Safe and Effective Headgear Accessory for Exercise-Induced Laryngeal Obstruction Studies (HALOS) - a Device Development Study
Phase: NA
Conditions: Exercise-Induced Laryngeal Obstruction
Sponsor: Liverpool University Hospitals NHS Foundation Trust

HALOS Protocol =
Liverpool University Hospitals
NHS Foundation Trust
' S t u d y  Protocol
Study Title: Safe and Effective Headgear Accessory for Exercise-Induced
Laryngeal Obstruction Studies (HALOS) — a Device Development Study >
Internal Refergnce No: SP0707
IRAS Project ID: 293234
EUDAMED: nla
U'Dl: nla
Version No: 1.0
Date: 22nd Sept 2021 .
IRAS Pr'oject ID 293234 
CONFIDENTIAL 
Page 1 of 35
HALOS Study Protocol V1.0 
. 
-
22nd Sept 2021' ‘

HALOS Protocol
SIGNATURE PAGE
The undersigned confirm that the following protocol has been agreed and accepted and that
the Chief Investigator agrees to conduct the study In compliance with the approved protocol
and will adhere to the principles outlined In the Declaration of Helsinki, the Liverpool
University Hospitals NHS Foundation Trust SOPs, and other regulatory requirement.
I agree to ensure that the confidential information contained in this document will not be used'
for any other. purpose other than the evaluation or conduct of the investigation without the
prior written consent of the Sponsor
I also confirm that I will make the findings of the study publicly available through publication
or other dissemination tools without any unnecessary delay and that an honest accurate and 
.
transparent account of the study will be given; and that any discrepancies from the study as
planned in this protocol will be explained. 
'
For and on behalf of Liverpool University Hospitals NHS Foundation Trust
Signature:
cupVI-gllooobounlnoa 
. .  . . . . . . ‘ . ‘ . . ' . . m . . . ‘ . . . 5 . ; . r . . . , . . . ~ . . . . " n u . . . " a n ” . . . u u u u .......................
. u - n " g o u g n ' u u - " u u u n u u o n u u - n c u n n o u n n n - n u n n u .  
t h a n . " L i - - u ‘ n ‘ . . ‘ . ‘ ( l i . ‘ - _ n ' u . u s i
Chief Investigator:
Signature: 
Date: 22/Sep/2021
Name: Dr Tristan Payne
IRAS Project ID 293234 
CONFIDENTIAL 
. 
_ Page 2 of 35
- HALOS Study Protocol V1.0 ‘ 
‘
22"d Sept 2021

HALOS Protocol
Key Study Contacts
Chief Investigator 
Dr Tristan Payne
- 
‘ 
Medical Physics and Clinical Engineering
Royal Liverpool Hospital
Liverpool University Hospitals NHS Foundation Trust
Duncan Building, 1st Floor
Prescot Street
Liverpool L7 8XP
Tel: 0151 706 4223
v 
E-  mail. tr.istan gayne@nhs.net
Study Co-ordinator 
Dr Tristan Payne
- 
Medical Physics and Clinical Engineering
Royal Liverpool Hospital
Liverpool University Hospitals NHS Foundation Trust
Duncan Building, 1st Floor
V Prescot Street
Liverpool L7 8XP
Tel: 0151 706 4223
E-mail: tristan.ga¥ne@nhs.net
Sponsor 
Heather Rogers
R&| Governance Manager
4th Floor Linda McCartney
Royal Liverpool Hospital
Prescot St
Liverpool L7 8XP
Tel: 0151 706 3702'
Fax: 0151 706 3703
Email: heathenrogersQlivergooift.nhaug
Group email: RGT@Iive[Qoolft.n'hs.uk
Joint-sponsor(s)/co-sponsor(s) 
n/a
Funder(s) 
Medical Physics and Clinical Engineering
' 
' 
and Respiratory Department
‘ 
‘ 
Liverpool University Hospitals NHS Foundation Trust
: Key Protocol Contributors 
Charlotte Orledge (left employment with the Trust
Sep/21)
Trainee Clinical Scientist (Clinical Engineering)
Medical Physics and Clinical Engineering
Royal Liverpool Hospital
Liverpool University Hospitals NHS Foundation Trust
E-  mail: Charlotte. orledgets 
net
‘ Joanne Clayton
Clinical Specialist Speech & Language Therapist.
Speech & Language Therapy Department
Royal Liverpool Hospital
Liverpool University Hospitals NHS Foundation Trust
E-mail: ioanne.clavton@livergoolft.nhs.uk
IRAS Project ID 293234 
CONFIDENTIAL 
Page 3 of 35
HALOS Study Protocol V1.0
22”‘1 Sept 2021

HALbS Protocol
Antonio Eleuteri
Consultant (statiStics) 
.
Medi’cal' Physics and Clinical Engineering
Royal Liverpool Hospital 
,
Liverpool University Hospitals NHS Foundation Trust
E-mail: antogio.eleuteriiverpoolft.nhs.u§ ,, , 
7
Committees 
n/a
IRAS Project ID 293234 
CONFIDENTIAL 
, 
Page 4 of 35
HALOS Study Protocol V1.0 
:
22"d Sept 2021

HALOS Protbco’l
Confidentiality Statement
This document. contains confidential information that must not be disclosed to anyone other
than the Sponsor, the Investigator Team, host (5), regulatory authorities, and members of the
Research Ethics Committee.
IRAS Project I D  293234 
CONFIDENTIAL 
Page 5 of 3 5
HALOS] Study Protocol V1.0v 
' ' 
.
22nd Sept'2021 
‘ '

HALOS Protocol
TABLE OF CONTENTS
1. 
' A M E N D M E N T  
HISTORY 
..
2. 
SYNOPSIS..........................
3. 
ABBREVIATIONS 
.
4. 
BACKGROUNDAND RATIONALE.........................
4 . 1  
c o n d i t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . _ . . . 4 " . . ;
 ......... 'n‘. . . . . . . Juanwgn'm'n.
4 . 2  
CurrentPractice.............‘...........
4.3 
Existing Research
4.4 ‘ RationaleforCurrentStudy.............
4.5 
Regulatory Compliance
5. 'OBJECTIVES .................................. 
.....
5.1 ‘ Prirriary O
b
j
e
c
t
i
v
e
.
.
.
 
