to 
conduct a review of the safety data. Full details of DSMC membership, responsibilities, 
statistical analyses and data presentations to be used in the safety review will be provided in a 
DSMC Charter which will be finalised prior to the first DSMC meeting. The Charter will 
include detailed guidance to the DSMC on the circumstances under which they should 
recommend temporary or permanent stopping of the trial.  


 
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11.0 WARNINGS, PRECAUTIONS AND CONTRA-
INDICATIONS 
As with any new drug, local or systemic allergic reactions, including anaphylaxis, may occur. 
Therefore medications for the treatment of anaphylactic reactions should be available for 
immediate use following administration of treatment (see Section 5.8.2). Subjects should be 
informed that such reactions are possible and prompt medical attention should be sought if 
allergic reactions occur. 
It is possible that subjects may experience injection site reactions, including injection site 
pain, swelling, erythema and pruritus. Intradermal injection may also cause bruising or 
bleeding. 
Blood sampling may result in bruising at the site of needle insertion and fainting. 
Asthmatic reactions following administration of other SPIRE treatments (e.g. Cat-PAD) have 
been found to be uncommon and all have appeared to resolve with the use of short-acting 
2 agonists. 
Concomitant use of beta-blockers, alpha-adrenoceptor blockers and monoamine oxidase 
inhibitors during Screening and Study Medication Administration is contraindicated and 
subjects using any of the above during these periods will be withdrawn from the study. 
 


 
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12.0 REFERENCES 
Alvarez-Cuesta E., Bousquet J., Canonica G.W., Durham S.R., Malling H.J., Valovirta E 
2006. EAACI Immunotherapy Task Force. Standards for practical allergen-specific 
immunotherapy. Allergy 61 Suppl. 82, 1-20. 
Arbes S.J. Jr, Gergen P.J., Elliott L., Zeldin D.C. 2005. Prevalences of positive skin test 
responses to 10 common allergens in the US population: results from the third National 
Health and Nutrition Examination Survey. J Allergy Clin Immunol 116, 377-383. 
Brożek J.L., Bousquet J., Baena-Cagnani C.E, Bonini S.,  Canonica G.W., Casale T.B., et al. 
2010. Allergic Rhinitis and its Impact on Asthma (ARIA) Guidelines. J Allergy Clin 
Immunol. 126:466-76. 
Bergmann K.C., Demoly, P., Worm, M., Fokkens W.J., Carrillo T., Tabar A.I. et al. 2013. 
Efficacy and safety of sublingual tablets of house dust mite allergen extracts in adults with 
allergic rhinitis. J Allergy Clin Immunol (Article in Press). 
Canonica G.W., Baena-Cagnani C.E., Bousquet J., Bousquet P.J., Lockey R.F., Malling H.J. 
et al 2007. Recommendations for standardization of clinical trials with Allergen Specific 
Immunotherapy for respiratory allergy.  A statement of a World Allergy Organization 
(WAO) taskforce.  Allergy, 62, 317-324. 
CHMP/EWP/18504/2006 Guideline on the Clinical Development of Products for Specific 
Immunotherapy for the Treatment of Allergic Diseases. (2008) 
Circassia, TH001 Clinical Study Report - An escalating, multiple-dose study in house dust 
mite allergic subjects to assess the safety of intradermal injection of ToleroMune HDM. 
2011. 
Circassia, TH002 Clinical Study Report - A double-blind, randomised, placebo-controlled 
study to evaluate three doses of ToleroMune HDM in house dust mite allergic subjects 
following challenge with house dust mite allergen in an environmental exposure chamber. 
2013. 
Circassia, TH003 Clinical Study Protocol – A Field Study to Observe Symptom Scores and 
Allergy Medication Usage in Subjects with a History of House Dust Mite-Induced 
Rhinoconjunctivitis. 2013. 
Circassia, TH004 Clinical Study Protocol – A Multi-Centre, Double-Blind, Randomised, 
Placebo-Controlled, Parallel-Group Study to Assess the Tolerability of ToleroMune House 


 
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Dust Mite in Subjects with Controlled Asthma and House Dust Mite-Induced 
Rhinoconjunctivitis. 2013 
Clark J. and Schall R. 2007. Assessment of combined symptom and medication scores for 
rhinoconjunctivitis immunotherapy clinical trials. Allergy 62, 1023-1028. 
Cox L., Larenas-Linnemann D., Lockey R.F., Passalacqua G. 2010. Speaking the same 
language: The World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction 
Grading System. J Allergy Clin Immunol 125, 569-574. 
Didier A., Melac, M., Montagut A., Lhéritier-Barrand M., Tabar A., Worm M. 2009. 
Agreement of efficacy assessments for five-grass pollen sublingual tablet immunotherapy. 
Allergy; 64:166-171. 
Global Initiative for Asthma (GINA) Guidance 2012. http://www.ginasthma.org. 
Gruchalla R.S., Pongracic J., Plaut M., Evans R., Visness C.M., Walter M.et al,. 2005. Inner 
City Asthma Study: relationships among sensitivity, allergen exposure and asthma morbidity. 
J Allergy Clin Immunol 115, 478-485. 
Guidance for Industry – Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials. FDA. Center for Biologics Evaluation and 
Research. September 2007. 
Linehan M.F., Hazell M.L., Frank P.I., Francis H.C., Niven R.M., Frank T.L. 2006. 
Respiratory symptoms and risk factors in children in Manchester UK. Eur Respir Soc 
Meeting Abstract P1402: 238s. 
Resuscitation Council United Kingdom [UK], 2008 and Anaphylaxis Emergency Action 
Plan. http://www.resus.org.uk/pages/anaalgo.pdf 
World Allergy Organization White Book. 2011. Chapter 2. 


 
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13.0 APPENDICES 
 
APPENDIX 1 
GINA Report 2012– Levels of Asthma Control 
(www.ginasthma.org) 
 
 


 
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A. Assessment of current clinical control (preferably over 4 weeks) 
Characteristic 
Controlled  
(All of the 
following) 
Partly Controlled 
(Any measure present) 
Uncontrolled 
Daytime symptoms 
None (twice 
or less/week) 
More than twice/week 
Three or more 
features of partly 
controlled asthma*†  
Limitations of activities 
None 
Any 
 
Nocturnal 
symptoms/awakening 
None 
Any 
 
Need for reliever/rescue 
treatment 
None (twice 
or less/week) 
More than twice/week 
 
Lung function (Peak 
Expiratory Flow or 
FEV1)‡ 
Normal 
< 80% predicted or personal best 
(if known) 
 
B. Assessment of Future Risk (risk of exacerbation, instability, rapid decline in lung function, 
side-effects) 
Features that are associated with increased risk of AEs in the future include: 
Poor clinical control, frequent exacerbations in the past year*, admission to critical care for asthma, low 
FEV1, exposure to cigarette smoke, high dose medications. 
*  Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate. 
†  By definition, an exacerbation in any week makes that an uncontrolled asthma week. 
‡  Without administration of bronchodilator 
Lung function is not a reliable test for children 5 years and younger. 


 
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APPENDIX 2 
Anaphylaxis Algorithms 
 


 
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Appendix 3  
Rescue Medication Package Description and Rescue Medication 
Plan 
The “Rescue Medication Package” is a package of medications that you may use during the 
period you are scoring your symptoms on the eDiary to relieve any troublesome allergy 
symptoms that you may experience.  The study doctor will give you the “Rescue Medication 
Package” and will explain when and how to use each type of medication.  The Package will 
include the following allergy medications: 
Rescue Medications for Allergy Symptoms (Rhinoconjunctivitis) 
Step 
Rescue Medication 
Dosing Instruction 
1 
Anti-Histamine Eye Drops  
1 drop in each affected eye a maximum of 
twice a day 
2 
Anti-Histamine Tablets  
Maximum of 1 tablet a day 
3 
Steroid Nasal Spray  
Maximum of 2 sprays (usually just one) 
in each nostril a day 
4 
Steroid Tablets  
Not included in the Rescue Medication 
Package but to be used as prescribed by 
the study doctor  
Rescue Medication Plan 
The Rescue Medication Package contains three medicines that are commonly used by doctors 
to treat allergy symptoms (rhinoconjunctivitis). You should wait until your allergy symptoms 
become troublesome before using any of the provided medication. The Rescue Medication 
Package medicines should be used as follows: 
When your allergy symptoms are mainly ocular, such as itchy, watery, or red eyes.  
If you mainly have ocular symptoms, wait until these become troublesome and then use the 
eye drops provided in the Rescue Medication Package.  If you find your ocular symptoms do 
not improve or they are still troublesome half an hour after using an eye drop take one of the 
anti-histamine tablets from the Rescue Medication Package.  
When you have nasal symptoms, such as runny nose, sneezing, blocked or itchy nose or 
when you have both nasal and non-nasal symptoms. 
If you mainly have nasal symptoms, or nasal and non-nasal symptoms, treat them by taking 
one of the anti-histamine tablets from the Rescue Medication Package.  If you find your nasal 
symptoms do not improve or they are still troublesome two hours after taking the tablet use 
the steroid nasal spray included in the Rescue Medication Package.  If you find your ocular 
symptoms do not improve or they are still troublesome at two hours after using the tablet use 
your 
anti-histamine 
eye 
drops 
included 
in 
the 
Rescue 
Medication 
Package.


 
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APPENDIX 4 
World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Symptom(s)/sign(s) of one organ system presenti 
Cutaneous 
Generalized pruritus, urticaria, flushing or 
sensation of heat or warmthii 
or 
Angioedema (not laryngeal, tongue or uvular) 
or 
Upper respiratory 
Rhinitis (e.g. sneezing, rhinorrhoea, nasal pruritus 
and/or nasal congestion) 
or 
Throat-clearing (itchy throat) 
or 
Cough perceived to come from the upper airway, 
not the lung, larynx, or trachea 
or 
Conjunctival 
Conjunctival erythema, pruritus or tearing 
Other 
Nausea, metallic taste, or headache  
Symptom(s)/sign(s) of more than one 
organ system present 
or 
Lower respiratory 
Asthma: cough, wheezing, shortness of 
breath (e.g., less than 40% PEF or FEV1 
drop, responding to an inhaled 
bronchodilator) 
 
 
or 
 
Gastrointestinal 
Abdominal cramps, vomiting, or 
diarrhoea 
or 
Other 
Uterine cramps 
Lower respiratory 
Asthma (e.g., 40% PEF or FEV1 drop, 
NOT responding to an inhaled 
bronchodilator) 
or 
Upper respiratory 
Laryngeal, uvula or tongue oedema 
with or without stridor 
Lower or Upper respiratory 
Respiratory failure with or without loss 
of consciousness 
 
or 
Cardiovascular 
Hypotension with or without loss of 
consciousness 
 
Death 
Patients may also have a feeling of impending doom, especially in Grades 2, 3, or 4. 
Note: children with anaphylaxis seldom convey a sense of impending doom and their behaviour changes may be a sign of anaphylaxis, e.g., becoming very quiet or irritable and cranky. 
 


 
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Scoring includes a suffix that denotes if and when epinephrine is or is not administered in relationship to symptom(s)/sign(s) of the systemic reaction: a, ≤5 minutes; b, >5 
minutes to ≤10 minutes; c, >10 minutes to ≤20 minutes; d, >20 minutes; z, epinephrine not administered 
The final grade of the reaction will not be determined until the event is over, regardless of the medication administered. The final report should include the first 
symptom(s)/sign(s) and the time of onset after the subcutaneous allergen immunotherapy injectioniii and a suffix reflecting if and when epinephrine was or was not 
administered, e.g., Grade 2a; rhinitis: 10 minutes. 
 
Final Report: Grade a-d, or z  
 
First symptom 
 
 
Time of onset of first symptom 
 
Commentsiv 
 
 
i. 
Each Grade is based on organ system involved and severity. Organ systems are defined as: cutaneous, conjunctival, upper respiratory, lower respiratory, gastrointestinal, 
cardiovascular and other. A reaction from a single organ system such as cutaneous, conjunctival, or upper respiratory, but not asthma, gastrointestinal, or cardiovascular is 
classified as a Grade 1. Symptom(s)/sign(s) from more than one organ system or asthma, gastrointestinal, or cardiovascular are classified as Grades 2 or 3. Respiratory 
failure or hypotension, with or without loss of consciousness, defines Grade 4 and  death Grade 5. The Grade is determined by the physician’s clinical judgment. 
ii. This constellation of symptoms may rapidly progress to a more severe reaction. 
iii. Symptoms occurring within the first minutes after the injection may be a sign of severe anaphylaxis. Mild symptoms may progress rapidly to severe anaphylaxis and death. 
iv.  If signs or symptoms are not included in the Table or the differentiation between a systemic reaction and vasovagal (vasodepressor) reaction, which may occur with any 
medical intervention, is difficult, please include comment, as appropriate. 
 
From: Cox L., Larenas-Linnemann D., Lockey R.F., Passalacqua G. (2010). Speaking the same language: The World Allergy Organization Subcutaneous 
Immunotherapy Systemic Reaction Grading System. J Allergy Clin Immunol;125:569-74 

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STATISTICAL ANALYSIS PLAN: PROTOCOL TH005 
Page 1 of 57 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
PROTOCOL: TH005 
A DOUBLE-BLIND, RANDOMISED, PLACEBO-CONTROLLED, MULTI-CENTRE 
FIELD STUDY TO ASSESS THE EFFICACY AND SAFETY OF HDM-SPIRE IN 
SUBJECTS 
WITH 
A 
HISTORY 
OF 
HOUSE 
DUST 
MITE-INDUCED 
RHINOCONJUNCTIVITIS 
AUTHOR: ROLAND KLOPPER 
VERSION NUMBER AND DATE: V2.0, 24MAR2017 
 
 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL TH005 
Page 2 of 57 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V2.0 (Dated 24MAR2017) for Protocol TH005. 
 
