Evaluating the Therapeutic Use of a Vibratory Positive Expiratory Pressure Device (Acapella® Choice) in the Treatment of Pathological Voice - A Feasibility Study
Phase: NA
Conditions: Muscle Tension Dysphonia, Vocal Fold Palsy, Vocal Cord Paralysis, Presbylarynx, Dysphonia
Sponsor: University College, London

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Evaluating the Therapeutic Use of a Vibratory Positive Expiratory Pressure Device 
(Acapella® Choice) in the Treatment of Pathological Voice - A Feasibility Study 
 
Evaluating the Feasibility of Acapella® Choice as a Dysphonia Treatment 
 
Chief Investigator: Brian Saccente-Kennedy MSc CertMRCSLT, The Royal National 
Throat Nose and Ear Hospital, UCLH NHS Foundation Trust 
 
 
Supported by:  
Smiths Medical,  
6000 Nathan Lane North 
Plymouth, MN  55442  
USA 
 
 
Sponsored by: 
University College London Hospitals NHS Foundation Trust (UCLH) 
 
Protocol version number and date: Version 2, 15/09/2020 
 
 
 
 
R&D / Sponsor Reference Number(s): 18/0434 
 
Study Registration Number: 
18/0434 
 
 
 
 
 
 
 
 
 

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PROTOCOL VERSIONS 
Version Stage 
Versions No 
Version Date 
Protocol 
updated 
& 
finalised by; 
Appendix No detail the 
reason(s) for the protocol 
update 
Current 
Version 2 
15/09/2020 
Brian Saccente-
Kennedy, Specialist SLT 
Following 
Substantial 
Amendment 1 
Previous 
Version 1 
18/01/2018 
Brian Saccente-
Kennedy, Specialist SLT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DECLARATIONS 
The undersigned confirm that the following protocol has been agreed and accepted and that 
the investigator agrees to conduct the study in compliance with the approved protocol and 
will adhere to the Research Governance Framework 2005 (as amended thereafter), the Trust 
Data & Information policy, Sponsor and other relevant SOPs and applicable Trust policies and 
legal frameworks. 
I (investigator) agree to ensure that the confidential information contained in this document 
will not be used for any other purposes other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor. 
I (investigator) also confirm that an honest accurate and transparent account of the study will 
be given; and that any deviations from the study as planned in this protocol will be explained 
and reported accordingly. 
 
Chief Investigator: 
Signature
 
Date 15/09/2020 
Print Name(in full): Brian Saccente-Kennedy CertMRCSLT 
Position: Specialist Speech and Language Therapist 
 
On behalf of the Study Sponsor: 

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Signature:................ 
.....................................................................        
Date.....22./10....../..2020..... 
Print Name Pushpsen Joshi  
Research Governance Manager 
 
STUDY SUMMARY 
Identifiers 
 
IRAS Number 
251733 
REC Reference No 
 
Sponsor Reference No 
18/0434 
Other research reference 
number(s) (if applicable) 
 
 
 
Full (Scientific) title 
Evaluating the Impact of a Vibratory Positive Expiratory Pressure 
Device (AcapellaⓇ Choice) on Pathological Voice - A Feasibility Study 
Health 
condition(s) 
or 
problem(s) studied 
Dysphonia (arising from muscle tension dysphonia, presbylaryngis and 
vocal fold palsy) 
Study Type i.e. Cohort etc 
Feasibility study 
Target sample size 
30 (10 of each condition) 
 
 
STUDY TIMELINES 
 
Study Duration/length 
18 Months 
Expected Start Date 
January 2020 
End of Study definition and 
anticipated date 
When 30 participants have been recruited and have taken part, or 18 
months have elapsed, whichever comes first. 
Key Study milestones  
 
Securing of funding, JRO submission, first patient recruitment, study 
close. 
FUNDING & Other 
 
Funding  
Sabah Mujeebuddin, Clinical Research Specialist, CHEM 
Smith’s Medical, 6000 Nathan Lane North, Plymouth, MN  55442 USA 
Other support  
N/A 
STORAGE of SAMPLES  
(if applicable) 
 
Data collected / Storage 
N/A 
KEY STUDY CONTACTS 
Full contact details including phone, email and fax numbers 
Chief Investigator  
Brian Saccente-Kennedy 
Brian.saccente-kennedy@nhs.net 
Tel/Fax: 020 3456 5180 
 
 
 
 
 

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KEY ROLES AND RESPONSIBILITIES 
SPONSOR: The sponsor is responsible for ensuring before a study begins that arrangements 
are in place for the research team to access resources and support to deliver the research as 
proposed and allocate responsibilities for the management, monitoring and reporting of the 
research. The Sponsor also has to be satisfied there is agreement on appropriate 
arrangements to record, report and review significant developments as the research proceeds, 
and approve any modifications to the design.  
 