.
5.2 
Secondary Objectives 
..
. 6. TRIAL DESIGN
6.1 
Summary of Trial DeSIgn 
..
6.2 
Primary and Secondary Endpoints/Outcome Méasures.....r...._...'.'...r..A...—.....z......
6.3 
Trial Participants 
..
6.4 
Study Procedures
6.5 
Discontinuation] Withdrawal of Participants from Study Treatment.,...., ........
6.6 
Source Data ................................ '. ................................... '.............. 
....... -.
‘7. TREATMENT OF TRIAL PARTICIPANTS..............; ............................ 
................
7.1 
Description of Study Intewention(s)..................:................................r..... ..
1o ,
__'_,._'12
13
13
15
15
I l l o l ' u i r l l ' n o l l l n o - I I I  
o u n u - n  - 
a n :
7.2 
Maintenance and storage of deVIce
7.3 
RlskManagement 
...............
8. SAFETYreporting; ................................................. 
............ .....
8.17 Deflmtlons
IRAS Project ID 293234 
_
HALOS Study Protocol V1.0 .
22"‘1 Sept 2021
CONFIDENTIAL
.. 
16.
16
1e
16 ‘
..... 16
16
17
17
.. 18
21
22
22
22
....25
25
26
26
Page 6 of 35

8.2 Reporting of AEs ......................... 
........................ 
28
8.3 
Reporting of DDs/SAEs/SADEs/USADEs.......-......................:.........-...-.....-..-...-....;;..»...» 28
8.“; 
Safety Reports ........... 
................................. 
29
9. STATISTICS 
........... 
..... ,1....29
9.1 
Description of Statisticél Methods 
29
9.2 ’ The Number of Paﬁicipants........; ......._ .......... ‘...................'............... ‘ ......... . 
29
I 9.3 
The Level of Statistical Significahce 
30
9.4 
Criteria for the Termination of the Trial 
30 '
9.5. 
Procedure for Accounting for Missing; Unused, and Spurious Data.......,‘..... 
..... 30
9.6 ‘ Procédure for Reporting any Deviation(s) from the Original Statistical Plan ........ 
30
9.7 
Inclusion in Analysns 
....................................;;.....-.,..30
10. 
Direct Access to'Source Data/Documents 
30
_ 11. 
Quality Control and ,ality 
Assurance Procedures 
30
12. Ethics .................... -. .........................7................................... 
31
12.1 Declaration of Helsinki...~....................._ ......................................................... 
31
12.2 ICH Guidelines for Good Clinical Practice 
....., 3 1  .
12.3 A
p
p
r
o
v
a
l
s
’
3
1
’ 12.4 Participant Confidentiality”................................................................................, ,_.,.,..531
_ 12.5 -Other Ethical Considerations............................................................; .......... f.....».r.;.,v32
13., 
Data Handling and Record keeping ...................... V........... 
32
. 1 4 . ,  Financing and l
n
s
u
r
a
n
c
e
3
2
15. 
End ofstudy defInItIon 
............................ , ........W 3 3
16. 
Publication i30|icy .................... , .............' 
...... ,......{..n.:..r..~.r.~.33
17. Archiving 
............. 
33
18. 
References 
....... 
......... 
........ 
....., 
......................- 
35
IRAS Project ID 293234, 
CONFIDENTIAL 
' 
Page 7 of 35
'HALOS P‘rotocol
HALOS Study Protocol V1.0
. 22ndSept2021 '

HALOS Protocol
IRAS Project ID 293234 
CONFIDENTIAL 
Page 8 of 35
HALOS Study Protocol V1.0 
. 
-
22nd Sept 2021

HALOS Protocol
1. AMENDMENT HISTORY
Initial version 1.0 issued 22/Sep/2021
Amendment 
Protocol 
’ 
Date 
A/uthor(s) of 
Details of Changes
No. 
Version No. 
issued 
changes 
made
IRAS Project ID 293234 
CONFIDENTIAL 
. 
Page 9 of 35
HALOS Study Protocol V1.0 
‘
22nd Sept .2021

HALOS Protoéol
2. SYNOPSIS
Study Title 
Safe and Effective Headgear Accessory for Exercise-Induced-
Laryngeal Obstruction Studies (HALOS)- a Device
7 
‘ 
Development733l
Internal ref. no. 
SP0707
JXEOf 
study 
7 Interyentional
Trial Design 
Single Group Assignment.
Trial Participants 
Adults with suspected Exercise- Induced Laryngeal Obstruction
(EILO) capable of undertaking a Continuous Laryngoscopy
__ ‘_ 
Vi# 
A during Exercise (CLE) test.
Pla‘nned Sample Size 
30 participants.
Follow-QB duration 
There will be no follow--up.
ﬂungd 
Ttial Eeriod — 12 months.
Primary Objective 
Ensure the HALOS headgear is suitable for facilitating CLE
tests.
Se'condary 
o 
Validate 
risk 
scores identified in risk management
Objectives 
documentation.
- 
Validate mitigations of hazards identified'In risk management
documentation.
0 
Uncover previously Unforeseen hazards, especially any
relat_ed to_usability.
Primary Endpoint 
Device effectiveness, measured by the proportion of CLE tests
where the endoscopy image Was clear and stable enough to
allow a diagnosis of EILO to be confirmed or ruled out. 
‘
Secondary Endpoints 
i) Device usability rating, measured by the fraction of
subjective usability ratings 2 4 on the post-test questionnaire.
Clinic1ian--reported usability will be scored on a five-point LIKERT
scale ranging from 1 (very hard to use) to 5 (very easy to use).
Observations will be made throughout the session 
K
ii) Device usability subjective feedback, focussing -on any
clinician- reported'concerns regarding set-up, operation and
cleaning.
iii) Device tolerability ratings measured by the fraction of
subjective tolerability ratings > 3 on the post-test questionnaire.
Participant-reported tolerability will be scéred on a four-point
LIKERT scale ranging from 1 (very intolerable) to 4 (very
.tolerable).
iv) Device tolerability subjective feedback, focussing on any
participant-reported concerns regarding the comfort of the
headgear including how hot their head felt, weight of the
headgear, how secure the headgear felt and the impact of the
headgear on their performance during the investigation.
Device Name 
Headgear Accessory for Larynggal Obstruction Studies (HALOS):
1 The LIKERT scale is a widely used type of psychometric response scale in which responders specify
their level of agreement to a statement typically in five points (Preegy & Watson, 2010). Empirical
evidence shows this scale has 90% reliability and 89% validity (Louangrath, 2018).
IRAS Project ID 293234 
CONFIDENTIAL 
' 
Page 10 of 35 '
HALOS Study Protocol V1.0
22nd Sept 2021

I HALOS Protocol .
Mandfacturer Name 
‘ Medical Physics and Clinical Engineering, Liverpool University
HospitaJ§ NHS Foundation Trust i 
- 
\
Principle intended 
The device is intended to be USed with an endosCope and
use 
' 
enable the larynx to be observed during CLE tests. It is' intended
for use oh patients with suspected EILO.
Length of time use 
The device is not currently in we as this is a new design.
the device has been
in use.
IRAS Project ID 293234 
CONFIDENTIAL 
- 
Page 11 of 35
HALOS St'udy‘ Protocol V1.0
22”‘1 Sept 2021