 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL TH005 
Page 3 of 57 
MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from Previous 
Authorized Version 
V1.0 
28SEP2016 
Roland Klopper 
Not applicable.  First version. 
V2.0 
24MAR2017 
Roland Klopper  
Added subgroup summaries to 
Disposition and Demographic sections 
Removed baseline-by-treatment 
interaction from efficacy model 
 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL TH005 
Page 4 of 57 
TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................................................................ 9 
2. 
STUDY OBJECTIVES ..................................................................................................................... 9 
2.1. 
Primary Objective ........................................................................................................................................9 
2.2. 
Secondary Objectives ..................................................................................................................................9 
2.3. 
Exploratory Objectives ................................................................................................................................9 
2.4. 
Safety Objectives ....................................................................................................................................... 10 
3. 
STUDY DESIGN ........................................................................................................................... 10 
3.1. 
General Description ................................................................................................................................... 10 
3.2. 
Sample Size Calculation ............................................................................................................................. 12 
3.3. 
Schedule of Events..................................................................................................................................... 12 
4. 
PLANNED ANALYSES ................................................................................................................ 12 
4.1. 
Data Safety Monitoring Committee (DSMC) .............................................................................................. 12 
4.2. 
Final Analysis ............................................................................................................................................. 13 
5. 
ANALYSIS POPULATIONS ....................................................................................................... 13 
5.1. 
All Subjects Enrolled [ENR] population ...................................................................................................... 13 
5.2. 
Randomised [RND] population .................................................................................................................. 13 
5.3. 
Intent to Treat [ITT] population ................................................................................................................. 13 
5.4. 
Safety [SAF] population ............................................................................................................................. 14 
5.5. 
Per Protocol [PP] population ..................................................................................................................... 14 
6. 
GENERAL CONSIDERATIONS ................................................................................................. 14 


 
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6.1. 
Reference Start Date and Study Day .......................................................................................................... 14 
6.2. 
Baseline ..................................................................................................................................................... 14 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 15 
6.4. 
Windowing Conventions ............................................................................................................................ 15 
6.5. 
Statistical Tests .......................................................................................................................................... 15 
6.6. 
Common Calculations ................................................................................................................................ 15 
6.7. 
Software Version ....................................................................................................................................... 16 
7. 
STATISTICAL CONSIDERATIONS .......................................................................................... 17 
7.1. 
Adjustments for Covariates and Factors to be Included in Efficacy Analyses ............................................. 17 
7.2. 
Multi-centre Studies .................................................................................................................................. 18 
7.3. 
Missing data .............................................................................................................................................. 18 
7.4. 
Multiple Comparisons/Multiplicity ............................................................................................................ 18 
7.5. 
Examination of Subgroups ......................................................................................................................... 19 
8. 
OUTPUT PRESENTATIONS ..................................................................................................... 19 
9. 
DISPOSITION AND WITHDRAWALS .................................................................................... 19 
10. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..................................................... 20 
10.1. 
Derivations ............................................................................................................................................ 22 
11. 
MEDICAL HISTORY ................................................................................................................... 22 
11.1. 
allergy medical history ........................................................................................................................... 23 
11.2. 
medical history other than asthma and rhinoconjunctivitis ................................................................... 23 
11.3. 
Smoking history ..................................................................................................................................... 24 
12. 
MEDICATIONS ............................................................................................................................ 24 


 
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13. 
STUDY MEDICATION EXPOSURE .......................................................................................... 25 
13.1. 
Derivations ............................................................................................................................................ 25 
14. 
STUDY MEDICATION COMPLIANCE ..................................................................................... 25 
14.1. 
Derivations ............................................................................................................................................ 26 
15. 
EFFICACY OUTCOMES .............................................................................................................. 27 
15.1. 
Primary Efficacy ..................................................................................................................................... 27 
15.1.1. 
Primary Efficacy Variable & Derivation .....................................................................................................27 
15.1.2. 
Missing Data Methods for Primary Efficacy Variable ...............................................................................28 
15.1.3. 
Primary Analysis of Primary Efficacy Variable ..........................................................................................28 
15.1.4. 
Sensitivity Analysis of Primary Efficacy Variable .......................................................................................29 
15.1.5. 
Supportive analyses of primary efficacy variable .....................................................................................30 
15.1.5.1. 
Responder Analysis ...........................................................................................................................30 
15.1.5.2. 
Treatment-by-pooled Region Interaction .........................................................................................31 
15.1.5.3. 
Alternative Combined Score Weighting ...........................................................................................31 
15.1.6. 
Normality and homogeneity of primary efficacy variable ........................................................................33 
15.2. 
Secondary Efficacy ................................................................................................................................. 33 
15.2.1. 
Secondary Efficacy Variables & Derivations .............................................................................................33 
15.2.1.1. 
Mean Total Rhinoconjunctivitis Symptom Score ..............................................................................33 
15.2.1.2. 
Mean Component Scores of Total Rhinoconjunctivitis Symptom Score ..........................................33 
15.2.1.3. 
Mean Rescue Medication Score .......................................................................................................34 
15.2.1.4. 
Clinical Global Impression of Change in Rhinoconjunctivitis Symptoms ..........................................35 
15.2.1.5. 
Proportion of Well Days ....................................................................................................................36 
15.2.1.6. 
Rhinoconjunctivitis Quality of Life Questionnaire ............................................................................36 
15.2.1.7. 
Mean Asthma Symptom Score .........................................................................................................37 
15.3. 
Other Exploratory Efficacy ..................................................................................................................... 40 
15.3.1. 
Other Exploratory Efficacy Variables & Derivations .................................................................................40 
15.3.1.1. 
Rhinoconjunctivitis Symptom Scores Measured Using Visual Analogue Scale .................................40 
15.3.1.2. 
The Pittsburgh Sleep Quality Index ...................................................................................................40 
15.3.1.3. 
Asthma Control Test .........................................................................................................................43 
15.3.1.4. 
Use of Concomitant Medications Associated with Rhinoconjunctivitis or Related Conditions ........43 
15.3.1.5. 
Home Environment Exposure and Control Measures ......................................................................44 
16. 
SAFETY OUTCOMES .................................................................................................................. 45 
16.1. 
Adverse Events ...................................................................................................................................... 45 
16.1.1. 
All TEAEs ...................................................................................................................................................46 
16.1.1.1. 
Severity .............................................................................................................................................46 


 
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16.1.1.2. 
Relationship to Study Medication.....................................................................................................46 
16.1.2. 
Serious TEAEs ............................................................................................................................................46 
16.1.3. 
TEAEs Leading to Death ............................................................................................................................46 
16.1.4. 
Life-threatening TEAEs..............................................................................................................................47 
16.1.5. 
TEAEs Leading to premature study OR treatment discontinuation ..........................................................47 
16.1.6. 
Treatment related TEAEs leading to premature treatment discontinuation ...........................................47 
16.1.7. 
TEAEs of Special Interest ..........................................................................................................................47 
16.1.8. 
TEAEs within 24 Hours of Any Dose ..........................................................................................................47 
16.2. 
Deaths ................................................................................................................................................... 47 
16.3. 
Laboratory Evaluations .......................................................................................................................... 47 
16.3.1. 
Laboratory Reference Ranges and Abnormal Criteria ..............................................................................48 
16.4. 
Vital Signs .............................................................................................................................................. 49 
16.4.1. 
Vital Signs Specific Derivations .................................................................................................................50 
16.5. 
Physical Examination ............................................................................................................................. 50 
16.6. 
Other Safety Assessments ..................................................................................................................... 50 
16.6.1. 
Forced expiratory volume in 1 second (FEV1) ...........................................................................................50 
16.6.2. 
Local reaction at injection site ..................................................................................................................51 
16.6.3. 
Pregnancy .................................................................................................................................................51 
17. 
REFERENCES ............................................................................................................................... 52 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS ........................................... 52 
Dates & Times ....................................................................................................................................................... 52 
Spelling Format ..................................................................................................................................................... 52 
Univariate Statistics .............................................................................................................................................. 52 
Frequencies and percentages (n and %): ............................................................................................................... 52 
Presentation of Treatment Groups ....................................................................................................................... 54 
Presentation of Visits ............................................................................................................................................ 54 
Listings .................................................................................................................................................................. 54 
APPENDIX 2. PARTIAL DATE CONVENTIONS .......................................................................... 55 
Algorithm for Treatment Emergence of Adverse Events: ...................................................................................... 55 


 
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Algorithm for Prior / Concomitant Medications: ................................................................................................... 55 
APPENDIX 3. COMPLETE QUESTIONNAIRES ............................................................................ 56 
 
 


 
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Page 9 of 57 
1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy and 
safety data for Protocol TH005. It describes the data to be summarised and analysed, including specifics of the 
statistical analyses to be performed.  
This Statistical Analysis Plan (SAP) is based on Protocol version 4.0 dated 01 April 2015. 
The rules, conventions and output presentations used for the Data Safety Monitoring Committee (DSMC) are set 
out in a separate DSMC SAP.  
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective is to evaluate the efficacy of House Dust Mite (HDM) Synthetic Peptide Immuno-
Regulatory Epitopes (HDM-SPIRE) in the reduction of symptoms and the use of allergy rescue medication 
associated with HDM allergy in subjects with clinically relevant symptoms. 
2.2. SECONDARY OBJECTIVES 
The secondary objectives are: 
 
To evaluate the safety and tolerability of HDM-SPIRE 
 
To evaluate the effect of HDM-SPIRE on rhinoconjunctivitis-specific quality of life using the rhinoconjunctivitis 
quality of life questionnaire (RQLQ) 
 
To evaluate the effect of HDM-SPIRE on sleep quality using the Pittsburgh Sleep Quality Index (PSQI) 
2.3. 
 EXPLORATORY OBJECTIVES 
The exploratory objectives are: 
 
To evaluate the effect of HDM-SPIRE on rhinoconjunctivitis symptom scores measured using a visual analogue 
scale (VAS) during the baseline allergy evaluation (BAE) period and each post-administration collection (PAC) 
period 
 
To evaluate the effect on mean combined score (CS) in the HDM-SPIRE treatment groups compared with 
placebo during PAC1 and PAC2 periods 


 
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 
To evaluate the effect on mean total rhinoconjunctivitis symptom score (TRSS) in the HDM-SPIRE treatment 
groups compared with placebo during PAC1 and PAC2 periods 
 
To evaluate the effect on mean rescue medication score (RMS) in the HDM-SPIRE treatment groups compared 
with placebo during PAC1 and PAC2 periods 
 
To evaluate the effect on mean component scores of the TRSS (nasal and non-nasal) in the HDM-SPIRE 
treatment groups compared with placebo during the PAC1 and PAC2 periods 
 
To evaluate the effect on overall RQLQ score in the HDM-SPIRE treatment groups compared with placebo at 
the end of the PAC1 and PAC2 periods 
 
To evaluate the effect on sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI) for the HDM-
SPIRE treatment groups compared with placebo at the end of the PAC1 and PAC2 periods 
 
To evaluate the effect on asthma control for asthmatic subjects at the end of the BAE, PAC1, PAC2 and PAC3 
periods 
 
To evaluate subject’s home environment and exposure to allergens 
2.4. SAFETY OBJECTIVES 
The safety and tolerability of HDM-SPIRE is to be assessed by the recording of: 
 
Adverse Events (AEs) 
 
Physical examination 
 
Vital signs 
 
Laboratory values (haematology, serum biochemistry, urine tests, immunology tests) 
 
Forced expiratory volume in 1 second (FEV1) 
 
Local reactions at the injection site 
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is a randomised, double-blind, placebo-controlled, parallel group, multi-centre field assessment of three 
dose regimens of HDM-SPIRE administered at 4 weekly intervals for 28 weeks. 


 
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A total of approximately 660 subjects are to be randomised into the study, with approximately 165 subjects in 
each of the three HDM-SPIRE treatment groups and 165 in the placebo group. 
Subjects are to attend the investigative centre for screening.  Subjects meeting the inclusion/exclusion criteria 
are to be randomised to either one of the following three active treatment groups or the placebo group in a 
1:1:1:1 ratio:  
 
8 x placebo, 4 weeks apart (placebo) 
 
4 x 12 nmol HDM-SPIRE followed by 4 x placebo, 4 weeks apart  
 
4 x 20 nmol HDM-SPIRE followed by 4 x placebo, 4 weeks apart  
 
8 x 12 nmol HDM-SPIRE 4 weeks apart  
Following randomisation a total of 8 doses of HDM-SPIRE or placebo are to be administered at the investigative 
centre, one dose every 4 weeks (±2 days), for a total duration of 28 weeks as shown in the Table 1 below:  
 
Table 1: Dosing Schedule 
Visit 
3A 
3B  
3C  
3D  
3E 
3F 
3G 
3H 
Week (± 2 days) 
0 
4 
8 
12 
16 
20 
24 
28 
Treatment Group 
Placebo 
P 
P 
P 
P 
P 
P 
P 
P 
HDM-SPIRE 4 x 12 nmol 
X 
X 
X 
X 
P 
P 
P 
P 
HDM-SPIRE 4 x 20 nmol 
X 
X 
X 
X 
P 
P 
P 
P 
HDM-SPIRE 8 x 12 nmol 
X 
X 
X 
X 
X 
X 
X 
X 
X = HDM-SPIRE doses, P = Placebo doses. 
 