FUNDER: The funder is the entity that will provide the funds (financial support) for the 
conduction of the study. Funders are expected to provide assistance to any enquiry, audit or 
investigation related to the funded work.  
 
PRINCIPLE INVESTIGATOR (PI): The person who takes overall responsibility for the design, 
conduct and reporting of a study, ensuring that the study is conducted as per the approved 
study protocol, and report/notify the relevant parties of any breaches or incidents related to 
the study. 
 
The PI role is to complete and to ensure that all relevant regulatory approvals are in place 
before the study begins. Ensure arrangements are in place for good study conduct, robust 
monitoring and reporting, including prompt reporting of incidents, this includes putting in 
place adequate training for study staff to conduct the study as per the protocol and relevant 
standards. 
 
The Principle Investigator is responsible for submission of annual reports as required. The 
Principle Investigator will notify the RE of the end of the study, including the reasons for the 
premature termination. Within one year after the end of study, the Principle Investigator will 
submit a final report with the results, including any publications/abstracts to the REC.  
 
 
 
 
 
 
 
 
 
 

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KEY WORDS 
Semi-occluded vocal tract exercise, positive expiratory pressure, tube phonation, Acapella, 
voice therapy.   
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AR 
Adverse Reaction 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
DMC 
Data Monitoring Committee 
GAfREC 
Governance Arrangement for NHS Research Ethics 
HTA 
Human Tissue Authority 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
MD 
Medical Device 
ISRCTN 
International Standard Randomised Controlled Studies Number 
PI 
Principle Investigator 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
RCT 
Randomised Clinical Study 
REC 
Research Ethics committee 
SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure 
SSI 
Site Specific Information 
TMF 
Trial Master File 
 
 
 
 
 
 
 
 
 
 
 
 

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CONTENTS 
1. 
INTRODUCTION 
8 
2. 
BACKGROUND AND RATIONALE 
8 
3. 
OBJECTIVES 
9 
3.1. 
Primary Objective 
9 
3.2. 
Secondary Objectives 
10 
4. 
STUDY DESIGN 
10 
5. 
STUDY SCHEDULE 
10 
6. 
CONSENT 
10 
7. 
ELIGIBILITY CRITERIA 
11 
7.1. 
Inclusion Criteria 
11 
7.2. 
Exclusion Criteria 
11 
8. 
RECRUITMENT 
11 
9. 
STATISTICAL METHODS 
12 
10. 
PATIENT AND PUBLIC INVOLVEMENT (PPI) 
12 
11. 
FUNDING AND SUPPLY OF EQUIPMENT 
13 
12. 
DATA HANDLING AND MANAGEMENT 
13 
13. 
PEER AND REGULATORY REVIEW 
14 
14. 
ASSESSMENT AND MANAGEMENT OF RISK 
14 
15. 
RECORDING AND REPORTING OF EVENTS AND INCIDENTS 
14 
15.1. 
Definitions of Adverse Events 
14 
15.2. 
Assessments of Adverse Events 
15 
15.2.1. 
Severity 
15 
15.2.2. 
Causality 
15 
15.2.3. 
Expectedness 
16 