HALQS_ Protocol
3. ABBREVIATIONS
AE 
‘ Adverse event
ADE 
Adverse Device Effect ' 
.\
Cl 
Chief Investigator
CLE : 
Continuous Léwngoscopy during Exercise ~
CRF , 
Case Report Form
.CRO 
Contract Research Organisation
CT 
Clinical Trials
CTA 
Clinical Trials Authorisétion
EILO 
Exercise Induced Laryngeal 
Obstruction
GCP 
Good Clinical Practice 
I
GP 
General Practitioner 
‘
HRA 
Health Research Authority
ICF 
Informed Consent Form
- ICH 
Inte'rnational Conference of Harmonisation
LUHFi’ 
Liverpool University Hospitals NHS Foundation Trust
MHRA 
Medicines and Healthcare products‘Regulatory Agency
NHS “ 
National Health Service
NRES 
National Research Ethics Service (previously known as COREC)
Pl 
Principal Investigator
PIL 
Participant/ Patient InformatiOn Leaflet
R&| 
R&| Department
REC 
Research Ethics Comrﬁittee
SAE 
Serious Adverse Event
SADE 
‘ Serious Adverse’ Device Effect
SIL 
Subject Information Leaﬂet (see PIL)
IRAS Project ID 293234 
CONFIDENTIAL
HALOS Study Protocol V1.0
22"d Sept 2021
Page 12 of 35

HALOS Protocol 
-
SOP 
Standard Operating Procedure
TMF 
Trial Master File
USADE 
Unanticipated Serious Adverse Device Effect
4. BACKGROUND AND RATIONALE
4.1 . Condition
Exercise-induced laryngeal obstruction (EILO) is a condition in Which closure of the larynx
occurs during high-intensity exercise. The reduction in airflow due to airway narrowing
results in breathlessness and wheeze, and the patient may also report a cough or throat _
. discomfort that can persist for some time (Hall, et al., 2016).
Whilst symptoms usually resolve soon after stopping exercise, an episode of EILO can
impact on athletic performance and in competitive sports people can thereby impact on their
careers. In all individuals, sudden onset EILO can lead to breathlessness inducing significant
fear, panic, loss of control and pain (Carel, etal., 2015).
4 . 2  
Current Practice 
.
Due to the presentation of the condition, there is a large differential diagnosis, and the
patient is often diagnosed with exercise-induced asthma (bronchocolnstriction) and
prescribed a short-acting bronchodilator. However, there are differences between thé two
conditions. The symptoms in EILO arise during high-intensity exercise and settle rapidly
(within 5 minutes of exercise cessation), whereas with exércise—induced bronchoconstriction
the symptoms onset following exercise ceséation (5-10 minutes). Additionally, the wheeze of
EILO is typically high pitched and occurs during the inspiratory phase of the breathing cycle.
How,ever, narrowing of the‘lower airway results in a polyphonic basal wheeze, and occurs
during the expiratory phase (Hall, et al., 2016).
Incorrect diagnosis éan lead to a large pharmacological burden for the patients with many
being incorrectly treated with regular doses of steroids with little or'no clinical effect
(Newman, et al., 1995; Traister, et al., 2013). 
V 
l
‘ EILO is often diagnosed in young athletes, and a cross-sectiona! study of 12-13 year-olds in
Sweden 
found a prevalence of approximately 6% (Johansson. et al., 2015). However, a '
study found that EILO may be as prevalent as exercise-induced bronchoconstriction, and
these two conditions may coexist in over 10% of individuals (Nielsen, et al., 2013).
IRAS Project ID 293234 
CONFIDENTIAL 
Page 13 of 35 '
HALOS Study Protocol V1.0 
- 
-
22nd Sept 2021' 
'

HALOS Protocol
Whilst clinical featufes can differentiate EILO from exercise-induced bronchoconstrictionp
studies have shown that discriminatory questions (e.g. difficulty breathing in when exercise)
have a poor diagnostic value. A ‘study has also shown that a diagnosis of EILO cannot be
made by resting or post-exercise spirometry, hr by peak flow measurement (Christensen, et ‘
al., 2013). Additionally, as EILO presents during high-intensity exercise, inv'estigations during
resting state may not provide a reliable diagnosis‘f
Clinicians have observed patients, either in person or by video recording, as they develop
symptoms to review the presentation and onset. However, 
this Method of investigation has
not yet beenformally studied (Hall, et al., 2016). 
'
The gold standard for a diagnosis of EILO is a continuous? laryngoscopy exercise (CLE) test,
in which a flexible endoscope is used to monitor the laryngeal movement in real-time dgring
exercise (Hall, et al., 2016). The tip of the endoscope is positioned in the mesopharynx
(identified in FigUre 1) by the'clinician, who uses the live image from the endoscope to guide
its position. A securing headgear is essential to keep the endoscope in a fixed position while
the patient exercises, both to achieve a Stable image and for the safety of the patient. An
, example of a CLE test set-up is displayed in Figure 2. This method of investigatiOn 1s not
currently 
offered by LUHFT, and other centres we have contacted provide the service using
a non-CE/UKCA marked headgear.
Nuophuyng
(EPIPIIWX)
Oropharynx
(Mesoplutynx)
Laryngophuynx
(HYPoPlIarynx)
Figure 1: showing the location of the mesopharynx, taken from (Jamés F. Bosma M.D., 1986)
IRAS Project ID 293234 
CONFIDENTIAL 
_ 
Page 14 of 35
HALOS Study Protocol V1. 0 '  
‘ 
_
22"‘1 Sept 2021 V ' 
' 
' 
\

HALOS Protocol
Tut-hill 
cum-In]
Wu: 
W
Dim 
W “
W 
"m 
_ 
5mm: 
“1*
Slkly Mum
ECG luck
I2 Ind
plIn‘
“WW
Figure 2: Continuous Iaryngoscopy exercise (CLE) test (Hall, et  al., 2016)
4.3 Existing Research
Studiés have been carried out to investigate EILO, and several. mention the use of a
specialised headgear (Hull, et al., 2019; Heimdal, et al., 2006; Olin, et al., 2016). However,
there has been no formal research published regarding the headgear itself.
4.4 Rationale for Current Study
A headgear is necessary to carry out CLE tests for the investigations of EILO, as the
endOscope must be kept stable for both image quality and patient safety. There is no
commercial option existing on he market at preSent, and 6ther centres have manufactured
their headgear in-house (Liverpool Heart and Chest Hospital (LHCH).‘Roya| Brombton
Hospital). 
' 
' *
Without a specialised héadgear it is not possible to carry but CLE tests at LUHFT, and
patients are sent for investigations at LHCH. This study is an essential step in improving the
- cafe that can be offered by LUHFT for sufferers of EILO. Evaluating the in-house design of
headgear is necessary to support its safe and effective clinical use in accordance with the.
Medical Device Directive (MDD) 93/42 and in the spirit of the European Medical Device '
Regulations (MDR) 2017/745. By producingan in-house manufactured headgear, it will
enable LUHFT to provide an additional service for patients, avoiding the inconvenience to '
them of having to travel further afield.
IRAS Project ID 293234 
' CONFIDENTIAL 
- Page 15 of 35-
HALOS Study Protocol V1.0
22nd Sept 2021