Subjects are to complete an electronic diary (eDiary) during the following four periods for efficacy evaluation:  
 
Baseline allergy evaluation (BAE) 
Subjects are to record Baseline Rhinoconjunctivitis symptom scores (RSS) and rescue medication score (RMS) in 
an eDiary during a period of approximately 3 weeks prior to randomisation.  
The RSS and RMS assigned to the BAE period for a subject is to be taken as all scores entered on the subject’s 
eDiary dated from the date of Visit 2A up to and including the date of Visit 2B.  
 
Post-administration collection period 1 (PAC1) 
Subjects are to record RSS and RMS during weeks 18 to 20 after first administration of study medication.   
The RSS and RMS assigned to the PAC1 period for a subject is to be taken as all scores entered on the subject’s 
eDiary dated from the date of Visit 4A up to the date of Visit 4C - 1.  
 
Post- administration collection period 2 (PAC2) 
Subjects are to record RSS and RMS during weeks 37 to 39 after first administration of study medication. 


 
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The RSS and RMS assigned to the PAC2 period for a subject is to be taken as all scores entered on the subject’s 
eDiary dated from the date of Visit 4C up to the date of Visit 4E - 1.  
 
Post-administration collection period 3 (PAC3) 
Subjects are to record RSS and RMS during weeks 50 to 52 after first administration of study medication.  
The RSS and RMS assigned to the PAC3 period for a subject is to be taken as all scores entered on the subject’s 
eDiary dated from the date of Visit 4E up to and including the date of the last subject visit date.  
The duration (days) of the BAE, PAC1, PAC2 and PAC3 periods are defined by the Visit dates specified above. At 
approximately 52 weeks post first administration of study medication, subjects are to undergo a final safety 
assessment. The total duration of the study for each subject will be approximately 62 weeks.  
3.2. SAMPLE SIZE CALCULATION 
The study is to recruit approximately 660 subjects (approximately 165 per treatment group). Based on the data 
from observational study TH003, if a mean CS of 1.6 is observed for the placebo group, and a mean CS of 1.28 for 
the active group, the expected treatment difference of 0.32 is to be a 20% improvement from placebo. The 
statistical model is to include the baseline CS as a covariate, taking this into account a standard deviation of 
0.986 is assumed, so that a sample of 150 patients is to have 80% power to detect a statistically significant 
difference in treatment. 
3.3. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 6.1 Schedule of Assessments of the Protocol. 
4. PLANNED ANALYSES 
The following analyses are to be performed for this study: 
 
Analyses for DSMC meetings 
 
Final analysis  
4.1. DATA SAFETY MONITORING COMMITTEE (DSMC)  
A Data Safety Monitoring Committee (DSMC) SAP, describing the methodology and presentation of results and 
access to results is to be provided by Quintiles Biostatistics as a separate document. 


 
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4.2. FINAL ANALYSIS  
The final, planned analysis identified in this SAP is to be performed by Quintiles Biostatistics following: 
 
Sponsor authorization of this SAP and output shells 
 
Sponsor authorization of analysis populations   
 
Database lock (100% cleaned data with no outstanding data queries) 
 
Routine study unblinding  
5. ANALYSIS POPULATIONS 
Prior to the locking of the database, agreement of subjects’ assignment to each of the analysis populations and 
identification of major protocol deviations are to be determined in collaboration with Circassia at a blind data 
review (BDR) meeting. The authorisation of analysis sets is required prior to the final locking of the database and 
routine study unblinding. 
The analysis populations below are described in detail in the latest version of the BDR plan, including the criteria 
to be used in defining each of these analysis populations.  
5.1. ALL SUBJECTS ENROLLED [ENR] POPULATION 
The Enrolled [ENR] population is to consist of all subjects that signed informed consent.  
5.2. RANDOMISED [RND] POPULATION 
The Randomised (RND) population is to consist of all subjects in the ENR population who passed both the 
Screening assessments and the BAE period and are subsequently randomised to study medication.  
5.3. INTENT TO TREAT [ITT] POPULATION 
The Intent to Treat (ITT) population is to consist of all subjects who are randomised, who have received at least 
one dose of study medication. Subjects are to be reported by the treatment they were randomised to. The ITT is 
the primary population for the study and all the primary and secondary efficacy analyses are to be based on the 
ITT population. 


 
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5.4. SAFETY [SAF] POPULATION 
The Safety (SAF) population is to consist of all subjects that received at least one dose of study medication (HDM-
SPIRE or placebo) and have at least one post-baseline safety assessment available. Subjects are to be reported by 
the treatment they actually received. The Safety population is to be used for all of the safety endpoints.  
5.5. PER PROTOCOL [PP] POPULATION 
The Per Protocol (PP) population is to consist of all subjects in the ITT population who have no major protocol 
deviations likely to affect the integrity of the study and who completed all study visits. Allocation of subjects to the 
PP population and all protocol deviations are to be fully documented in the BDR report. The PP population is to be 
evaluated for the primary variable to confirm results from the ITT population. Subjects are to be reported by the 
treatment they were randomised to.  
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Study Day is to be calculated from the reference start date, and is to be used to show start/stop day of 
assessments and events.  
Reference start date is defined as the day of the first administration of study medication, (Day 1 is the day of the 
first administration of study medication), and is to appear in every listing where an assessment date or event 
date appears.  
 
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1. 
 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, Study Day, and any corresponding durations are to 
appear partial or missing in the listings. 
6.2. BASELINE 
For all safety variables, unless otherwise specified, Baseline is defined as the last non-missing measurement 
taken prior to reference start date (including unscheduled assessments or retests). In the case where the last 
non-missing measurement and the reference start date coincide, that measurement is to be considered pre-
baseline, but AEs and medications commencing on the reference start date are to be considered post-baseline. 


 
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Page 15 of 57 
For all efficacy variables Baseline is defined as the measurement taken during the BAE period prior to reference 
start date.  
6.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit is to be presented. Unscheduled 
measurements are not to be included in by-visit summaries, but may contribute to the Baseline value.  
In the case of a retest at any post Baseline visit (same visit number assigned but a different date and/or time of 
assessment), the first measurement (original value) for that visit is to be used for by-visit summaries.  
Listings are to include scheduled, unscheduled, retest and early discontinuation data. 
6.4. WINDOWING CONVENTIONS  
Windows for PAC1, PAC2 and PAC3 are to the applied based on scheduled visit dates as defined in Section 3.1 
General Description.  
For inclusion in the PP population a window is to be defined for the PAC3 period only. The window start date is 
defined as the planned Visit 4E date ± 10 days, relative to the Visit 3A date (Baseline), that is, 50 weeks after the 
Baseline date ± 10 days. Similarly, the window end date is defined as the planned Visit 4F date ± 10 days, that is, 
52 weeks after the Baseline date ± 10 days.  
Any subjects for whom being out of window doesn’t affect whether or not their symptoms might have been 
confounded with seasonal allergies are also to be included. For this latter category, a review is to be done 
manually by Circassia. 
Review of the PAC3 windows and decisions regarding inclusion/exclusion form the PP population is to be 
documented in the BDR meeting minutes.  
6.5. STATISTICAL TESTS 
The default significance level is to be 5%; confidence intervals are to be 95% and all tests are to be two-sided, 
unless otherwise specified in the description of the analyses. 
6.6. COMMON CALCULATIONS 
For quantitative measurements: 
 
Change from Baseline is to be calculated as 
o 
Test Value at Visit X – Baseline Value 
 
 


 
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 
Percentage change from Baseline is to be calculated as 
o 
[(Test Value at Visit X – Baseline Value) / Baseline Value] x 100  
 
Descriptive statistics are to include n, mean, standard deviation (SD), median, minimum and maximum 
For qualitative measurements (e.g. Gender): 
 
Summaries are to include frequency (n) and percentage (%) of subjects. Percentages are to be calculated as 
either 
o 
The number of subjects within a category relative to the total number of subjects in the relevant analysis 
population with data available. In this case a missing category is to be added to indicate the number of 
subjects with no data and the missing counts are not to be included in the denominator for the percentage 
calculation, or  
o 
The number of subjects in a category relative to the total number of subjects in the relevant analysis 
population 
The applicable method of percentage calculation is indicated in each relevant analysis section.  
6.7. SOFTWARE VERSION 
All analyses are to be conducted using SAS Version 9.4 or higher.  
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL TH005 
Page 17 of 57 
7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN EFFICACY 
ANALYSES 
The following covariates and factors are to be used in the analyses. For details of their inclusion in the models, 
see the specific analysis section. 
 
Study period  
o 
PAC1 
o 
PAC2 
o 
PAC3 
 
Pooled region as finalised prior to the analysis during the BDR meeting 
o 
Pooled Region 01 
o 
Pooled Region 02 
o 
Pooled Region 03 
o 
Pooled Region 04 
o 
Pooled Region 05 
o 
Pooled Region 06 
o 
Pooled Region 07 
o 
Pooled Region 08 
 
 
Gender as captured on the Demographics eCRF (DEM) 
o 
Male 
o 
Female 
 
Asthma status as captured on the Asthma Diagnosis eCRF (ASTHMASCR) 
o 
No asthma  
o 
Controlled  
o 
Partly/Uncontrolled  
 
Baseline score 
o 
Represents the Baseline value of the relevant score being analysed from the BAE period 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL TH005 
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7.2. MULTI-CENTRE STUDIES 
This study is to be conducted by multiple investigators at multiple centres internationally. Randomisation to 
treatment groups is not stratified by country/centre. 
If a region has less than 5 subjects, pooling with other centre(s) is to be performed based on geographical region 
of the centres, providing the combination of data from small centres within a geographic region does not create 
a disproportionately large combined region. Distribution of subjects across pooled regions is to be assessed and 
pooling criteria finalised during the BDR meeting. 
7.3. MISSING DATA 
Missing safety data is not to be imputed. Partial start/stop dates for concomitant medications and AEs are not to 
be imputed. Treatment emergence of AEs and study period of medication use (prior or concomitant) is to be 
assigned based on available information as described in Appendix 2: Partial Date Conventions.  
Daily derived efficacy scores (such as TRSS and CS) may be missing and will not be imputed as explained in 
Section 15.1.1 Primary Efficacy Variable & Derivation and Section 15.2.1 Secondary Efficacy Variables & 
Derivations. 
Means of all derived daily efficacy scores during BAE, PAC1, PAC2 and PAC3 are to be calculated based on all days 
with non-missing scores within the respective periods defined in Section 3.1 General Description.  
The primary efficacy analysis is to be performed using all available data on the assumption that the probability of 
missing observations is independent of unobserved measurements (missing at random). Therefore the missing 
values are not to be imputed for the primary analysis.  
A Pattern-mixture model based on control-based imputation is to be utilised as the sensitivity analysis of the 
primary efficacy variable as described in Section 15.1.4 Sensitivity Analysis of Primary Efficacy Variable. 
7.4. MULTIPLE COMPARISONS/MULTIPLICITY 
For the primary efficacy analysis a hierarchical (step-down) approach is to be used to control the overall Type I 
error rate at 5%. 
For declaring statistical significance, a step-down approach ( first 4 x 12 nmol versus placebo, then 4 x 20 nmol 
versus placebo and then 8 x 12 nmol versus placebo) is to be used to control the overall Type I error at 0.05.  
Thus: 
 
Step 1: If 4 x 12 nmol HDM-SPIRE versus placebo is significantly different at the 0.05 significance level, move to 
Step 2. If there is no statistical significance, no further statistical significance is to be declared 
 
Step 2: If 4 x 20 nmol HDM-SPIRE  versus placebo is significantly different at the 0.05 significance level, move to 
Step 3. If there is no statistical significance, no further statistical significance is to be declared 


 
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 
Step 3: If 8 x 12 nmol HDM-SPIRE versus placebo is significantly different at the 0.05 significance level, declare 
statistical significance. 
Statistical significance is declared for each step individually if p<0.05 and overall statistical significance is to be 
declared if Step 1, Step 2 and Step 3 has p<0.05.  
 
7.5. EXAMINATION OF SUBGROUPS 
A treatment-by-pooled region interaction is to be added to the primary efficacy analysis as a supportive analysis 
as described in Section 15.1.5.2 Treatment-by-pooled region Interaction. In the event that the treatment-by-
pooled region interaction term is observed to be statistically significant (p<0.10), the primary efficacy analysis as 
described in Section 15.1.3 Primary Analysis of Primary Efficacy Variable is to be analysed in subgroups of pooled 
region. Additionally, Baseline and Demographic Characteristics are to be summarised in subgroups of pooled 
region (see Section 10 Demographic and Baseline Characteristics).   
8. OUTPUT PRESENTATIONS 
The templates provided with this SAP describe the planned presentations for this study and therefore the format 
and content of the summary tables, figures and listings to be provided by Quintiles Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
Disposition and withdrawals are to be summarised for the ENR population.  
Additionally, disposition and withdrawal summaries are to be presented for the following subgroups: 
 
Asthma status (Absent/Present/Missing) as captured on the Randomization eCRF (RAND) 
o 
Where Controlled and Partly/Uncontrolled are categorised as Present and 
o 
No Asthma is categorised as Absent 
 
TRSS categorised as TRSS <16, TRSS ≥ 16 or Missing as captured on the Randomization eCRF (RAND) 
The frequency (n) and percentage (%) of the following disposition and withdrawal categories are to be reported: 
 
Subjects screened 
 
Screen failures, defined as subjects where the Study Entry eCRF completed at the Screening visit indicates 
screening was not passed 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL TH005 
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 
Subjects that initially failed Screening may have been re-screened for eligibility following modifications to 
eligibility criteria in protocol amendments. Re-screened subjects are to be provided with a new Screening 
number and a link to the previous Screening number is to be captured on the Rescreening Status eCRF. Re-
screened subjects that pass Screening are not to be counted as screen failures under their previous Screening 
numbers and are only to be accounted for once using the newly assigned Screening number and status.  
 