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15.3. 
Recording adverse events 
16 
15.4. 
Procedures for recording and reporting Serious Adverse Events 
17 
15.5. 
Reporting Urgent Safety Measures 
19 
15.6. 
Protocol deviations and notification of protocol violations 
19 
15.7. 
Reporting incidents involving a medical device 
19 
15.8. 
Trust incidents and near misses 
19 
16. 
MONITORING AND AUDITING 
20 
17. 
TRAINING 
20 
18. 
INTELLECTUAL PROPERTY 
20 
19. 
INDEMNITY ARRANGEMENTS 
20 
20. 
ARCHIVING 
21 
21. 
PUBLICATION AND DISSEMINATION POLICY 
21 
22. 
REFERENCES 
21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. INTRODUCTION 
This feasibility study is the natural extension of our recently completed study (R&D 16/0242) 
which assessed how the use of an Acapella Choice (Smiths Medical) positive expiratory 
pressure (PEP) device as a semi-occluded vocal tract exercise (SOVTE) impacted acoustic, 
electroglottographic and aerodynamic measures of the voice in a group of normophonic 
volunteers. In that study, Acapella Choice was found to offer significantly greater oscillating 
intraoral pressures than techniques in current clinical practice and was found to have 
measurable benefits in terms of producing a louder and more economical voice.  It offered the 
largest oscillating pressures, likened to a ‘massage’ of the vocal organs, giving it great 
therapeutic promise for patients with excess vocal tract tension.  
 
We seek in this study to evaluate the immediate effects of Acapella Choice as a voice exercise 
in patients with Muscle Tension Dysphonia, Presbylaryngis and Vocal Fold Palsy, and compare 
this to our currently-used technique of phonation into a tube held under water (henceforward 
referred to as “Tube”). Patients will be recruited from four weekly Voice Clinics held at the 
Royal National Throat Nose and Ear Hospital where their diagnosis will be confirmed. They will 
be invited to attend a single experimental session during which time they will exercise both 
with Acapella Choice and with Tube. Baseline and outcome voice measures will be taken and a 
short questionnaire will be completed, eliciting perceptions of the two exercises and any 
changes which were felt to have resulted from them.  
 
Our previous work suggests that Acapella Choice as a SOVTE may offer significant clinical 
benefits in terms of improved efficacy of therapy. We suggest that it also offers patients a 
more convenient and user-friendly form of exercise which may well improve compliance and 
result in better outcomes.  
2. BACKGROUND AND RATIONALE 
The therapeutic use of a semi-occluded vocal tract has a very long history and includes time-
honoured techniques such as voiced fricatives, lip trills, tongue trills and even humming. 
Despite been used for generations by singers, the benefits to the voice were until recently 
purely anecdotal and their scientific basis unexplored. In the early 2000s, Prof Ingo Titze 
undertook a scientific investigation of the benefits of narrowing the vocal tract, specifically 
with thin flow-resistant straws. His work1 concluded that benefits to the voice are derived 
from a heightened interaction of the vibration source (vocal folds) with the vocal tract to make 
the voice more economic and to reduce collision forces of the vocal fold tissues. A good review 
of the phenomenon can be found in Titze 20062.  
 

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Another form of SOVTE, initially introduced in Finland in the 1960s, involved phonation 
through glass tubes in air and glass tubes submerged in water. First written about by Dr Antti 
Sovijärvi3, it was little used outside of Finland until it was introduced in the English-speaking 
literature in the mid-2000s4. By submerging the distal end of a tube under water, bubbling is 
generated, adding an oscillatory component to the static intraoral pressure 5–8. This pressure 
modulation by water bubbling has been described as producing a ‘massage effect’ 4–6,9–11 on 
the laryngeal muscles that supposedly counteracts harmful maladaptation such as 
hyperfunctional phonation. This technique is one of the most commonly used by our 
department at the Royal National Throat, Nose and Ear Hospital.  
 
Clinical experience has shown that many dysphonic patients respond quite well to a form of 
SOVTE and it comprises a key part of therapeutic intervention. There is a growing body of 
recent literature which is investigating what effect these exercises have on the phonation of 
both healthy subjects and those with voice disorders7,10–18.  Various studies have shown that 
SOVTEs induce a lower laryngeal position7,19 (often a marker of a deconstricted vocal tract), a 
firmer closure at the velopharyngeal port20, a narrowed epilarynx and widened pharynx 19 
which contribute to richer harmonics, improved vocal fold closure 2 - all leading to improved 
voice quality and laryngeal efficiency.  
 
Vibratory PEP devices, such as Acapella Choice, are traditionally used to mobilize secretions in 
the treatment of excessive sputum or secretion retention in conditions such as cystic fibrosis 
and neurogenic diseases21,22. PEP devices are usually composed of a mouthpiece attached to a 
tube with a distal oscillatory flap that closes and opens with airflow, producing an oscillatory 
pressure within the airways. They aim to match the frequency of vibration of the ciliary 
epithelium in the lungs, hence promoting the expectoration of secretions. 
 