HALOS Protocol
Therefore, the hypothesis for this study is that the HALOS headgear is sufficiently éffective
for clinical use, and that the risks are understood adequately for an accurate benefit/risk ratio
evaluation.
4.5 Regulatory Compliance
The device is intended to be used with an endoscope and enable the larynx to be observed
during CLE tests. According to the MDD it is classified as an accessory for a medical device
and therefore the MDD would apply. However, the headgear is not intended to be mgde
commercially available or UKCA/CE marked, nor will it be used outside the Trust where it is
' manufactured. Consequently, as it is not being ‘put into servicé’ nor 'placed on the market’, it
is not sUbject to the requirements of the MDD. 
Nonetheless, the headgear has been
specified, designed and manufactured following a Quality Management System (QMS)
aligned ‘ w i t h  BS EN ISCS 134852016 QMS requirements for medical devices, the MDD and
EUropean MDR. This includes Post Market Surveillance activities.
' 5. OBJECTIVES
5.1 
Primary Objective
En'sUre the HALOS headgear is suitable for facilitating CLE tests.
5.2 Secondary Objectives
Validate risk scores identified in risk management docﬁmentation.
Validate mitigations of hazards identified in risk management documentation,
Uncover previously unforeseen hazards, especially any ielated to usability.
6. TRIAL. DESIGN
6.1 Summary of Trial Design
The study is an interventional clinical trial involving a singl‘e group of 30 participants
undergoing a CLE test with the HALOS headgear.
Participants will be required to attend a single consultation and screening appointment to
discuss the investigation procedure, and this will occur at least a week before the OLE teét.
Participants 
Will then attend one appointment 
for the OLE test. There will be no follow up
assessments using the headgear.
IRAS Project ID 293234 
CONFIDENTIAL 
Page‘16 of 35
HALOS ‘ Study Protocol V1.0 
'
22"d Sept 2021

HALOS Protocol
6.2 Primary and Secondary Endpoints/Outcome Measures
6.2.1 Primary Outcome Measure -
Device effectiveness, measured by the proportioh of CLE tests where the endoscopy image
was clear and stable enough to allow a diagnosis of EILO to be confirmed or ruled out.
6.2.2 Secondary Outcome Measures
i) Device usability rating, measured by the fraction of subjective usability ratings 2 4 on 'the
post—test questionnaire. Clinician-reported usability will be scored on a five-point LIKERT
scEale2 ranging from 1 (very hard to use) to 5 (very easy to use). Observations will be made
throughout the session.
ii) Device usability subjective feedback, focuséing 6n any clinician-reborted concerns
regarding set-up, operation and cleaning.
iii) Device tolerability, ratings-measured by the fraction of subjective tolerability ratings 2 3
on the post-test questionnaire. Participant-reported tolerability will be scored on a four-point
LIKERT scale ranging from 1 (very intolerablle) to 4 (very tolerable).
iv) DeVice tolerability subjective feedback, focussing on any participant-reported Concerns
regarding the comfort of the headgear including how hot their head felt, weight of the
headgear, how secure‘ the headgear felt and the impact of the héadgear on their
performance during the investigation.
6.3 
Trial Participants
6.3.1 Overall Descripfion of Trial Partiéi/pants
Participanté will be patients of the Liverpool University Hospitals NHS Foundation Trust with
suspected EILO and who have been selected for OLE testing to confirm the diagnosis.
6.3.2 
Inclusion Criteria
0 
Participant is willing and able to give informed consent for participation in the study,
20' Male, female or non-binary, aged 18 years or above.
a 
Able (in the Investigators opinion) and willing to comply with all study requirements;
2 The LIKERT scale is a widely Used type of psychometric response scale in which responders specify
their level of agreement to a statement typically in five points (Preedy & Watson, 2010). Empirical
evidence shows this scale has 90% reliability and 89% validity (Louangrath. 2018).
IRAS Project ID 293234 
' 
CONFIDENTIAL 
' 
Page 17 of 35
HALOS Study ~Protocol V1.0 
'
22nd Sept 2021

HALOS Protocol
0 
Able to undergo a CLE test as judged by the clinician, and where a clinical need of
the test for the delivery of healthcare has been identified.
6.3.3 Exclusion Criteria
The participant may not enter the study if ANY of ‘the following apply:
. 
' P a i n .  sore areas, broken skin at the site of contact with the headgear.
9 
Devices, 6.9. cochlear implants, that impege the(use of the headgear;
0 
Head circumference is less than 500m or greater than 63cm, reflecting the ‘3'“ centile
for females and 97‘h centile for males, respectively (Bushby, 1992).
o 
Exclusion criteria for endoscopy procedures:
cu Sk_u|| base/facial surgery or fracture within the previous six weeks
0 
Major or life threatening epistaxis within the previous six weeks
0_ Trauma to nasal cavity secondary to surgery or injury within the previous six
weeks
Sinojnasal and anterior skull base tumours/surgery
Nasopharyngeal stenosis 
'
O 
O 
O
CranidfaciaI anomalies
Hereditary haemorrhagic telangiectasia
O
0
Severe movement disorders and/or seVefe agitation
o Vasovagal history
— o Bleeding risks
0 
Any Other exclusion criteria as identified by the current endoscopy procedure; ‘
6.4 Study Procedures
6.4.1 
Informed Consent
The participant must personally 
sign and date the latest approved version of the informed
consent form before any; study specific procedures are performed.
Written and verbal versions of the participant information and Informed consent will be
presented to the participants detailing no less than: thé exact nature of the-study; the
implications and ,constraints of the‘ protocol; the known Side’effects and any risks involved in
taking part. 
It will be clearly stated that the participant 
is free to withdraw from the study at‘
any time for any reason without prejudice to future care, and with no obligation to give the
reason for withdrawal. Participants will be assured that their individual results will be used to
‘ help diagnose and treat their breathlessness.
IRAS Project ID 293234 ~ 
CONFIDENTIAL 
. 
Page 18 of 35
vHALOS Study Protocol V1.0
22nd Sept 2021