BAE failures, defined as subjects where the Study Entry eCRF (SENTRY) completed at the end of the BAE period 
indicates that the BAE period was not passed 
 
Randomised subjects, as indicated on the Randomisation eCRF (RAND). Subjects are to be eligible for 
randomisation if they passed both Screening as well as BAE.  
 
Completed study medication, early withdrawal from treatment period as well as primary reason for 
termination of study medication as entered on the End of Treatment eCRF (EOT) 
o 
Completed study medication is defined as receiving 8 doses of study medication from Visit 3A to Visit 3H 
 
Completed the study, early withdrawal from the study as well as primary reason for early withdrawal from the 
study as entered on the End of Study eCRF (EOS) 
Completed the study is defined as completing the Follow-up Period (Visit 5) without prior early withdrawal from 
the study as indicated on the End of Study eCRF (EOS), regardless of completion of study medication as indicated 
on the End of Treatment eCRF (EOT). The frequency (n) and percentage (%) of subjects assigned to each analysis 
population is to be provided for the Randomized, ITT, PP and SAF populations, as well the reasons for exclusion 
from each population.  
Percentages are to be calculated relative to the total number of subjects in the analysis population.  
The following listings are planned for presentation: 
 
Subjects screening status (ENR population) 
o 
Includes eligibility criteria and inclusion/exclusion criteria exceptions 
 
Subject disposition (RND population) 
 
Analysis population assignment (ENR population) 
 
Major protocol deviations (RND population) 
10. DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic data and Baseline characteristics are to be presented for the ITT population. 
Additionally, demographic and baseline  summaries are to be presented for the following subgroups: 
 
Asthma status (Absent/Present/Missing) as captured on the Randomization eCRF (RAND) 


 
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o 
Where Controlled and Partly/Uncontrolled are categorised as Present and 
o 
No Asthma is categorised as Absent 
 
TRSS categorised as TRSS <16, TRSS ≥ 16 or Missing as captured on the Randomization eCRF (RAND) 
 
Pooled region 01 to pooled region 08 as determined at the BDR meeting and documented in the BDR report 
No statistical testing is to be performed for demographic or other Baseline characteristics. 
Continuous demographic and Baseline characteristic variables (e.g. Age) are to be summarised using descriptive 
statistics. Categorical variables (e.g. Gender) are to be summarised by frequency (n) and percentage (%). 
Percentages are to be calculated relative to the total number of subjects in the analysis population with data 
available.  
The following demographic and Baseline characteristics are to be reported for this study: 
 
Age (years) relative to date of informed consent is to be calculated using the following SAS code 
o 
Age = int((intck(‘month’ , <date of birth> , <date of informed consent> - (day(<date of informed consent>) 
< day(date of birth>))) / 12) 
o 
In the event that the date of birth is incomplete, the age at informed consent is to be imputed using the 
age as captured on the Randomisation eCRF  
 
Age group  
o 
18 to 49 
o 
50 to 70 
 
Gender from the System Screening eCRF (SCR) 
o 
Male  
o 
Female 
 
 
Race from the Demographics eCRF (DEM) 
o 
White 
o 
Black or African American 
o 
Asian 
o 
American Indian or Alaska Native 
o 
Native Hawaiian or other Pacific Islander 
o 
Not Collected 
o 
Other 
 
Ethnicity from the Demographics eCRF (DEM) 
o 
Hispanic or Latino 
o 
Not Hispanic or Latino 
o 
Not Reported 


 
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o 
Unknown 
 
 
Height (cm) from the Vital Signs eCRF (VS) at the Screening visit 
 
Weight (kg) from the Vital Signs eCRF (VS) at the Screening visit 
 
Body mass index (BMI) (kg/m2) 
 
History of asthma from the Asthma Diagnosis eCRF (ASTHMASCR) 
o 
Yes 
o 
No 
 
Asthma status from the Asthma Diagnosis eCRF (ASTHMASCR) 
o 
No Asthma 
o 
Controlled 
o 
Partly/Uncontrolled 
 
Asthma relationship to exposure to allergens from the Asthma Diagnosis eCRF (ASTHMASCR) 
o 
No Relationship 
o 
To HDM 
o 
To Other Allergens 
 
Demographic and Baseline characteristics are to be listed.  
10.1. DERIVATIONS 
Height is to be converted from inches (in) to cm as follows: 
 
Height (cm) = Height (in) x 2.54 
 
Weight is to be converted from lbs to kgs as follows: 
 
Weight (kg) = Weight (lb) x 0.453592 
BMI is to be calculated as: 
 
BMI (kg/m2) = Weight (kg) / [Height (cm) ÷ 100)]2 
11. MEDICAL HISTORY 
Medical History conditions are to be presented for the ITT population.  


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL TH005 
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11.1. ALLERGY MEDICAL HISTORY 
Allergy medical history includes all medical history conditions reported on the Allergy Medical History eCRF 
(AMHX). 
The frequency (n) and percentage (%) of the following allergies are to be presented:  
 
House dust mite 
 
Cat 
 
Animal dander (other than cat) 
 
Cockroach 
 
Other additional allergies indigenous to a subject’s area, under the following categories 
o 
Other dust mites 
o 
Mould  
o 
Grass 
o 
Weed 
o 
Tree 
o 
Animal dander 
o 
Other 
 
Allergies specified as ‘Other’ category for ‘Other additional allergies indigenous to the subject’s geographic area’ 
are only to be listed. 
Percentages are to be calculated relative to the total number of subjects in the analysis population.  
11.2. MEDICAL HISTORY OTHER THAN ASTHMA AND RHINOCONJUNCTIVITIS 
Medical history other than asthma and Rhinoconjunctivitis includes all conditions captured on the Medical 
History – Other than Asthma and Rhinoconjunctivitis eCRF (MHX). 
Medical history other than asthma and Rhinoconjunctivitis is to be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) Version 19.0 
The frequency (n) and percentage (%) of conditions is to be presented by System Organ Class (SOC) and 
Preferred Term (PT). The summary is to be sorted by descending total frequency for each SOC, and within each 
SOC by the descending total frequency per PT. 
Percentages are to be calculated relative to the total number of subjects in the analysis population.  


 
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11.3. SMOKING HISTORY 
The frequency (n) and (%) of subjects within the following categories are to be presented for the ITT population 
as captured on the Smoking History eCRF (SMOK).  
 
Current smokers 
 
Former smokers 
 
Have never smoked 
Percentages are to be calculated relative to the total number of subjects in the analysis population with data 
available.  
Descriptive statistics are to be presented for the following categories captured on the Smoking History eCRF 
(SMOK) for current smokers and former smokers: 
 
Average number of cigarettes per day 
 
Average number of cigars per day 
 
Average number of pipes per day 
 
Number of years smoked 
 
Number of pack years 
12. MEDICATIONS 
Medications are to be presented for the ITT population and coded using the World Health Organization-Drug 
Dictionary (WHO-DD) Version 01MAR2016.  
Prior (P) and concomitant (C) medications are to be presented by generic name for Allergy Medications and 
Other Medications respectively.  
 
Allergy medications are defined as medications where the Concomitant Medications eCRF (CMDT) question, ‘Is 
the medication used for HDM allergy?’ or ‘Is the medication used for other allergy?’ are indicated as ‘Yes’ 
 
Other medications are defined as medications where the Concomitant Medications eCRF (CMDT) question, ‘Is 
the medication used for HDM allergy?’ and ‘Is the medication used for other allergy?’ are indicated as ‘No’ 
The summaries are to be sorted by descending total frequency per generic name. 
Prior and concomitant medications are defined as follows: 
 
‘Prior’ medications are medications which started and ended prior to the first administration of study 
medication.  


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL TH005 
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 
‘Concomitant’ medications are medications which:  
o 
Started on or after the first administration of study medication and continues during the study and/or up 
to the end of study, OR 
o 
started prior to first administration of study medication and ended on or after the date of first 
administration of study medication or were ongoing AND 
o 
are not part of the medications from the rescue medication plan as specified in protocol Appendix 3: 
Rescue Medication Package Description and Rescue Medication Plan 
See Appendix 2 for handling of partial dates for medications.  
Separate by-subject listings for allergy medications and other medications are to be presented.  
13. STUDY MEDICATION EXPOSURE 
Exposure to study medication in days is to be presented for the ITT population. 
Exposure to study medication is to be summarised by descriptive statistics and treatment group.  
The date of first study medication administration is to be taken from the Study Medication Administration eCRF 
(SDA1). The date of last study medication administration Is to be taken as the last available administration date 
on the Study Medication Administration eCRF (SDA1/2).  
Additionally exposure to study medication is to be summarised as the frequency (n) and percentage (%) of 
subjects receiving study medication at each Study Medication Administration (Visits 3A-3H) visit. Subjects are 
considered to have received study medication at each visit if the response to the question ‘Was the study 
medication administered in accordance with the protocol?’ is indicated as ‘Yes’ on the Study Medication 
Administration eCRF (SDA1/2).  
13.1. DERIVATIONS 
Duration of exposure (days) = (Date of last study medication administration – Date of first study medication 
administration) + 1.  
14. STUDY MEDICATION COMPLIANCE  
Compliance to study medication is to be presented for the ITT population. 
Compliance to study medication is to be summarised by descriptive statistics and treatment group for 
 
Compliance over first 4 doses (Visit 3A to Visit 3D) 
 
Compliance over last 4 doses (Visit 3E to Visit 3H) 
 
Overall compliance (Visit 3A to Visit 3H) 


 
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14.1. DERIVATIONS 
Compliance with double-blind study medication is to be calculated as the number of injections received (as 
indicated on the Study medication Administration eCRF (SDA1/2)) divided by the planned number of injections, 
expressed as a percentage, see calculations below: 
 
Compliance over first 4 doses = (Number of doses received from Visit 3A to Visit 3D / Planned number of doses 
[4]) X 100  
 
Compliance over last 4 doses = (Number of doses received from Visit 3E to Visit 3H / Planned number of doses 
[4]) X 100  
 
Overall compliance = (Total number of doses received / Planned number of doses [8]) X 100  
Subjects are expected to receive one dose per visit from Visit 3A to Visit 3H for a total of 8 doses.  
 
 


 
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15. EFFICACY OUTCOMES  
15.1. PRIMARY EFFICACY 
15.1.1. 
PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy analysis is to be performed for the ITT population and repeated for the PP population. 
The primary efficacy variable is the mean of the daily combined score (CS) during the PAC3 period as recorded on 
each subject’s eDiary.  
The daily total rhinoconjunctivitis symptom score (TRSS) and the daily rescue medication score (RMS) are to be 
combined and a daily CS is to be calculated for each subject as follows: 
 
CS = (TRSS / 8) + RMS  
For each subject the mean of the daily non-missing CS during the BAE, PAC1, PAC2 and PAC3 periods is to be 
calculated as follows: 
 
Sum(All CS in respective period) / Number of non-missing days in respective period 
The TRSS is the sum of 8 individual TRSS symptom scores, namely runny nose, sneezing, blocked nose, itchy nose, 
itchy eyes, watery eyes, red eyes and itchy ear/palate. All symptoms are reflective over the previous 24 hours.  
For each symptom, the subject is to rate (each morning) the severity as follows: 
0 = absent 
1 = mild, barely noticeable 
2 = moderate, annoying/troublesome 
3 = severe, very annoying/very troublesome 
The TRSS is to have a range of 0 to 24. The TRSS on each day is to be calculated as follows: 
TRSS = Runny Nose + Sneezing + Blocked Nose + Itchy Nose + Itchy Eyes + Watery Eyes + Red Eyes + Itchy 
Ear/Palate. 
Rescue medications are to be provided to subjects to be used according to a pre-specified Rescue Medication 
Plan as specified in protocol Appendix 3: Rescue Medication Package Description and Rescue Medication Plan. 
The use of allergy rescue medications is to be scored based on Didier (Didier et al, 2009) as follows: 
 