A practical limitation for implementing tube-in-water voice exercises is the obvious 
requirement of an accessible water container. PEP, which offers an alternative source of 
oscillatory pressure without such requirements, might therefore have potential as a form of 
SOVTE. It was for this reason that we sought to investigate its potential in voice therapy in our 
previous study.   
 
Our previous study was the first to investigate the use of a PEP device in voice rehabilitation. 
We found that Acapella® offered significantly greater oscillatory and static pressures than was 
obtainable from tube-in-water therapy and was the only exercise to create a significant 
change in loudness alongside improved vocal economy. As this study involved only 
participants with healthy voice, it remains to be seen how different categories of pathological 
voice, i.e. hyperfunctional and hypofunctional, would respond to exercising with Acapella®.  
 
3. OBJECTIVES 
3.1. Primary Objective  
 
To determine what impact the use of an Acapella Choice device has on the voices of people 
with voice disorders when it is used as a form of semi-occluded vocal tract exercise. 
 

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3.2. Secondary Objectives  
To identify whether this patient group is able to make use of Acapella Choice for this purpose 
 
To identify if this intervention can be incorporated into the standard patient clinical pathway 
 
To identify if sufficient subjects can be recruited and retained 
 
To identify sample sizes for possible future research 
 
4. STUDY DESIGN 
This is a feasibility study using a ‘before and after’ design to test the immediate effects of 
exercising with Acapella Choice in comparison to the immediate effects of exercising with 
Tube. Dysphonic subjects will be recruited from referrals received from four RNTNE-based 
voice clinics with an endoscopically-confirmed diagnosis of muscle tension dysphonia (MTD), 
presbylaryngis (age-related vocal fold atrophy) or vocal fold palsy. They will attend only one 
research session which will last approximately one hour. 
 
The aim is to recruit ten subjects from each diagnosis for a total of 30 patients. As this is a 
feasibility study, a sample size calculation has not been performed. Instead, the target number 
for recruitment is instead informed by a recent audit of referrals to the department. 
 
5. STUDY SCHEDULE 
 
Enrolment will begin from day one of the study. Prospective participants will be identified by 
the Speech Therapist in attendance at voice clinics held at the Royal National Throat Nose and 
Ear Hospital. The therapist will briefly explain the study, give the patient and information 
sheet, and get consent for the PI to contact them over the following week to carry out a 
telephone screening of their eligibility.  
 
Following successful screening by the PI, the participant will be given an appointment to 
attend an approximately one hour long research session where the interventions will be 
carried out and data collected. This single session will conclude the participant’s involvement 
in the study, and they will return to their ordinary clinical pathway, awaiting commencement 
of their Speech Therapy input, as indicated. There will be no study follow-up for participants. 
 
A participant may withdraw at any time and their normal clinical pathway from referral to 
treatment will remain unaffected.  
 
The end of the study will be reached as soon as the target number of participants has been 
recruited, or eighteen months has elapsed from the commencement of the study, whichever 
comes first. 
 
 
6. CONSENT 
Written informed consent will be obtained at the beginning of the study visit. By this point the 
participant will have already received and had a chance to read the participant information 
sheet and ask any questions during their recruitment telephone conversation with the PI.  

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7. 
ELIGIBILITY CRITERIA 
7.1. 
Inclusion Criteria 
 
 
Able to understand written English without the need for an interpreter,  
 
No diagnosed communication impairment  
 
Endoscopically confirmed primary ENT diagnosis of either: 
1. muscle tension dysphonia (with no laryngeal abnormality),  
2. Vocal fold palsy 
3. Presbylaryngis. 
7.2. 
Exclusion Criteria 
● Under 18 years of age or over 90 years of age. 
● Previous SLT input 
● Any of the following possible contraindications for PEP therapy:  
○ Inability to tolerate increased work of breathing,  
○ ICP (intracranial pressure) > 20mm Hg,  
○ Recent facial/oral/skull surgery or trauma,  
○ Oesophageal surgery,  
○ Untreated pneumothorax,  
○ Known or suspected tympanic membrane rupture/other middle ear 
pathology,  
○ Haemodynamic instability,  
○ Acute sinusitis,  
○ Epistaxis,  
○ Active haemoptysis,  
○ Nausea 
 
8. RECRUITMENT 
Whenever possible, participants are to be preferentially recruited from within joint- or Speech 
Therapy-led voice clinics (four in total each week). In this way, a member of the Speech 
Therapy team who has knowledge of the study and the inclusion criteria can assist in making a 
preliminary assessment of the participant’s suitability for the study. The participant will then 
be given a brief verbal explanation of the study and a participant information sheet to take 
away with them.  
 