HALOS Protocol
. The participant will be allowed as much time as wished to consider the information, and the
opportunity to question the Investigator, their GP or other independent parties to decide
whether they will participate in the study. Written Informed Consent will then be obtained by
means of participant dated signaturé and dated signature of the person who presented and
obtained the informed consent. The person who obtained the consent must be suitably
qualified and experienced, and have 
been authorised to do so by the Chief/Principal '
Investigator. A copy of the signed Informed Consent will be given to‘ the participants. The
original signed form will be retained at the study site.
6.4.2 
Screening a n d  Eligibility Assessment
The Principal Investigator Will review patient records from an existing list of patients awaiting
CLE tests. _All [patients will have been referred for opinion regarding their breathlessness.
Participants will be checked for eligibility to enter the. study prior to arranging a clinic session.
This service is not currently offered by LUHFT.
For all potential study participants, a consultation appointment will be arranged to be
conducted at least a week before the investigation appointment. During the consultation, the .
‘ study will be explained, and the participant will be'given the Participantlnformation Sheet.
The séreen'ing procedure will be conducted during the consultation appointment. This will
involve an eligibility check to ensure that the participant meets the inclusion criteria and none'
of the exclusion criteria apply, as defined in Sections 6.3.2 and 6.3.3, respectively.
6.4.3 
Baseline Assessments
Head circumference. recorded during the investigation appointment.-
6.4.4 
Subsequent assessments
FolloWing the consultation appointment, the participant will attend qne investigation.
appointment to undergo the OLE test on-site at the Outpatient Departmen't, Alexandra Wing,
Broadgreen Hospital. There will be no follow-up assessments.
O n  the day of the investigation appointment, the Principal Investigator will address any
.questions or concerns before the investigation begins. If the participant still wishes to partake
in the study, signed conSent will be obtained from the participant. The right of the participant
to refuse to participate Without giving reasons will be respected. After the participant has
entered the study the clinician remains free to give alternative treatment to that specified in
the protocol at any stage if he/she feels it is in the participant’s best interest, but the reasons
IRAS Project ID 293234 
CONFIDENTIAL 
Page 19 of 35
HALOS Study Protocol V1.0
22nd Sept 2021

HALOS Protocol
for doing so should be recorded. In the’se cases, the participants remain within the study for-
the purposes of data analysis.
Eligibility will be reviewed for any changes, ensuﬁng that the participant meets the inclusion
criteria and none of the exclusion criteria apply. As part of this, the circumference of the
participant’s head around the forehead will .be measured and recorded. Signed Consent will
then be obtained. The participant will then undergo the OLE test following standard clinical
. practice.
The order of events of the aspeété of the investigation related to the headgear will be:
1. The headgear is preparéd for use. '
The headgéar' is fitted onto the participant’s head.
The endoscope is inserted into the participant.
The endoscope is fitted onto the headgear.
5. The CLE iest is carried out.
‘ 6. The endoscope is removed from the headgear.
- 7.. Thé endoscope is rémoved from the participant.
8. The headgear is removed from the participant.
9. The headgear is cleaned and stored.
Following completion of the OLE test, the participant will complete a questionnaire:
0 
How tolerable was the headgear during the investigation?
. 1) Highly intolerable
2) Intolerable
3) Tolerable
4) Highly tolerable
0 
Please tell us any concerns about the headgear. thinking about how comfortable it
was, how hot your head felt, the weight of the headgear, how secure it felt and the
impact of the headgear on your performance during the investigation.
' Following the appointment, the clinician will cOmplete a questionnaire 
including:
0 
Was the endoscopy image clear and stable enough to allow a diagnosis of EILO to
be confirmed or ruled out? (Note that participants are withdrawn from the study if the
IRAS Project ID 293234 
CONFIDENTIAL 
Page 20 of 35
HALOS Study Protocol V1.0
22nd Sept 2021

HALOS Protoc_ol
CLE test is unable to allow a diagnosis of ElLO to be confirmed or ruled out due to
reasons unrelated to the headgear.) .
How easy wéé it to use the headgear?
1) Very hard to use;
2) Hard to use;
3) Neither hard nor easy to use;
4) Easy to use;
5) Very easy to use.
Please record any concerns about the headgear, thinking particularly about set-up,
operation and cleaning.
Data will be handled as detailed in SeCtion 13 Data Handling and Record Keeping.
6.5 
Discontinuation] Withdrawal of Participants from Study Treatment
Each participant has the right to withdraw study at any time. In additioh, the investigator may
discontinue a participant from the study at any time if the investigator considers it necessary
for any reason including:
Pregnancy
Ineligibility (either arising during the study or retrospective having been overiooked at
screening)
Significant protocol deviation
Significant non—complianCe with study requirements
An adverse event, adverse device effect; serious'adverse device effect or
unanticipated adverse device effect which results in cessatioln - o f ‘ t h e  CLE test or
inability to continue to comply with study procedures 
I
Consent withdrawn 
‘
If the participant cannot wear the headgear, e.g. it does_ not fit.
If the OLE test is unable to allow a diagnosis of EILO to be confirmed or ruled but due
to reasons unrelated to the headgear, e.g. the participant cannot tolerate the
endoscopy.
Withdrawn participants will be replaced.
The reason for withdrawal will be recorded in'the Casé Report Form (CRF).
IRAS Project ID 293234 
CONFIDENTIAL 
Page 21 of 35
HALOS Study Protocol v1.0 
.
22"d Sept 2021

HALOS Protocol
If the participant is withdrawn due to an adverse event, thé investigator will arrange for
follow-up visits or telephone calls until the adverse event has resolved . o r  stabilised.
6.6 Source Data-
Source documents are original documents, data, and records from which participants’ CRF
'data are obtained. 
These include, but are not limited to, hospital records (from which
medical history and previous and concurrént medication may be summarised into the CRF)‘,
clinical and office charts, Device, laboratory and'pharmacy’l records, 
diaries, microfiches,
radiographs, and correspondence.
CRF entries will be considered sodrce data if the CRF is he site of the original recording
(e. 9. there is no other written or electronic record of data). In this study the CRF will be used
_ as the source document for the participant head circumference, the participant questionnaire
results, and the clinician questionnaire results.
All documents will be stored safely in confidential conditions. 
On all study-specific
documents, other than the signed consent, the participant will be referred to by the study
participant 
number/code not by name. 
‘ 
’
7. TREATMENT OF TRIAL PARTICIPANTS
7.1 ' Description of Study lntervention(s)
TWo headgears of the same design will be manufactured. The headgear is constructed from
a modified safety helmet with a clamp fixed on the front to hold the endoscope, and a
countewveight fixed on the back for comfort and stability:
A label will be attached indicating that the device is for use in the HALOS pilot study 0t by
trained ihdividuals. User instructions and training will be provided.
Headgear propegtigs:
‘0 Components:
0 [ W h i t e  Hard Hat with. Chin Strap (ABS, High-Strength Polyester, Nylon,
Polycarbonate, Polyethylene)
'.° C|amp(AIuminum)
- o Clamp mount (Steel)
0 Secondary fixture (Steel)
IRAS Project ID 293234 
CONFIDENTIAL 
- - 
. 
Page 22 of 35 "
HALOS Study Protocol v 1 0 .
22nd sept 2021