RMS = 0; no allergy rescue medication used per day  
 
RMS = 0.5; at least one dose of antihistamine eye drops used per day  
 
RMS = 1; at least one dose of oral antihistamine used per day  
 
RMS = 2; at least one dose of intranasal corticosteroid used per day  


 
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 
RMS = 3; at least one dose of systemic corticosteroid used per day 
The RMS score is not additive, the maximum value per day is used and therefore the maximum RMS per day is 3. 
The maximum CS per day is therefore 6. 
The CS ranges from 0-6 and provides equal weighting (a maximum score of 3 each) for the contribution of the 
symptoms and for the rescue medication use. 
If any of the 8 individual TRSS, namely sneezing, runny nose, blocked nose, itchy nose, itchy eyes, watery eyes, 
red eyes or itchy ear/palate for a given day is missing, the TRSS for that day is to be considered missing. If either 
the TRSS or the RMS is missing for a particular day then the CS is to be considered missing. 
15.1.2. 
MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE 
The primary analysis is to be performed using all available data on the assumption that the probability of missing 
observations is independent of unobserved measurements (missing at random). Therefore the missing values will 
not be imputed for the primary analysis. 
A sensitivity analysis is to be performed to check the robustness of the primary results, assuming a missing not at 
random (MNAR) process. A pattern-mixture model based on control-based imputation is to be utilised for the 
sensitivity analysis. 
The sensitivity analysis is described in Section 15.1.4 Sensitivity Analysis of Primary Efficacy Variable.  
15.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The primary objective of this study is to test the hypothesis that there is no significant difference in adjusted 
mean CS between the active HDM-SPIRE treatment groups and placebo.  
The null and alternative hypothesis is given by: 
𝐻0: 𝜇𝐴 = 𝜇𝑃 
𝐻1: 𝜇𝐴 ≠ 𝜇𝑃 
Where 𝜇𝐴 is the adjusted mean for the active treatment groups and 𝜇𝑃 is the adjusted mean for the placebo 
treatment group.  
A point estimate and two-sided 95% confidence interval for the difference in adjusted mean between the active 
treatment groups and placebo is to be calculated using a Mixed Model Repeated Measures (MMRM) analysis for 
the PAC1, PAC2 and PAC3 period mean CS. 
The MMRM is to include treatment, period and pooled region as main effects, gender, asthma status and 
Baseline CS as covariate, treatment-by-period and baseline-by-period interaction. An unstructured covariance 
matrix is to be used to assess within-subject dependence of the 3 observations (PAC1, PAC2 and PAC3) of mean 
CS per subject. 
The following SAS®code is to be used: 
 


 
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PROC MIXED data=<input dataset> IC INFO;  
CLASS subject treatment period pooled_region gender asthma_status;  
MODEL CS=baseline treatment period pooled_region gender asthma_status treatment*period 
baseline*period / DDFM=KR; 
ESTIMATE ‘4 x 12 nmol HDM-SPIRE vs Placebo at PAC3’ treatment 1 0 0 -1  
                                                                                   
     treatment*period 0 0 1 0 0 0 0 0 0 0 0 -1 / CL; 
REPEATED period / SUBJECT=subject TYPE=UN; 
RUN; 
Appropriate estimate statements are to be added for the contrasts of each HDM-SPIRE treatment group vs 
placebo for the PAC1, PAC2 and PAC3 periods.  
 
The treatment difference corresponding to the PAC3 period is to be utilised for the primary analysis 
 
The treatment difference corresponding to the PAC1 and PAC2 periods are to be utilised as exploratory 
analyses 
Statistical significance is to be declared as set out in Section 7.4 Multiple Comparisons/Multiplicity.  
Observed and change from Baseline values are to be summarised by descriptive statistics for the BAE, PAC1, 
PAC2 and PAC3 periods by treatment group.  
15.1.4. 
SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The sensitivity analysis is to be performed for the ITT population.  
A pattern-mixture model based on non-ignorable missing observations, i.e. missing not at random (MNAR) is to 
be used where the conditional distribution of missing data, given the observed data, can be used to create 
multiple imputations for the missing values of subjects randomised to active treatment groups under the 
assumption that those subjects behave similar to those in the placebo treatment group after discontinuation, 
that is, the drug effect diminishes after subjects discontinue from the study. The approach is to be implemented 
by multiple imputations, where missing values are multiply replaced by sampling from the Bayesian posterior 
predictive distribution based on the model. The data is then analysed using the same primary analysis method as 
described in Section 15.1.3 Primary Analysis of Primary Efficacy Variable.  
For imputation the following programming steps are to be performed using the SAS® procedures MI, MIXED and 
MIANALYZE: 
Step 1) Impute non monotone missing data using the MCMC option of SAS PROC MI to obtain a monotone 
missing data pattern for all subjects 
The following SAS code is to be used: 
PROC MI data=<input data> OUT=imp1 NIMPUTE=100 SEED=<seed>; 
 
BY trtn; 
 
MCMC CHAIN=multiple IMPUTE=monotone; 
 
VAR BAE PAC1 PAC2 PAC3; 
RUN; 


 
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Where trtn refers to the treatment group and BAE, PAC1, PAC2 and PAC3 refers to the mean score of each 
respective period.  
The resulting output dataset imp1 is to have 100 copies of the original dataset of subjects where each copy is to 
have a monotone missing pattern. 
Step 2) The missing values for each pattern is to be imputed via the chained equation method, using SAS PROC 
MI option MONOTONE REG. The MNAR imputation is achieved by using only appropriate study data for each 
pattern. For example, to impute for period PAC3 assuming that the active arm missing data has the trajectory of 
placebo only placebo observations up to and including PAC3 is to be used.  
The following SAS code is to be used: 
PROC MI data=imp1 SEED=<> NIMPUTE=1 OUT=imp2; 
 
BY _Imputation_; 
 
CLASS trt; 
 
VAR BAE0 PAC1 PAC2 PAC3; 
 
MONOTONE REG; 
 
 
 
MNAR MODEL (PAC1 / MODELOBS =(trt='Placebo')); 
 
MNAR MODEL (PAC2 / MODELOBS =(trt='Placebo')); 
 
MNAR MODEL (PAC3 / MODELOBS =(trt='Placebo')); 
RUN; 
Step 3) Analyse the resulting dataset using the same method as described in Section 15.1.3 Primary Analysis of 
Primary Efficacy Variable for each of the 100 imputed datasets resulting in 100 estimates of the difference in 
adjusted mean CS between the active HDM-SPIRE treatment groups and placebo. 
Step 4) An overall result is to be obtained by combining the estimates and using SAS PROC MIANALIZE to obtain 
the overall result. 
The following SAS code is to be used:  
PROC MIANALYZE data = imp2; 
MODELEFFECTS estimate;  
STDERR stderr; 
BY trt period;  
RUN; 
Where estimate refers to each estimate of the difference in adjusted mean CS between HDM-SPIRE and placebo 
and stderr refers to the standard error of each estimate.  
15.1.5. 
SUPPORTIVE ANALYSES OF PRIMARY EFFICACY VARIABLE 
15.1.5.1. 
Responder Analysis 
The primary analysis is to be supported by a responder analysis identifying the number of subjects who show a 
reduction from Baseline CS at PAC3 at each 10th percentile of the percentage reduction from Baseline in CS for 
each HDM-SPIRE treatment and placebo. The percentage reduction can only range from 0% to 100% and a 
subject with an increase from Baseline is not considered a responder in any percentile.  


 
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A subject is considered a responder at the 10th percentile if they show a reduction in mean CS at PAC3 of ≥10%. 
In general, a subject is considered a responder at the ith percentile if they show a reduction in mean CS at PAC3 
≥i%. Where i = 10, 20 ,30…,100. The rate of subjects with a reduction from Baseline of < 10% is to be included in 
the analysis under the following categories: 
 
< 0% reduction  
 
< 0%  to < 10% reduction  
Only subjects with both a Baseline and PAC3 CS are to be included in the analysis.  
The response rate (%) at each 10th percentile is to be calculated as follows 
 
Response rate at PAC3 (%) = Number of responders / Total number of subjects with data at BAE and PAC3 * 
100 
The response rate is to be presented for each 10th percentile and treatment group.  The response rate is to be 
cumulative, meaning, if a subject is regarded as a responder in the highest percentile the same subject will also 
be counted as a responder in all other (lower) percentiles.  
The responder status (yes or no) is to be analysed using a logistic regression model with treatment, pooled 
region, gender, asthma status as main effects and Baseline CS as covariate to compare the response rates of  
HDM-SPIRE treatment groups against placebo. Odds ratio of HDM-SPIRE/placebo with 95% confidence interval 
and p-value is to be presented.  
The following SAS code is to be used for the logistic regression: 
PROC LOGISTIC data=<input dataset>;  
CLASS treatment (ref = ‘Placebo’) period pooled_region gender asthma_status / PARAM = ref;  
MODEL resp (ref = ‘Y’) = baseline treatment period pooled_region gender asthma_status;  
RUN; 
Where resp refers to the derived response variable of ‘Yes’ or ‘No’ per subject.  
A waterfall plot of the clinical response showing percentage change in CS from Baseline to PAC3 for each 
individual subject is to be plotted by treatment group. 
15.1.5.2. 
Treatment-by-pooled Region Interaction 
The effect of pooled region on the primary efficacy variable for the ITT population is to be investigated using the 
same MMRM as described in Section 15.1.3 Primary Analysis of Primary Efficacy Variable with the addition of a 
treatment-by-pooled region interaction effect.  
The interaction is to be further explored by doing subgroup analysis for each pooled region if the effect is found 
to be statistically significant.  
15.1.5.3. 
Alternative Combined Score Weighting  
The CS provides equal weighting (a maximum score of 3 each) for the contribution of the symptoms and the 
rescue medication use.  


 
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Two alternative CS are to be calculated for sensitivity testing of the impact of different weighting of TRSS and 
RMS as follows: 
The TRSS (0 to 24) and the RMS (0 to 3) is to be combined for analysis of the alternative primary variable as 
follows: 
 
Alternative 1 CS (ALT1 CS) = (4/3 * TRSS/8)+ (2/3* RMS) 
Mean ALT1 CS is to be calculated in BAE, PAC1, PAC2 and PAC3 by taking the mean ALT1 CS over all the days with 
complete data for the BAE and each PAC period. 
 
Alternative 2 CS (ALT2 CS) = (2/3 * TRSS/8) + (4/3* RMS) 
Mean ALT2 CS is to be calculated in BAE, PAC1, PAC2 and PAC3 by taking the mean ALT2 CS over all the days with 
complete data for the BAE and each PAC period. 
A third and fourth alternative CS is to be calculated for sensitivity testing of the impact of increased weighting of 
oral corticosteroid use. 
An alternative RMS (ALT RMS) for the purpose of testing the impact of oral corticosteroid use is to be evaluated 
as follows: 
 
ALT RMS = 0; no allergy rescue medication used per day 
 
ALT RMS = 0.5; at least one dose of antihistamine eye drops used per day 
 
ALT RMS = 1; at least one dose of oral antihistamine used per day 
 
ALT RMS = 2; at least one dose of intranasal corticosteroid used per day 
 
ALT RMS = 6; at least one dose of systemic corticosteroid used per day 
The TRSS (0 to 24) and the ALT RMS (0 to 6) is to be combined for analysis of the alternative primary variable as 
follows: 
 
Alternative 3 CS (ALT3 CS) = TRSS/8 + ALT RMS/2 
This formula maintains equal weighting (a maximum score of 3 each) for the contribution of the symptoms and 
the rescue medication use and maintains the maximum score of 6. 
Mean ALT3 CS is to be calculated in BAE, PAC1, PAC2 and PAC3 by taking the mean ALT3 CS over all the days with 
complete data for the BAE each PAC period. 
 
Alternative 4 (ALT4 CS) = TRSS/8 + ALT RMS 
This formula ensures that the use of oral corticosteroids results in a combined score of at least 6 even if no 
symptoms are present; the maximum score is 9. 
Mean ALT4 CS is to be calculated in BAE, PAC1, PAC2 and PAC3 by taking the mean ALT4 CS over all the days with 
complete data for the BAE and each PAC period. 
A point estimate and two-sided 95% confidence interval for the difference in adjusted means of ALT1 CS, ALT2 


 
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CS, ALT3 CS and ALT4 CS between the active treatment groups and placebo is to be calculated using the same 
MMRM as described in Section 15.1.3 Primary Analysis of Primary Efficacy Variable.  
15.1.6. 
NORMALITY AND HOMOGENEITY OF PRIMARY EFFICACY VARIABLE 
The residuals from the primary efficacy MMRM, sensitivity analysis MMRM as well as supportive primary efficacy 
analysis MMRM are to be visually checked for normality and homogeneity of variance. Normality is to be 
examined by normal probability plots, while homogeneity of variance is to be assessed by plotting the residuals 
against the predicted values for the model. Any deviation from either assumption may result in further analysis 
using non-parametric analysis of the primary efficacy variable.  
15.2. SECONDARY EFFICACY 
The secondary efficacy analyses are to be performed for the ITT population.  
The secondary efficacy analyses are to be prioritised in order of importance as outlined below.  
15.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
15.2.1.1. 
Mean Total Rhinoconjunctivitis Symptom Score  
The daily TRSS is to be derived as described in Section 15.1.1: Primary Efficacy Variable & Derivation.  
The means of the daily TRSS for the BAE, PAC1, PAC2 and PAC3 periods are to be calculated over all days with 
complete data.  
Analysis of Mean Total Rhinoconjunctivitis Symptom Score  
A point estimate and two-sided 95% confidence interval for the difference in adjusted means between the active 
treatment groups and placebo is to be calculated using the same MMRM as described in Section 15.1.3 Primary 
Analysis of Primary Efficacy Variable.  
 