As a result of significantly reduced patient numbers in joint voice clinics, and the temporary 
halting of Speech Therapy-led voice clinics (both as a result of Covid-19 precautions), 
participants may alternatively be identified from the waiting list of patients referred to ENT 
Speech Therapy by an ENT consultant but who have not yet received voice therapy. In this 
way, the PI will be able to review the patient’s video recorded laryngeal exam and make an 
assessment of their suitability for the study. Those who are suitable will be contacted via 
telephone and given a brief verbal explanation of the study and a participant information 
sheet put in the post for those who are interested in finding out more. 
 
The prospective participant will then be telephoned by the PI during the following week. The 
PI will ask over the telephone whether they have any of the contraindications for PEP which 
would result in their being deemed unsuitable for inclusion in the study and will answer any 

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questions the participant might have. Should they meet all inclusion criteria, the PI will then 
set up a day and time to come in, give informed consent, and participate in a single research 
session lasting around one hour. Should they not be eligible for inclusion in the study, this will 
be documented in the study file’s Screening Log. 
 
This research session will complete the subject’s involvement in the study, and they will then 
be returned to the normal clinical pathway and receive Speech Therapy input as indicated and 
in a timely fashion dependent on their place on the waiting list. Participants will be 
compensated for their time with a £10 gift voucher and their travel expenses will be 
reimbursed up to a maximum of £12.50 (London Zone 1-6 daily cap) providing presentation of 
valid receipts. 
9. STATISTICAL METHODS 
As this is a feasibility study and this is the first time that this particular exercise has been 
trialled in pathological voice, effect sizes are as yet unknown. The decision to recruit 10 
participants of each voice type was informed by a recent audit of departmental referrals 
(January 2015 to July 2017). Over this period, we received an average of 57 referrals per 
month. Monthly referrals for MTD account for 15.8% of that total (9), referrals for vocal fold 
palsy account for 6.5% (4) and referrals for presbylaryngis account for 5.9% (3).  It was felt that 
10 of each group was reasonable to recruit within the planned timescale of the study (initially, 
12 months, but owing to a significant drop in throughput of patients in voice clinics as a result 
of Covid-19, this timescale has been extended to 18 months), large enough to inform about 
the practicalities of recruiting for a larger future study and large enough to provide some 
indication of the effects of each treatment on baseline variables.  
 
Despite it being unclear what effects will be seen in these clinical populations, our previous 
pilot using normophonic volunteers was able to identify statistically significant change in 
sound pressure level (SPL) and mean flow during voicing, both biologically relevant changes for 
voice production. For this study, descriptive statistics will be used and will include box plots, 
means/medians, standard error and tests of significant differences between groups and 
exercises will be carried out using ANOVAs. Baseline data for consideration will include expert-
rated perceptual, acoustic, aerodynamic and electroglottographic measures of the voice.  
 
Questionnaire data will also be collected and will be analysed for pre-post changes in self-
rated voice quality and ease of voice production. Views on the exercises (i.e. ease of use, 
portability, likelihood of carrying out task if it were given in a therapy programme) will also be 
compared between exercises and between groups. 
10. PATIENT AND PUBLIC INVOLVEMENT (PPI) 
Patients are the participants (research subjects) in this study, and as such, are a key part of the 
research process. Not only will they participate in the two interventions being investigated, 
but their opinions of the recruitment process and experience of data collection will be sought 
so as to inform a future and larger study. It is hoped that in this way we will be able to ensure 
the smoothest and optimal patient experience for future studies.  
 
However, in terms of the present proposed study, as it is a rather small scale feasibility study 
we do not anticipate there will be any need for patient or public involvement in the research 
management, research undertaking, analysis or finding dissemination. However, we did seek 

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the input of members of the public (voice clinic attendees) to help us hone the clarity of our 
patient information sheets and settle on the amount of participant compensation (gift 
certificates and travel costs).  As a result of their input, the information sheets were revised 
and compensation levels increased. 
11. FUNDING AND SUPPLY OF EQUIPMENT  
The study funding has been reviewed by the UCL/UCLH Research Office, and deemed sufficient 
to cover the requirements of the study. NHS costs will be supported via UCLH and/or the Local 
Clinical Research Network.  
 