HALOS Protocol
' o Endoscope strap (Velcro)
0. Chin strap (Velcro)
o 
Couritewveight (steel). 4
0 
Weight: 1.5 kg
. Below are photos of the HALOS headgear device placed 9n a dummy head with and without
the endoscope inserted. 
' 
_ 
. 
\
Clamp mount 
Hard hat
Clam 
‘ 
‘
P \  
' 
‘ 1  
’ Adjustable
vents
Velcro — 
‘
strap 
7 
_ _ 
1.
Secondary 
Countewveight
ﬁxture.
( 
.
- Knob for
' 
\ 
djusting
Chln / 
a
straps 
ggzdband
Figure 3: A labelled diagram of the HAEOS headgear positioned on a dummy head
. IRAS. Project ID 293234 
CONFIDENTIAL 
‘ 
'Page 23 of 35
HALOS. Study Prqtocol V1.0_ 
'
_ 22"d Sept 2021 '

HALOS Protocol
f
L 
‘l
l
1C 
i
L .  
A. 
‘ 
H
7“?“
> ' ' 
- 
-‘ » 
‘ 
‘ ﬁ 
_
Figure 5: A front view of the HALOS 
' 
Figure 5: A top view of the HALOS
headgear positioned on a dummy head ‘ 
‘ 
headgear 
'
_ IRAS Project ID 293234 « 
CONFIDENTIAL 
V 
Page 24 of 35
HALOS Study. Protocol V1.0
22"“ Sept 2021

HALOS Protocol
' (a)
(c) 
‘ ' (d) 
n)
‘ 1 -
O
"
n_" 
. 
L' _ 
; 
. 
A
Figure 6: The HALOS headgear with the endoscope inserted positioned on a dummy head,
showing views from (a) left side, (b) right side, (0) front, (d)Jtop, (6) back
7.2 
Maintenance and storage of device
The two headgear‘devices will be stored on-‘site at Broadgreen Hospital, LUHFT, in warm
and dry conditions.
After each participant use, the headgear will be thoroughly wiped with disinfectant wipes, and
removable fabric straps will be washed with soap and water. 
Cleaning events wil!r be
recorded.
The Velcro strap used to Secure the endoscope on the front of the headgear is single-use,
and to be disposed of after each participant assessment.
"(.3 
Risk Management
Device risks are managed by following the Department of Medical Physics and Clinical
Engineering Quality Mahagement System, which complies with ISO 1497122012 Medical
IRAS Project ID 293234 
CONFIDENTIAL 
Page 25 of 35
HALOS Study Protocol V1.0
22"d Sept 2021

HALOS Protocol
devices — Application of risk management to medical devices. A Risk Management Plan and
Risk Assessment are in use.
8. SAFETY REPORTING
8.1 Deﬁnitions"
8.1.1 Device Deficiency (DD). 
. 
7 ‘ 
7 - 
-4
This is the inadequacy of a medical device with respect to its identity, quality, durability,
. reliability, usability, safety or performance. Device deficiencies include malfunction, use error
and inadequate labelling. 
,
8.1.2 Adverse Event (AE) ‘
Any untoward mediéal occurrence, unintended disease of injury or any untoward clinical
signs (including an abnormal laboratory finding) in subjects, users or other persons, whether
or not related to the investigational medical device and whether anticipated or unanticipated.
This includes events related to the investigational device or the comparator and events
related to the procedures involved (any procedure in the study protocol). For users or other
persons, i.e. where the medical occurrence,_ unintended disease or injury -is not in the
subjegt. this definition is restricted to events related to the uée of investigational medical
devices or Comparators. 
I
No potential AEs are identified.
The categories of adverse events are shown in Table 1.
3 Source: BS EN ISO 14155:2020 Clinical Investigation of Medical Devices for Human Subjects '—
Good Clinical Practice. 
'
IRAS Project ID 293234 
CONFIDENTIAL 
. 
Page 26 of 35
HALOS Study Protocol V1.0 
-
22nd Sept 2021

HALOS Protocol
Table 1: Categories of adverse events (taken from BS'EN ISO 141552020 Table F. 1)
Adverse events 
Non-device-related 
Device- or investigational procedure-related
N 
. 
Adverse event (AB)a 
‘ 
Adverse device effect [ADE]c
on-serlous 
_ 
(3-2) 
[3.1]
Serlous adverse event 
Serious adverse device effect [SADE]
SAE '3
([145?) 
[3.44]
Serious ‘ 
‘ 
Anticipated 
Unanticipated
Anticipated serious 
Unanticipated serious
adverse device effect 
adverse device effect
(ASADE)° 
(USADE)
(3.1, Note 1 to entry) 
(3.51)
3 
Includes a l l  categories.
b 
Includes all categories that are serious.
- 
C 
Includes all'categories  that are related to the device or  the investigational proéedure.
8.1.3 Serious ‘Adverse 
Event (SAE):
SAE is an adverse event that led to any of the fdllowing:
. 0 
death 
. 
_
:- 
foetal distress, foetal death or ' c o n g e n i t a l  
abnormality or birth defect including
physical or mental impairment.
o. serious deterioration.in the Health of the subject, users nor other persons as defined by
one or more of the following: 
I
‘o a life-threatening illness or injury
.0 
a permanent impairment of a body’structure or a body function inclqding ‘
chronjc diseasgs
o in-patient or prolonged hospitalisation
0 medical or surgical intervention to prevent life-threatehing illness br injury', or
permanent impairment to a body structure or a body function
Planned hospitalisation for a pre-existing condition, or a procedure required by the Study.
Protocol, without serious deterioration in health, is not considered a serious adverse event.
8.1.4 
Adverse Device Effect (ADE)
Adverse event related to the use of an investigation medical device. This includes AEs
resulting from 
insufficient or inadequate instructions for use, deployment, implantation,
insfallation, or operation, Or any malfunction of the investigational medical device. ' This
includes the comparator if the comparétor is a medical device.
- IRAS Project ID 2932341 
' 
CONFIDENTIAL 
- Page 27 of 35
. HALOS Study Protocol V1.0 
' 
-
2.2"d Sept 202 ‘ 
'

HALOS Protocol .
.0
All AEs judged by either the reporting medically qualiﬁed professional or the sponsor as
having a reasonable suspected causal relationship to the device qualify as ADEs. For
guidance on causality assessment. refer to MEDDEV 2.7/3 Clinical Investigations: Serious
Adverse Event Reporting Under Directive 90/385/EEC and 93/42/EEC.
8.1.5 
Serious Adverse Device Effects (SADE):
' Adverse device effect that has resulted in any of the consequences of a serious adverse
-event.
All cases judged by either the reporting medically qualified professional or the sponsor. ‘
8.1.6 
Unanticipated 
Serious Adverse Device Effect (USADE):
Any serious adverse device effect which by its nature, incidence, severity or outcome has not.
been identified in the current risk assessment.
8.2 Reporting of AB:
All AEs occurring during the study observed by the investigator or reported by the participant;
whether or not attributed to the device under investigation, will be reported, without undue
delay, to the Chief Investigator and LUHFT R&D and recorded on the hospital incident
reporting system, in the source data (medical notes) and the‘ CRF. 
'Any Questions
concerning adverse event reporting should be directed to the Chief Investigator in the first
instance. 
‘
8.3 Reporting of DDsISAEsISADEs/USADEs
All SAEs, SADEs, and USADEs will be repoﬁed to the sponsor/legal representative, Chief
Investigator and LUHFT’R&DIimmediately; regardless of relationship to the device. DDs
, that might have led to an SADE if suitable action had not been taken, intervention had not
been made or if circumstances had been less fortunate are similarly reported. All SAEs.
SADEs‘and USADEs Will be recorded on the hospital incident reporting system, in the source
data (medical notes) and the CRF.
IRAS Project ID 293234 
CONFIDENTIAL 
Page 28 of 35
HALOS Study Protocol V1.0
22"“ Sept 2021