The treatment difference corresponding to the PAC3 period is to be utilised for the secondary analysis 
 
The treatment difference corresponding to the PAC1 and PAC2 periods are to be utilised as exploratory 
analyses 
Observed and change from Baseline values are to be summarised by descriptive statistics for the PAC1, PAC2 and 
PAC3 periods by treatment group.  
15.2.1.2. 
Mean Component Scores of Total Rhinoconjunctivitis Symptom Score  
The TRSS consists of two components: 
 
Total Nasal Symptom Score (TNSS) 


 
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The TNSS is the sum of four individual nasal symptoms: runny nose, sneezing, blocked nose, and itchy nose. The 
TNSS will have a range of 0-12. The TNSS is to be calculated on each day as follows:  
TNSS = Runny Nose + Sneezing + Blocked Nose + Itchy Nose.  
Mean TNSS is to be calculated for the BAE, PAC1, PAC2 and PAC3 periods over all days with complete data.  
 
Total Non-nasal Symptom Score (TNNSS) 
The TNNSS is the sum of four individual non-nasal symptoms: itchy eyes, watery eyes, red eyes and itchy 
ear/palate.  
The TNNSS will have a range of 0-12. The TNNSS is to be calculated on each day as follows:  
TNNSS = Itchy Eyes + Watery Eyes + Red Eyes + Itchy Ear/Palate.  
Mean TNNSS is to be calculated for the BAE, PAC1, PAC2 and PAC3 periods over all days with complete data.  
Analysis of Mean Component Scores of Total Rhinoconjunctivitis Symptom Score 
For both the TNSS and TNNSS a point estimate and two-sided 95% confidence interval for the difference in 
adjusted means between the active treatment groups and placebo is to be calculated using the same MMRM as 
described in Section 15.1.3 Primary Analysis of Primary Efficacy Variable.  
 
The treatment difference corresponding to the PAC3 period is to be utilised for the secondary analysis 
 
The treatment difference corresponding to the PAC1 and PAC2 periods are to be utilised as exploratory 
analyses 
Observed and change from Baseline values are to be summarised by descriptive statistics for the PAC1, PAC2 and 
PAC3 periods by treatment group.  
15.2.1.3. 
Mean Rescue Medication Score  
The daily RMS is to be derived as described in Section 15.1.1: Primary Efficacy Variable & Derivation.  
The means of the daily RMS for the BAE, PAC1, PAC2 and PAC3 periods are to be calculated over all days with 
complete data.  
Analysis of Rescue Medication Score 
A point estimate and two-sided 95% confidence interval for the difference in adjusted means between the active 
treatment groups and placebo is to be calculated using the same MMRM as described in Section 15.1.3 Primary 
Analysis of Primary Efficacy Variable.  
 
The treatment difference corresponding to the PAC3 period is to be utilised for the secondary analysis 
 
The treatment difference corresponding to the PAC1 and PAC2 periods are to be utilised as exploratory 
analyses 
Observed and change from Baseline values are to be summarised by descriptive statistics for the PAC1, PAC2 and 
PAC3 periods by treatment group.  


 
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15.2.1.4. 
Clinical Global Impression of Change in Rhinoconjunctivitis Symptoms 
During the Follow-up Visit (Visit 5) subjects are to complete a Clinical Global Impression (CGI) of change in 
Rhinoconjunctivitis symptoms. 
Subjects are to rate their overall allergy symptoms at the end of the study relative to Baseline on a 7-point scale 
as follows: 
0 = Very much better 
1 = Moderately better 
2 = A little better 
3 = Unchanged 
4 = A little worse 
5 = Moderately worse 
6 = Very much worse 
The following additional categories of global impression are to be derived: 
 
Moderately or very much better 
 
Any improvement (a little better, moderately better or very much better) 
 
No change (unchanged) 
 
Any worsening (a little worse, moderately worse or very much worse) 
Analysis of Clinical Global Impression of Change 
The frequency (n) and percentage (%) of subjects in each category of CGI is to be presented.  
A p-value for the difference in CGI between each HDM-SPIRE treatment group and placebo across all 7 categories 
is to be calculated using the Cochran-Mantel-Haenszel (CMH) row mean score differ.  
The frequency (n) and percentage (%) of subjects in each of the following derived categories is to be presented  
 
Moderately or very much better 
 
Any improvement 
 
No change  
 
Any worsening 
A Chi-square test is to be used to calculate a p-value for the difference in each derived CGI category between 
each HDM-SPIRE treatment group and placebo.  


 
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15.2.1.5. 
Proportion of Well Days 
A well day is defined as any day where a subject has no moderate or severe RSS without the use of rescue 
medication. If any of the 8 RSS or the RMS is missing for a specific day the day is not to be considered as a well 
day.  
The proportion of well days is to be calculated as the sum of days where all 8 RSS are non-missing and less than 
or equal to 1 and RMS is equal to 0, divided by the total number of days in the relevant assessment period (BAE, 
PAC1, PAC2 or PAC3) as follows: 
 
Proportion of well days (%) = Number of well days / Total number of days in the relevant assessment period * 
100  
 
The total number of days in each assessment period (denominator) refers to the total number of days with 
complete RSS and RMS as required to define a well day.  
Analysis of Proportion of Well Days 
A point estimate and two-sided 95% confidence interval for the difference in adjusted means between the active 
treatment groups and placebo is to be calculated using the same MMRM as described in Section 15.1.3 Primary 
Analysis of Primary Efficacy Variable.  
The treatment difference corresponding to the mean proportion of symptom free days of the PAC1, PAC2 and 
PAC3 periods is to be utilised for the secondary analysis.  
Observed and change from Baseline values are to be summarised by descriptive statistics for the PAC1, PAC2 and 
PAC3 periods by treatment group.  
15.2.1.6. 
Rhinoconjunctivitis Quality of Life Questionnaire  
The rhinoconjunctivitis quality of life questionnaire (RQLQ) is to be completed as a one off assessment at the end 
of the BAE, PAC1, PAC2 and PAC3 periods.  
The RQLQ has 28 questions in the following seven domains: 
 
Activities 
 
Sleep 
 
Non-nose/eye symptoms 
 
Practical problems 
 
Nasal symptoms 
 
Eye symptoms 
 
Emotional 
 
Overall RQLQ 


 
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The domains consist of the following individual questions: 
 
Activities: Questions 1 to 3 
 
Sleep: Questions 4 to 6 
 
Non-nose/eye symptoms: Questions 7 to 13 
 
Practical problems: Questions 14 to 16 
 
Nasal symptoms: Questions 17 to 20 
 
Eye symptoms: Questions 21 to 24 
 
Emotional: Questions 25 to 28 
Refer to Appendix 3: Complete Questionnaires for the complete questionnaire. For each question subjects record 
how troubled they have been during the last week on a 7-point scale. For all domains, except Emotional, the 
scores are (0 = Not troubled to 6 = Extremely troubled). For the Emotional domain the 7-point scale is (0 = None 
of the Time to 6 = All of the Time).  
The overall RQLQ score is the mean of all 28 responses and the individual domain scores are the means of the 
items within those domains. 
If any individual item within a domain is missing the domain score is to be set to missing.  
Analysis of Rhinoconjunctivitis Quality of Life Questionnaire 
A point estimate and two-sided 95% confidence interval for the difference in adjusted means between the active 
treatment groups and placebo during the PAC1, PAC2 and PAC3 periods are to be calculated using an analysis of 
covariance (ANCOVA) with treatment, period and pooled region as main effects, gender, asthma status and 
Baseline RQLQ as covariate and a treatment by-period interaction for the Overall RQLQ score as well as each of 
the 7 domains individually.  
 
The treatment difference corresponding to the PAC3 period is to be utilised for the secondary analysis 
 
The treatment difference corresponding to the PAC1 and PAC2 periods are to be utilised as exploratory 
analyses 
Observed and change from Baseline values are to be summarised by descriptive statistics for the PAC1, PAC2 and 
PAC3 periods by treatment group, for the Overall RQLQ score as we all each of the 7 domains individually.  
15.2.1.7. 
Mean Asthma Symptom Score 
The asthma symptom scores  (ASS) has six questions which are answered daily by the subject for each 
assessment period (BAE, PAC1, PAC2 and PAC3), describing their condition in the past 24 hours. All subjects 
(including non asthmatic subjects) are to describe their condition with regards to: 
 
 Coughing  


 
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 
Wheezing 
 
Shortness of breath 
In addition for asthmatic subjects only, the ASS is to include the following questions:  
 
Limitation of activities 
 
Nocturnal symptoms or awakenings due to asthma 
 
Need for short-acting inhaled β2agonist treatment 
There is a 4 point scale (0 to 3) for each question. For cough, wheezing and shortness of breath symptoms the 
subject is to rate the severity as follows: 
0 = absent 
1 = Mild, barely noticeable 
2 = Moderate, annoying/troublesome 
3 = Severe, very annoying/ very troublesome 
For limitations of activities the subject is to rate the severity as follows: 
0 = Not limited 
1 = Very slightly limited 
2 = Slightly limited 
3 = Moderately limited or worse 
For nocturnal symptoms or awakenings due to asthma the subject is to rate how asthma has affected them 
overnight (last night) as follows: 
0 = Not at all 
1 = Hardly at all 
2 = A few minutes disturbance 
3 = Several times or more 
For use of short-acting inhaled β2 agonist treatment the subjects are to record how many puffs of reliever 
medication (e.g. albuterol or salbutamol) they have used as follows: 
0 = None 
1 = One 
2 = Two 
3 = Three or more 
The questions are equally weighted and the ASS for each day is to be calculated as the mean of all six questions 
(for asthmatic subjects) as well as the mean using only the 3 symptoms (for all subjects including asthmatics) 


 
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separately. The ASS is therefore between 0 and 3. The mean of the daily ASS for each assessment period is to be 
calculated over all days with complete data.  
Subjects are to be classified as asthmatic or non asthmatic based on the System Screening eCRF. Asthmatic 
subjects are defined as subjects with either ‘Controlled’ or ‘Partially/Uncontrolled’ asthma status and non 
asthmatic subjects are defined as subjects with ‘No asthma’.  
Analysis of Mean Asthma Symptom Score 
The ASS is to be analised for asthmatic subjects only, as well as all subjects (including asthmatics) separately.  
A point estimate and two-sided 95% confidence interval for the difference in adjusted means between the active 
treatment groups and placebo is to be calculated using the same MMRM as described in Section 15.1.3 Primary 
Analysis of Primary Efficacy Variable.  
 
The treatment difference corresponding to the PAC3 period is to be utilised for the secondary analysis 
 
The treatment difference corresponding to the PAC1 and PAC2 periods are to be  utilised as exploratory 
analyses 
Observed and change from Baseline values are to be summarised by descriptive statistics for the PAC1, PAC2 and 
PAC3 periods by treatment group.  
 
 


 
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15.3. OTHER EXPLORATORY EFFICACY  
Other exploratory efficacy analyses are to be performed for the ITT population.  
15.3.1. 
OTHER EXPLORATORY EFFICACY VARIABLES & DERIVATIONS 
15.3.1.1. 
Rhinoconjunctivitis Symptom Scores Measured Using Visual Analogue Scale  
At start of the BAE period and the start of each PAC period subjects are to record their RSS symptoms using a 
Visual Analogue Scale (VAS) in their eDiaries.  
Subjects are to rate their allergy symptoms on a visual scale where 0 = no allergy symptom and 10 = my allergy 
symptom is the worst it could possibly be with respect to the following categories: 
 
Runny nose 
 
Sneezing 
 
Blocked nose 
 
Itchy nose 
 
Itchy eyes 
 
Watery eyes 
 
Red eyes 
 
Itchy ear/palate symptoms 
Analysis of Rhinoconjunctivitis Symptom Scores Measured Using Visual Analogue Scale  
Observed and change from Baseline values for each symptom’s VAS score individually is to be summarised by 
descriptive statistics for the PAC1, PAC2 and PAC3 periods by treatment group.  
15.3.1.2. 
The Pittsburgh Sleep Quality Index  
The Pittsburgh Sleep Quality Index (PSQI) assesses sleep quality during the past month and is to be completed as 
a once off assessment by subjects at the end of the BAE, PAC1, PAC2 and PAC3 periods. It consists of 19 self-
rated questions and five completed by a bed-partner/roommate. Refer to Appendix 3: Complete Questionnaires 
for the complete questionnaire. For the self-rated questions there are four questions about bed and sleep times 
and fifteen questions (each scored in one of four categories) that elicit the quality of sleep.  
The range of values for questions 5 through 10 are all 0 to 3. 
Questions 1 through 9 are not allowed to be missing except as noted below.  If these questions are missing then 
any scores calculated using missing questions are also missing.  Thus it is important to make sure that all 


 
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questions 1 through 9 have been answered.   
In the event that a range is given for an answer (e.g., ‘30 to 60’ is written as the answer to Q2, minutes to fall 
asleep), split the difference and enter 45. 
The total PSQI and component scores (duration of sleep, sleep disturbance, sleep latency, day dysfunction due to 
sleepiness, sleep efficiency, overall sleep quality and need medications to sleep) are calculated from the 
questionnaire and the scoring instructions in Table 2 below:  
Table 2 : Scoring Instructions 
Domain 
Question (Q) Result or Algorithm  
Analysis 
Value 
Duration of Sleep 
Q4 > 7 
0 
  
6 < Q4 <= 7  
1 
 
5 <= Q4 <= 6 
2 
 
Q4 < 5  
3  
Sleep Disturbance 
Q5b + Q5c + Q5d + Q5e + Q5f + Q5g + Q5h + Q5i + Q5j = 0 
NOTE: If Q5j-Other reason(s), is null or Q5j is null, set the value of Q5j to 
0  
0 
 