The research costs for the study have been supported by a grant from Smith’s Medical in the 
amount of £14,257 (inclusive of one year of 0.2 WTE backfill of clinician time, equipment 
upgrade, consumables, participant incentive voucher purchase, travel and accommodation at 
international conference). Smith’s Medical will also be supplying twenty-six (26) Acapella 
Choice Devices to be used by the participants of this study (to supplement the four devices 
which the department already holds in stock).  
 
All instrumental assessment to be carried out using equipment already present in the Royal 
National Throat, Nose and Ear Hospital’s Voice Lab, namely a PENTAX Computerised Speech 
Lab (Model 4150), EGG Module (Model 6103) and Phonatory Aerodynamic System (Model 
6600). 
 
12. DATA HANDLING AND MANAGEMENT 
 
The study is compliant with the requirements of General Data Protection Regulation 
(2016/679) and the Data Protection Act (2018). All investigators and study site staff will 
comply with the requirements of the General Data Protection Regulation (2016/679) with 
regards to the collection, storage, processing and disclosure of personal information, and will 
uphold the Act’s core principles. UCLH is the data controller; the UCLH Data Protection Officer 
can be contacted on deborah.dillon2@nhs.net The data processors are UCLH. The study will 
be collecting the following personal data:   
 
● Basic demographic and diagnosis data drawn from medical and electronic records, (i.e. 
age, gender, findings of ENT exam) 
 
Experimental data, which is non-identifiable, that will be collected in the course of the 
research include: 
 
● Electronic 
voice 
recordings, 
electronic 
intraoral 
pressure 
recordings, 
electroglottographic recordings and patient questionnaire data.  
 
Electronic files will be anonymised with participant codes and held on the hospital shared 
drive, questionnaires will be codified into an electronic spreadsheet and the hard copies 
stored in the study file, which is maintained in the RNTNE SLT (ENT) Department. The study file 
will contain a record of all written consents and a list of participant codes; the study file will 
not leave the premises. 
 

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Instrumental data, anonymised by participant code, will occasionally be electronically 
transferred to the study’s co-author, Dr Pedro Amarante Andrade  (Visiting Researcher, 
Academy of Performing Arts in Prague, Malá Strana, Czechia), for specialist analysis. This will 
not include personally identifiable data.    
 
13. PEER AND REGULATORY REVIEW 
The study has been peer reviewed in accordance with the requirements outlined by UCLH. 
 
This study has been peer reviewed within UCLH and by an independent and relevant peer 
reviewer on 13th November 2018 and 21st November 2018, respectively. The Sponsor has 
accepted these reviews as adequate evidence of peer review.  
14. ASSESSMENT AND MANAGEMENT OF RISK 
The manufacturer cautions against using excessive pulmonary pressures with the Acapella 
Choice (i.e. in excess of 20 cmH2O) as this might lead to an adverse effect in those who are 
sensitive to increased transpulmonary pressures. The manufacturer advises that adverse 
effects might include: 
● Increased work of breathing that might lead to hyperventilation 
● Increased cranial pressure 
● Cardiovascular compromise (myocardial ischaemia, decreased venous return) 
● Air swallowing with increased likelihood of vomiting and aspiration 
● Claustrophobia 
● Pulmonary barotraumas 
 
In our recent pilot study involving only normal and healthy volunteers, not one of the 22 
participants exceeded this level of ‘excessive’ pressure. During the pilot, the mean pressure 
during Acapella exercise was in fact only 6.22 cmH2O, (range 3.98-16.75 cmH2O). As the 
participants in this study are more likely to have lower pulmonary pressures (owing to an 
expected higher mean age), it seems unlikely that this pressure will be exceeded. Additionally, 
the list of adverse effects is indeed related to the list of contraindications for PEP exercising 
(i.e. those who are sensitive to increased transpulmonary pressure), and these are included in 
our exclusion criteria. Furthermore, the experimental protocol involves live monitoring 
intraoral pressure during exercising. As such, the task will be aborted if this upper pressure 
limit is being reached. 
 