HALOS Protocol
Reports of related and unexpected SAEs should be submitted to the Research Ethics
Committee (REC) Within 15 days of the Chief Investigator becoming aware of the event,
using the SAE report form for non-CTIMPs published on the HRA website“.
All reporting to LUHFT R&D should be by email to RGT@rlbuht.nh§.uk giving as much
information about the incident as possible, and should be signed by the Pl or Co-investigator.
The LUHFT SADE reporting form should be used for LUHFT sponsored studies. ,
The LUHFT R&D Department will undertake an initial review of the information and enéure it
'is reviewed. Events will be followed up until resolution, any appropriate further information
will be sent by the research team in a timely manner.
8.4 
Safety Reports
In addition to the' above reporting the Chief Investigétor will submit on request a
progress/safety report to thelREC and R&D. 
'
9. STATISTICS
9.1 
Descriptio'n of Statistical Methods
A single proportion test will be applied to the primary outcome measure (see Section 6.2.1),
using a reference proportion of 49 in 50. 'This is derived from a clinical estimate of the I
threshold for acqeptable performance of the headgear being where the resulting endoscopy
- image is not sufﬁciently clear and stable in no more thanl1 in 50 cases. .
The Secondary outcome measures (see Section 6.2.2) will be used as follows:
0 
The device usability and tolerability ratings Will be used to support the risk/benefit
ratio assessment of the device. 
' 
l
‘ 0 
Device usability and to‘lerability subjective feedbédk will be used to inform and
prioritise how residual risks associated with usability and tolerability can be reduced.
9.2 
The Number of Participants
I
The number of participanté is limited to 30 for practical reasons, based on the expected rate
that participants can be recruited.
The following rationale was applied to determine this as én acceptable number of samples:-
4 hmszllwwwhc n . 
' «l accessed
16/Aug/2021 
_
IRAS Project I D  293234 
CONFIDENTIAL ' ' 
. Page 29 Of 35
HALOS Study Protocol V1.0
22"d Sept 2021 
' 
,

HALOS Protocol
»0 This is a CIass I (MDD), [ow-risk 
device, 
aﬁd risk management according' to ISO
14971 has been used to predict a favourable ovefall risk/benefit ratio.
0 
Bench testing has been carried out to verify that the design meets the specifications.
.0 
Limited validation of the headgear 
has been carried out to partially 'show that .the
device is fit for purpose. This included testing on humans but without the endoscope
inserted into them. The results demonstrated to a large extent that the design is safe
7 ,. W and' effective. 
, I 7 
, 
' 
7 
7
9.3 The Level of Statistical Significance
- A conservative level Of Significance of p=0.01 will be used to control the false discovery rate,
due to the expec'téd small limiting sample‘size (Harrell, 2015). 
'
9.4 
Criteria for the Termination of the Trial
The trial will be terminated in the event of any device-related SAE, SADE or USADE.
. 9.5 
Procedure for Accounting for Missing, 
Unused, and Spurious 
Data
If the data is missing completely at random, and the fraction of missing data is no larger than
5%, then the missing data will be ignored in the analysis. If the data is missing, at random,
deletion is not a viable strategy, so imputation p'rocedures 
will be applied to avoid biased
estimates (Harrell, 2015).
' 9 . 6  Procedure for Reporting any Deviation(s) from the Original Statistical Plan
Any signiﬁcant deviations from thestatiétical plan will be notified to the study _sponsor.
9.7 Inclusion in Analysis
All eligible participants will be included in analysis.
I 10. DIRECT ACCESS TO SOURCE DATAIDOCUMENTS
Direct access will be granted to authorised representatives from the qnsor, 
host institution
and the regulatory authorities to permit trial-related monitoring, audits and inspections.
11.QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES
The study will be conducted in accordance with the current approved protocol, ICH GCP, BS
EN ISO 14155, other relevant regulations and standard operating procedures.
IRAS Project ID 293234 
CONFIDENTIAL 
Page 30 of 35
HALOS Study Protocol V1.0 
‘
22"d Sept 2021 
.

' 
HALOS Protocol
Regular monitoring will bé performed according to ICH GCP. Data will be evaluated for
compliance with the protocol and accuracy in relation to source documents. Folllowing written
standard operating procedures, the monitors will verify that the clinical trial is conducted and
data are generated, documented and reported in compliance with the protocol, GOP and the
applicable regulatory requirements.
12. ETHICS
12.1 Declaration of Helsinki
The Investigator will ensure that this study is conducted in accordance with the principles of
the Declaration of Helsinki.
12.2 ICH Guidelines for Good Clinical Practice
The lhvestigator will ensure that this study is conducted in full conformity with relevant
regulations and with the ICH Guidelines for Good Clinical Practice E6 (R2).
12.3 Approvals
The protocol, informed Consent form, participant information_'sheet and any proposed
advertising material will be submitted to an appropriate REC, Health Research Authority and
host institution(s) for written approval. Local capacity and capability approval will be sought
from each participating NHS organisation.
A letter of no objection from the MHRA is not required as this is not a clinical inVestigation of
7 a‘devic'e intended to be UKCA/CE-marked, o r  commercialised.
The Investigator will submit and, where necessary, obtain approval from the above part_ies
for all substantial amendments to the original apprOVed documents.
_ 12.4 ParticipantConfidentiality
_ The trial staff wili ensure' that the participants’ anonymity is maintained, énd all documents 7
will be stored securely and only accessible by trial staff and authorised personnel. All paper
documentation and participant identifiable dat‘a will be securely held in a locked drawer in the
‘Voice clinic rdom, Broadgreen Hospital. This includes thé consent forms, CRFs, and the
participant list in an enrolment lbg. The participants will be identified only by participant’s ID
nu‘mberon the CRF. 
'
Pseudonymised electronic data will be held by Medical Physics and Clinical Engineering for
analysis. The data for analysis will be held on secure, password protected. and firewalled
IRAS Project ID 293234 
CONFIDENTIAL 
' 
Page 31 of 35
HALOS Study Protocol V1.0'
22nd Sept 2021 
x