Q5b + Q5c + Q5d + Q5e + Q5f + Q5g + Q5h + Q5i + Q5j  >= 1 and <= 9 
1 
 
Q5b + Q5c + Q5d + Q5e + Q5f + Q5g + Q5h + Q5i + Q5j >=10 and <= 18 
2 
 
Q5b + Q5c + Q5d + Q5e + Q5f + Q5g + Q5h + Q5i + Q5j >= 19 and <= 27 
3 
Sleep Latency 
Step 1: 
 
 
If 0 <= Q2 <= 15 then set Q2 = 0  
 
 
If 15 < Q2 <= 30 then set Q2 = 1  
 
 
If 30 < Q2 <= 60 then set Q2 = 2 
 
 
If Q2 > 60 then set Q2 = 3 
 
 
Step 2: 
 
 
Q5a + Q2 = 0 
0 
 
1 <= Q5a + Q2 <= 2  
1 
 
3 <= Q5a + Q2 <= 4  
2 
 
5 <= Q5a + Q2 <= 6  
3 
Day Dysfunction 
Due to Sleepiness  
Q8 + Q9 = 0 
0 
  
1 <= Q8 + Q9 <= 2 
1 
 
3 <= Q8 + Q9 <= 4 
2 
 
5 <= Q8 + Q9 <= 6 
3 
 
 
 


 
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Domain 
Question (Q) Result or Algorithm  
Analysis 
Value 
Sleep Efficiency 
Step 1: 
 
 
Get difference in seconds between day and time of day Q1 and day Q3 
(DIFFSEC) 
 
 
Step 2: 
 
 
Convert to hours (DIFFHOUR): Absolute value of DIFFSEC / 3600 
 
 
Step 3:  
 
 
Calculate the hours between GMT (Q1) AND GMT (Q3) (NEWTIB): 
If DIFFHOUR > 24 then NEWTIB = DIFFHOUR – 24 
If DIFFHOUR <= 24 then NEWTIB = DIFFHOUR 
 
 
Step 4:  
 
 
Get Q4 as a percentage of NEWTIB (TMPHSE): 
THPHSE = (Q4 / NEWTIB) * 100 
 
 
Step 5:  
 
 
85 <= TMPHSE  
0 
 
75 <= TMPHSE < 85  
1 
 
65 <= TMPHSE < 75 
2 
 
TMPHSE < 65  
3 
Overall Sleep 
Quality 
Q6 
Value of 
Q6 
Need Meds to 
Sleep 
Q7 
Value of 
Q7 
PSQI Total 
Step 1: 
 
 
Calculate total score (TOTAL) 
Duration of Sleep + Sleep Disturbance + Sleep Latency + Day Dysfunction 
Due to Sleepiness + Sleep Efficiency + Overall Sleep Quality + Need Meds 
to Sleep 
TOTAL 
 
Step 2:  
 
 
TOTAL <= 5 
Good 
 
TOTAL > 5   
Poor 
Analysis of the Pittsburgh Sleep Quality Index 
Observed and change from Baseline values for the overall and component scores of the PSQI are to be 
summarised by descriptive statistics for the PAC1, PAC2 and PAC3 periods by treatment group.  
The frequency (n) and percentage (%) of subjects in each category (good or poor) of PSQI Total Score is to be 
presented by treatment group for BAE, PAC1, PAC2 and PAC3.  
A point estimate and exact 95% confidence interval for the difference in proportion of subjects that had a good 
response is to be calculated for each treatment group vs placebo using the following SAS code:  


 
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PROC FREQ; 
TABLES treatment*outcome / CMH; 
EXACT OR RISKDIFF RELRISK(METHOD=SCORE); 
RUN; 
15.3.1.3. 
Asthma Control Test 
The Asthma Control Test (ACT) consists of 5 questions and is to be completed by all asthmatic subjects at the 
clinical Visits at the end of BAE, PAC1, PAC2 and PAC3. The questions are to be completed by the subjects stating 
how they have been over the last 4 weeks with regards the following: 
 
How much of the time did your asthma keep you from getting as much done at work, school or at home? 
 
How often have you had shortness of breath? 
 
How often did your asthma symptoms (wheezing, coughing, shortness of breath, chest tightness or pain) wake 
you up at night or earlier than usual in the morning? 
 
How often have you used your rescue inhaler or nebulizer medication? 
 
How would you rate your asthma control? 
Each question has a 5 point scale (1 to 5) where 1 represents the least control and 5 represents optimal control. 
The ACT score is the mean of the 5 questions and therefore also between 1 (severely uncontrolled) and 5 (totally 
controlled).  
Analysis of the Asthma Control Test 
Observed and change from Baseline values for the ACT score is to be summarised by descriptive statistics for the 
PAC1, PAC2 and PAC3 periods by treatment group.  
15.3.1.4. 
Use of Concomitant Medications Associated with Rhinoconjunctivitis or Related Conditions 
Concomitant medication use associated with rhinoconjunctivitis or related conditions are to be analysed for the 
SAF population.  
Medications associated with rhinoconjunctivitis or related conditions are defined as medications where the 
Concomitant Medications eCRF (CMDT) question ‘Is the medication used for HDM allergy?’ or ‘Is the medication 
used for other allergy?’ are indicated as ‘Yes’. Concomitant medications are defined as in Section 12 Medications.  
Subjects are to be categorised as either ‘used’ or ‘not used’ any concomitant medications associated with 
rhinoconjunctivitis or related conditions.  
Analysis of the Concomitant Medication Use 
The frequency (n) and percentage (%) of subjects in each category is to be presented per treatment group.  
A point estimate and exact 95% confidence interval for the difference in proportion of subjects that used 
concomitant medication for rhinoconjunctivitis or related conditions is to be calculated for each treatment group 


 
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vs placebo using the following SAS code:  
PROC FREQ; 
TABLES treatment*outcome / CMH; 
EXACT OR RISKDIFF RELRISK(METHOD=SCORE); 
RUN; 
15.3.1.5. 
Home Environment Exposure and Control Measures 
Control Measures 
The frequency (n) and percentage (%) of subjects implementing the following control measures are to the 
presented for BAE, PAC1, PAC2 and PAC3 by treatment group, as captured on the House Dust Mite Control 
Measures eCRF (HDM1/2). 
 
Allergy-proof coverings for mattresses, pillows or quilts 
 
Sprays or chemicals to kill house dust mites  
 
Air filters  
 
Air management equipment  
 
Curtains 
All additional information on control measures is to be listed only. 
Home Environment Exposure  
Subjects are to be issued with home dust collection kits on Consent Visit 1A and PAC3 Visit 4E.  
House dust samples are to be collected following Consent Visit 1A and prior to the end of PAC3 Visit 4F/5. In the 
event that multiple samples are collected on different dates prior to Visit 4F/5 the last sample collected is to be 
analysed as the Visit 4F/5 sample.  
Dust samples are to be tested for the following allergens and reported in mg/kg: 
 
Mite allergens der p 1 
 
Mite allergens der f 1 
 
Cat allergens fel d 1 
 
Dog allergens can f 1  
 
Mouse allergens mus m 1 
 
Rat allergens rat n 1 
 
Cockroach allergens  bla g 2  


 
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 
Alternaria allergens alt a 1 
Observed and change from Baseline values for each allergen is to be summarised by descriptive statistics for 
Baseline and Visit 4F/5 by treatment group.  
Assessments reported as “< X”, i.e. below the lower limit of quantification (BLQ), or “> X”, i.e. above the upper 
limit of quantification (ULQ), are to be converted to X for the purpose of quantitative summaries, but are to be 
presented as recorded, i.e. as “< X” or “> X” in the listings. 
All allergens identified as entered on the Issue dust Collection Pack eCRF (DMKIT) is to be listed.  
16. SAFETY OUTCOMES 
All outputs for safety outcomes are to be based on the SAF population.  
There is to be no statistical comparisons between the treatment groups for safety data, unless otherwise 
specified within the relevant section.  
16.1. ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence in a subject administered study treatment that does not 
necessarily have a causal relationship with the treatment. An AE can therefore be any unfavourable and 
unintended sign (i.e, an abnormal laboratory finding), symptom (i.e., rash, pain, discomfort, fever, dizziness, 
etc.), disease (i.e., peritonitis, bacteraemia, etc.) or outcome of death temporally associated with the use of 
study treatment, whether or not considered causally related to the study medication. 
Adverse Events (AEs) are to be coded using MedDRA Version 19.0. 
Adverse events are to be classified as either pre-treatment AEs or treatment-emergent adverse events (TEAEs) 
based on the start date of the event as follows: 
 
Pre-treatment AEs: Defined as any AE which started or worsened on or after informed consent and before 
study medication administration 
 
TEAE: Defined as any AE which started or worsened on or after first study medication administration. 
See Appendix 2 for handling of partial dates for AEs. In the case where it is not possible to define an AE as 
treatment-emergent or not, the AE is to be classified as the worst case; i.e. treatment-emergent.  
An overview of the frequency (n) and percentage (%) of subjects is to be provided for the following TEAEs 
together with the actual number of mentions (m) of the event per category: 
 
Any TEAE 
 
Serious TEAEs 
 
TEAEs leading to death 


 
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 
Life-threatening TEAEs 
 
TEAEs leading to premature study and treatment discontinuation 
 
Treatment related TEAEs leading to premature treatment discontinuation 
 
Severe TEAEs 
 
TEAEs related to study medication 
 
TEAEs of special interest 
 
TEAEs within 24 hours of any dose of study medication 
In addition to the overview of TEAEs, incidence of all TEAEs in the sub-sections below is to be presented by 
System Organ Class (SOC) and Preferred Term (PT). If an AE occurs more than once the subject is to be counted 
once per SOC and PT as relevant.  
16.1.1. 
ALL TEAES  
16.1.1.1. 
Severity 
Severity is classed as mild/moderate/severe (increasing severity). TEAEs with a missing severity are to be 
classified as severe. If a subject reports a TEAE more than once within that SOC/PT, the AE with the worst case 
severity is to be used in the corresponding severity summaries. 
16.1.1.2. 
Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as ‘Not related’, ‘Unlikely to be related’ or ‘Related’ 
(increasing severity of relationship). TEAEs with a missing relationship to study medication are to be regarded as 
‘Related’ to study medication. If a subject reports the same AE more than once within that SOC/ PT, the AE with 
the worst case relationship to the study medication is to be used in the corresponding relationship summaries.  
16.1.2. 
SERIOUS TEAES 
Serious TEAEs are those events recorded as ‘Serious’ on the Adverse Events Details eCRF (AEDT).  
16.1.3. 
TEAES LEADING TO DEATH 
Treatment-emergent AEs leading to Death are those events for which the Outcome is recorded as ‘Death’ or the 
reason for seriousness of the event is indicated as ‘Death’ on the Adverse Events Details eCRF (AEDT).  


 
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16.1.4. 
LIFE-THREATENING TEAES 
Life-threatening TEAEs are those events where the reason for seriousness of the event is specified as “Life-
threatening” on the Adverse Events Details eCRF (AEDT).  
16.1.5. 
TEAES LEADING TO PREMATURE STUDY OR TREATMENT DISCONTINUATION 
Treatment-emergent AEs leading to premature study discontinuation are to be identified as TEAEs where the 
Outcome on the Adverse Events Detail eCRF (AEDT) is indicated as “Subject withdrawn because of this event”.  
16.1.6. 
TREATMENT RELATED TEAES LEADING TO PREMATURE TREATMENT DISCONTINUATION 
Treatment related TEAEs leading to premature treatment discontinuation are to be identified as TEAEs where the 
Outcome on the Adverse Events Detail eCRF (AEDT) is indicated as “Subject withdrawn because of this event” 
and the Causality is indicated as “Related” and the primary reason for treatment termination on the End of 
Treatment eCRF (EOT) is indicated “Adverse Event”.  
16.1.7. 
TEAES OF SPECIAL INTEREST 
TEAEs of special interest are defined as TEAEs for which “Adverse Event of Special Interest (AESI)” is indicated as 
“Yes” on the Adverse Events Detail eCRF (AEDT). 
16.1.8. 
TEAES WITHIN 24 HOURS OF ANY DOSE 
TEAEs within 24 Hours of any dose are defined as any AE that has a start date within 24 Hours of any dose, not 
only the first study drug administration date and time. If the AE onset time is missing and the start date of the 
TEAE is on or one day after any dosing date, the AE is to be assumed to have occurred within 24 hours of the 
dose.  
16.2. DEATHS 
If any subjects die during the study as recorded on the Death eCRF (DTH), the information is to be presented in a 
data listing. 
16.3. LABORATORY EVALUATIONS 
Results from the central laboratory are to be included in the reporting of this study for Haematology, 
Biochemistry, Urine dipstick and Immunology. Quantitative laboratory assessments are to be summarised by 
descriptive statistics and presented in International System of Units (SI). Categorical assessments are to be 
presented by frequency (n) and percentage (%) of subjects.  