HALOS Proto_col
network facilities. provided by the departmenf.‘ Security arrangements include nightly
backups _and access controls to restrict access 'to those who need it.
The Chief Investigator will preserve the confidentiality of pérticipants taking part in the‘study
and will abide by the Data Protection 
Act 2018 and the UK GDPR as amended from time to
time, any successor legislation in the UK and any other directly applicable regulation relating
to data protection and privacy. 
' 
I
12.5 Other Ethical Considerations
There are no other ethical considerations.
13. DATA HANDLING AND RECORD KEEPING
The data is recorded on a hard copy of the CRF. A copy of this is given to the Chief
Investigator for analysis.
A participant list is held by the Principal Investigator in an enrolment log to identify
participants. The partic'ipantswill be identified by a study specific participants number. The _
participant numbers will be prefixed with the letter ‘H’, and participants will be allocated a.
participant number incrementally starting at ‘Hi’. The name and any other identifying detail.~
will NOT be included in any study data electronic._file. 
\
Following analysis, and within 12 months of the end of thé study, electronic data will be
anonymisedarid archived as described in Section 17. '
14. FINANCING AND INSURANCE
LUHFT will act as Sponsor for this study. It is recognised that as an employee of LUHFT the
Chief Investigator has been delegated specific duties, as detailed in the Sponsorship
Approval letter.
NHS bodies are legally liable for the negligent acts and omissions of their employees. If a'
participant is harmed whilst taking part in a clinical trial as a result of negligence on the part
of a member of the study team, this liability cover would apply.
Non-negligent harm_ is not covered by the NHS indemnity scheme. ‘ L U H F T ,  therefore,
cannot agree in advance to pay compensation in these circumstances. In exceptional
circumstances an ex4gratia payment may be offered. 
‘
IRAS Project ID 293234 
CONFIDENTIAL 
. 
Page 32 of 35
HALOS Study Protocol V1.0
22'“? Sept 2021

_ HALOS Protocol
15. END OF STUDY DEFINITION
The study will formally end when the data collection has been completed from the last
participant and data analysis is complete.
The study will be ended prematurely by the CI in the following cases:
0 A SADE ‘orAUSADE occurs; .
. 
A DD is identified that might have led to a SADE if suitable action had not been
taken, intervention had not been made or if circumstances had been less fortunate; .
V° Emergent information about the device risk causes the risk/benef-it evaluation to
become unfavourable.
16. PUBLICATION POLICY
An internal report will be produced detailing the findings from the study in the form of a
clinical evaluation in line with MEDDEV 2.7/1 Clinical Evaluation: A Gui_de for Manufacturers.
The study will also be used to update the Risk Log for the device.
Although the main reason for this Study is it to enable LUHFT to provide an additional
service for patients, publication in a peer reviewed scientific journal or as a report on our
website will be considered to disseminate the findings of this study to interested parties.
Authors will be defined as those who have made:
0 
Substantial contributions to the conception or design 6f the work; or the acquisition,
analysis, or inferpretation of data fof the work; AND
0 
Drafting the work or revising it critically for important intellectual content; AND
0 
Final approval of the version to be published; AND
0 
Agreement to be accountable for all aspects of the work in ensuring that questions
related to the accuraCy or integrity of any part of the work are appropriately ‘
investigated and resolved.
Contributors who have contributed materially to the paper but whose Contributions do not
justify authorship will be described clearly in acknowledgements.
17.ARCHIVING
A|| appropriate documentation and anonymised participant data will be archived by the Chief
Investigator and stored securely behind a firewall in Medical Physics & Clinical Engineering
for a minimum of 15 years after the.completion of the study in accordance with the Sponsor
IRAS Project ID 293234 
CONFIDENTIAL - 
Page 33 of 35
HALOS Study Protocol V1.0 
‘
22nd Sept 2021

HALOS Protocol
archiving SOP. Acce§s to the archived data will be restricted to those involved in research
within Medical Physics & Clinical Engineering.
IRAS Project ID 293234 
CONFIDENTIAL 
Page 34 of 35
HALOS Study Protocol V1.0
22"“. Sept 2021

HALOS Prbtocol
18.REFERENCES .-
Bushby, K. M., Cole, T., Matthews, J. N. & Goodship, J. A., 1992. Centiles for adult head
circumference. 
Archives 
of 
disease 
in 
childhood, 
67(10), 
pp. 
1286—1287.
https://doi.orq/10.1136/adc.‘67.10.1286
Carel, H., “-Macnaughton, J. & Dodd, J., 2015. Invisible suffering: breathlessness in and
beyond the clinic. The Lancet Respiratory Medicine, 3(4), pp. 278-279.
Christensen, P. M., Maltbaek, N., Jargensen , |. M. & Nielsen; K. G ,  2013. Can flow-volume
loops be used to diagnose exercise-induced laryngea'l obstructions? A comparison study
l
examining the accuracy and inter-rater agreement of flow-volume loops as a diagnostic tool.
Primary Care Respiratory Journal, pp. 306-311.
Hall, A., Thomas, M., Sandhu, G. & Hull, J., 2016. Exerdise—induced laryngeal obstruction: a .-
common and overlooked cause of exertional breathlessness. British Journal of General_
PractiCe, 66(650), pp. 683-685.
Harréll F. E. Jr. Regression Modeling Strategies, 2nd edition; Springer 2015.
- H e i m ’ , d a |  
J. -H. et al., 2006. Continuous Laryngoscopy Exercise Test: A Method for Visualizing
Laryngeal Dysfunction during Exercise The Laryngoscope I p . p  52-  57.
Hull, J. H. et al., 2019. Feasibility of portable continuous laryngoscopy during exercise
testing. ERJ Open Research. 
’
' J o h a n s s o n ,  
H. et al., 2015. Prevalence of exercise-induced. bronchoconstriction and
exercise-induced laryngeal _obstructiqn 'm a general adolescent population. Thorax, pp. 57-
63. 
' 
'
Newman, r K . ,  Masoh, U. & Schmaling, K., 1995. Clinical featurés of vocal'cord dysfunctiqn.
Am J Respir Crit Care, Volume 152, p. 1382—1386.
Nielsen, E. W., Hull, J. & BaCker, V., 2013. High Prevalence of Exercise-Induced Laryngeal
Obstruction in Athletes. Medicine & Science in‘Spon‘s & Exercise, pp. 2030-2035.
Olih, J. T. et al., 2016. Continuous laryngoscopy quantitétes Iai'yngeal behaviour in exercise
and recovery. European Respiratory Journal, Volume 48, pp. 1192-1200.
Traister, R. ‘et al., 2013. A retrospegtive analysis comparing subjects with isolated and
I
coexistent-vocal cord dysfuncfion and asthma. Allergy Asthma Proc, 34(4), pp. 349-355.
IRAS Project ID 293234 
' . CONFIDENTIAL 
' 
. 
' , Page 35 of 35
HALOS Study Protocol V1.0 
.
22”d Sept 2021