 
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Quantitative laboratory assessments reported as “< X”, i.e. below the lower limit of quantification (BLQ), or “> X”, 
i.e. above the upper limit of quantification (ULQ), are to be converted to X for the purpose of quantitative 
summaries, but are to be presented as recorded, i.e. as “< X” or “> X” in the listings. 
The following summaries are to be provided for laboratory data: 
 
Actual and change from Baseline by visit (for quantitative measurements) 
 
Shift from Baseline according to normal reference range criteria (for quantitative measurements and 
categorical measurements) by visit 
 
Listings of all laboratory assessments 
The following assessments are to be measured and presented: 
 
Haematology: Haematocrit, haemoglobin, red blood cells, white blood cells (WBC), WBC differentials 
(neutrophils, eosinophils, basophils, lymphocytes, monocytes) and platelets 
 
Biochemistry: Sodium, potassium, chloride, urea, creatinine, calcium, phosphorus, total protein, albumin, uric 
acid, total bilirubin, glucose (random), lactate dehydrogenase, creatine phosphokinase, alanine transaminase, 
aspartate transaminase, gamma glutamyltransferase and alkaline phosphatase 
 
Urine dipstick: pH, protein, ketones, blood and glucose 
 
Immunology: All relevant perennial allergen specific IgE 
 
Tryptase for anaphylactic response 
Blood sample for tryptase is only to be taken in the event of a suspected anaphylactic reaction. 
The initial sample should be taken approximately 1 hour after the reaction, with a further sample 
at approximately 3 hours and then repeated every 3 hours until the Investigator is satisfied that 
the subject may be discharged. Tryptase laboratory results are to be listed separately.  
16.3.1. 
LABORATORY REFERENCE RANGES AND ABNORMAL CRITERIA 
Quantitative laboratory assessments are to be compared with the relevant laboratory reference ranges in SI units 
and categorised as: 
 
Low: Below the lower limit of the laboratory reference range 
 
Normal: Within the laboratory reference range (upper and lower limit included) 
 
High: Above the upper limit of the laboratory reference range 
 
Normal/Abnormal results and clinical significance as reported by the investigator is only to be presented in 
data listings. 


 
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16.4. ANTIBODIES TO PANEL OF DER P ALLERGES   
At Consent Visit 1A a blood sample is to be taken for measurement of levels of IgE antibodies to a fixed panel of 
Der p allergens, using an immune-affinity based analysis technology such as ImmunoCAP®. 
Observed values are to be summarised by descriptive statistics and treatment group for each panel. 
Specific IgE for allergen components will be summarised as number of subjects with positive (three grade 
categories) vs negative (<0.3 kU/L) results for all allergen components. 
Positive results will be divided in the three grade categories as described below for specific IgE values. 
 
Low: ≥ 0.3 - < 1 kU/L 
 
Moderate/high: ≥ 1 - < 15 kU/L 
 
Very high: >= 15 values kU/L 
16.5. VITAL SIGNS 
The following vital signs assessments are to be taken rested and in the sitting or semi-recumbent position and 
reported for this study: 
 
Systolic Blood Pressure (mmHg) 
 
Diastolic Blood Pressure (mmHg) 
 
Pulse Rate (bpm) 
 
Respiratory Rate (breaths/min) 
 
Oral body temperature (⁰C) 
 
At each medication administration visit (Visit 3A to Visit 3H), vital signs are to be taken pre-dose as well as 30 
minutes post-dose.  
The following summaries are to be provided for vital signs data by descriptive statistics and treatment group for 
each visit: 
 
Actual and change from Baseline/pre-dose observation by visit  
o 
For medication administration visits (Visit 3A to Visit 3H), change from pre-dose to 30 minutes post-dose 
observation is to be presented 
o 
For all other visit assessments (including the pre-dose assessment at Visit 3A to Visit 3H), change from 
Baseline is to be presented 


 
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 
Listing of all vital signs data 
16.5.1. 
VITAL SIGNS SPECIFIC DERIVATIONS  
Body temperature assessments recorded in Fahrenheit (⁰F) are to be converted to Celsius (⁰C) as follows: 
 
⁰C = (⁰F −32) ×
5
9 
16.6. PHYSICAL EXAMINATION 
At Screening subjects are to undergo a full examination comprising of: 
 
Eye, ears, nose, throat, neck, including a check for nasal polyps 
 
Respiratory system 
 
Central and peripheral nervous system 
 
Cardiovascular system 
 
Gastrointestinal system (including the mouth) 
 
Musculoskeletal system 
 
Skin 
 
Lymph node palpation 
 
Other systems if abnormality is suspected 
At Visit 3I and Visit 5 targeted physical examinations are to be performed with organ systems examined if the 
medical history or AEs of a subject indicate a reason for examination.  
Shift from Screening to Visit 3I and Visit 5 in physical examination finding (Normal, Abnormal, Not Done) is to be 
presented by organ system and treatment group.  
Abnormal physical examination findings are to be listed.  
16.7. OTHER SAFETY ASSESSMENTS 
16.7.1. 
FORCED EXPIRATORY VOLUME IN 1 SECOND (FEV1) 
The FEV1 is to be measured at Screening, prior to and 30 minutes post study medication administration (Visits 


 
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3A-3H), at the End of Dosing Assessment (Visit 3I), and at the end of the PAC1 (Visit 4B), PAC2 (Visit 4D) and PAC3 
(Visit 4F) periods.  
At each assessment FEV1 is to be measured according to the American Thoracic Society guidelines with the 
subject sitting and the highest reading is to be recorded in the eCRF.  
Absolute and change from Baseline/pre-dose values of FEV1 is to be summarised by descriptive statistics and 
treatment group for each visit.  
 
For medication administration visits (Visit 3A to Visit 3H), change from pre-dose to 30 minutes post-dose 
observation is to be presented 
 
For all other visit assessments (including the pre-dose assessment at Visit 3A to Visit 3H), change from Baseline 
is to be presented 
 
FEV1 data is to be listed 
 
An additional listing is to be created for any reduction in FEV1 of more than 20% from Baseline/pre-dose, as 
well as a reduction of more than 30% from Baseline/pre-dose 
o 
The frequency (n) and percentage (%) of subjects with a reduction of more than 20% from Baseline/pre-
dose as well as a reduction of more than 30% from Baseline/pre-dose is to be presented by treatment 
group at each applicable visit.  
Percentages are to be calculated relative to the total number of subjects in the analysis population with 
data available. 
16.7.2. 
LOCAL REACTION AT INJECTION SITE 
Grading of each of the four components of an injection site reaction (pain, tenderness, induration/swelling and 
erythema/redness) is to be categorised as ‘Grade 0’, ‘Grade 1’, ‘Grade 2’, ‘Grade 3’ or ‘Grade 4’ in accordance 
with the severity of the reactions as specified in Table 7, Section 6.2.2.1 of the protocol. 
Frequency (n) and percentage (%) of subjects with local reactions at the injection site are to be summarised by 
reaction grade and visit for each treatment group. 
All injection site reactions are to be listed.  
16.7.3. 
PREGNANCY  
A pregnancy test is to be performed for women of childbearing potential at Screening, each Study Drug 
Administration visit, End of Treatment and Follow-up Visit.  
Pregnancy test results as captured on the Pregnancy eCRF (PREG) per Visit is to be listed only.  


 
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17. REFERENCES  
Dobson, A. J. (2002). An introduction to generalized linear models, 2nd ed. Chapman & Hall/CRC. 
EMA. (n.d.). Guideline on Missing Data in Confirmatory Clinical Trials. Retrieved December 15, 2011, from European 
Medicines Agency: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/WC500096793.pdf 
Little, R., & Yau, L. (1996). Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs. Biometrics , vol 52, 
1324-1333. 
 
 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
DATES & TIMES 
 
Depending on data available, dates and times are to take the form ddMMMyyyy HH:MM. 
SPELLING FORMAT 
 
The spelling format to be used is English UK.  
UNIVARIATE STATISTICS 
 
Statistics should be presented in the same order across tables (i.e., n, Mean, SD, Median, Minimum, Maximum) 
 
If the original data has N decimal places, then the summary statistics should have the following decimal places: 
o 
Minimum and maximum: N 
o 
Mean, median and CV%: N + 1 
o 
SD: N + 2 
o 
Missing statistic: N 
FREQUENCIES AND PERCENTAGES (N AND %): 
 
Percent values should be reported inside parentheses and reported to one decimal place 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL TH005 
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 
Missing category for categorical data is only to be presented if there is missing data for a specific category and 
percentage is not to be calculated for missing category counts. An example is given below: 
Gender 
 
 
 
 Male 
n (%) 
 
xxx (xxx.x) 
 Female 
n (%) 
 
xxx (xxx.x) 
 Total 
n (%) 
 
xxx (100.0) 
 Missing 
n 
 
xxx 
 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL TH005 
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PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups are to be represented as follows and in that order: 
Treatment Group 
For Tables, Listings and Graphs 
Placebo  
Placebo 
HDM-SPIRE 4 x 12 nmol 
HDM-SPIRE 4x12 nmol 
HDM-SPIRE 4 x 20 nmol  
HDM-SPIRE 4x20 nmol 
HDM-SPIRE 8 x 12 nmol  
HDM-SPIRE 8x12 nmol  
PRESENTATION OF VISITS 
For outputs, visits are to be represented as follows and in that order: 
Long Name (default) 
Short Name  
Visit 1A 
1A  
Screening 
1B/C 
Visit 2A 
2A 
Visit 2B 
2B 
. . .  
. . .  
Visit 4F  
4F 
End of Dosing 
3I 
Follow-up 
5 
LISTINGS 
All listings are to be ordered by the following (unless otherwise indicated in the template): 
 
Randomised treatment group (or treatment received for safety output), first by placebo then active dose [by 
ascending dose group]. 
 
Centre-subject ID,  
 
Date (where applicable), 
For listings where non-randomised subjects are included, these are to appear in a category after the randomised 
treatment groups labelled ‘Not Randomised’. 
 
 


 
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APPENDIX 2. 
PARTIAL DATE CONVENTIONS 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
Adverse events (AEs) are allocated to study periods (pre-treatment or treatment-emergent) based on their start 
dates as specified in Section 16.1 Adverse Events. 
Incomplete dates are to be handled as follows: 
Partial start or stop dates:  
 
The events are allocated to the study periods using the available partial information on start and end date, no 
imputation is to be done. If, for instance, for the AE start date only month and year are available, these data 
are compared with the month and year information of the first and last study medication administration.  
Completely missing start date:  
 
The event is allocated as treatment-emergent, except if the end date of the AE falls before the date of first 
study medication administration then it is classified as pre-treatment. 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
Concomitant medications (CMs) are allocated to study periods (prior or concomitant) based on their start or end 
dates as specified in Section 12 Medications.  
Partial start or stop dates:  
 
In case of a partial start and/or stop date, the medication is allocated to each possible study period using the 
available partial information, no imputation is done. If, for a medication start and/or stop date, only month and 
year is available, this date is compared with the month and year information of the first and last dose of study 
medication administration for assignment. 
 
In case of a completely missing start date, the medication is considered as having started before the study. In 
case of a completely missing stop date, the medication is considered as ongoing at the end of the study. 
  
 
 


 
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APPENDIX 3. 
COMPLETE QUESTIONNAIRES  
Rhinoconjunctivitis Quality of Life Questionnaire 
01. REGULAR ACTIVITIES AT HOME AND AT WORK (tasks that you have to do regularly at work and around your 
home) 
02. SOCIAL ACTIVITIES (e.g., activities with your family and friends, playing with children and pets, sex, hobbies) 
03. OUTDOORS ACTIVITIES (e.g., gardening, mowing the lawn, sitting outdoors, sports, going for a walk) 
04. Difficulty getting to sleep 
05. Wake up during night 
06. Lack of a good night’s sleep 
07. Fatigue 
08. Thirst 
09. Reduced productivity 
10. Tiredness 
11. Poor concentration 
12. Headache 
13. Worn out 
14. Inconvenience of having to carry tissues or handkerchief 
15. Need to rub nose/eyes 
16. Need to blow nose repeatedly 
17. Stuffy/blocked 
18. Runny 
19. Sneezing 
20. Post nasal drip 
21. Itchy eyes 
22. Watery eyes 
23. Sore eyes 
24. Swollen eyes 
25. Frustrated 
26. Impatient or restless 
27. Irritable 
28. Embarrassed by your symptoms 


 
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Pittsburgh Sleep Quality Index 
01. 
During the past month, what time have you usually gone to bed at night?  
02. During the past month, how long (in minutes) has it usually taken you to fall asleep each night?  
03. During the past month, what time have you usually gotten up in the morning? 
04. During the past month, how many hours of actual sleep did you get at night? (This may be different than the 
number of hours you spent in bed.)  
05. During the past month, how often have you had trouble sleeping because you… 
a) Cannot get to sleep within 30 minutes  
b) Wake up in the middle of the night or early morning  
c) Have to get up to use the bathroom  
d) Cannot breathe comfortably  
e) Cough or snore loudly  
f) Feel too cold  
g) Feel too hot  
h) Had bad dreams  
i) Have pain  
j) Other reason(s), please describe How often during the past month have you had trouble sleeping because of 
this?  
06. During the past month, how would you rate your sleep quality overall? 
07. During the past month, how often have you taken medicine to help you sleep (prescribed or “over the 
counter”)?  
08. During the past month, how often have you had trouble staying awake while driving, eating meals, or 
engaging in social activity?  
09. During the past month, how much of a problem has it been for you to keep up enough enthusiasm to get 
things done?  
10. Do you have a bed partner or room mate?  
If you have a room mate or bed partner, ask him/her how often in the past month you have had 
a) Loud snoring 
b) Long pauses between breaths while asleep 
c) Legs twitching or jerking while you sleep  
d) Episodes of disorientation or confusion during sleep  
e) Other restlessness while you sleep; please describe