The other task examined in this study (“Tube”) is part of the normal input of our department, 
is limited by design to 5 cmH2O intraoral pressure and has never resulted in the need to report 
an adverse effect in the many years of its therapeutic use at the Royal National Throat, Nose 
and Ear Hospital.  
15. RECORDING AND REPORTING OF EVENTS AND INCIDENTS 
15.1. Definitions of Adverse Events  
Term 
Definition 

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Adverse Event (AE) 
Any untoward medical occurrence in a patient or study participant, 
which does not necessarily have a causal relationship with the 
procedure involved.  
Serious Adverse Event 
(SAE). 
Any adverse event that: 
● 
results in death, 
● 
is life-threatening*, 
● 
requires hospitalisation or prolongation of existing 
hospitalisation**, 
● 
results in persistent or significant disability or incapacity, or 
● 
consists of a congenital anomaly or birth defect 
*A life- threatening event, this refers to an event in which the participant 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. 
** Hospitalisation is defined as an in-patient admission, regardless of length of stay. 
Hospitalisation for pre-existing conditions, including elective procedures do not constitute an SAE. 
15.2. Assessments of Adverse Events  
 
Each adverse event will be assessed for severity, causality, seriousness and expectedness as 
described below. 
15.2.1. Severity 
 
Category 
Definition 
Mild 
The adverse event does not interfere with the participant’s daily routine, and does 
not require further procedure; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the participant’s routine, or 
requires further  procedure, but is not damaging to health; it causes moderate 
discomfort 
Severe 
The adverse event results in alteration, discomfort or disability which is clearly 
damaging to health 
 
15.2.2. Causality 
 
The assessment of relationship of adverse events to the procedure is a clinical decision based 
on all available information at the time of the completion of the case report form.   

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The following categories will be used to define the causality of the adverse event: 
Category 
Definition 
Definitely: 
There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
Probably: 
There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely 
Possibly 
There is some evidence to suggest a causal relationship (e.g. the event occurred 
within a reasonable time after administration of the study procedure). However, 
the influence of other factors may have contributed to the event (e.g. the 
participant’s clinical condition, other concomitant events). 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. the event did 
not occur within a reasonable time after administration of the study procedure). 
There is another reasonable explanation for the event (e.g. the participant’s 
clinical condition). 
Not related 
There is no evidence of any causal relationship. 
Not Assessable 
Unable to assess on information available. 
 
15.2.3. Expectedness 
Category 
Definition 
Expected 
An adverse event which is consistent with the information about the procedure 
listed in the manual of operation or clearly defined in this protocol. 
Unexpected 
An adverse event which is not consistent with the information about the procedure 
listed in the manual of operation* or clearly defined in this protocol. 
* this includes listed events that are more frequently reported or more severe than previously 
reported 
15.3. Recording adverse events 
 
All adverse events will be recorded in the medical records in the first instance. 
All Adverse events will be recorded in the CRF following consent. 
All adverse events will be recorded with clinical symptoms and accompanied with a simple, 
brief description of the event, including dates as appropriate.  

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15.4. Procedures for recording and reporting Serious Adverse Events 
 
All serious adverse events will be recorded in the medical records and the CRF, and the 
sponsor’s AE log. 
All SAEs (except those specified in section 16.5 as not requiring reporting to the Sponsor) must 
be recorded on a serious adverse event (SAE) form. The PI or designated individual will 
complete an SAE form and the form will be preferably emailed to the Sponsor within 5 
working days of becoming aware of the event. The Chief or Principal Investigator will respond 
to any SAE queries raised by the sponsor as soon as possible.  
Where the event is unexpected and thought to be related to the procedure this must be 
reported by the Investigator to the Health Research Authority within 15 days. 
 
 
Completed forms for unexpected SAES must be sent within 5 working days of becoming 
aware of the event to the Sponsor  
Email forms to randd@uclh.nhs.uk (if sponsored by UCLH)  
Research-incidents@ucl.ac.uk (if sponsored by UCL) 

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Flow Chart for SAE reporting  
 
 
No 
Record in medical 
records and CRF (if 
applicable) 
AE occurs 
Assign Severity Grade 
Was the event Serious? 
Was the event an Other 
Notifiable event?  
See section 16.5 for notifiable 
events which should also be 
reported as serious 
No 
Yes 
Yes 
Yes 
No 
Submit SAE form to Sponsor within 5 working days 
 
Record in medical records,  
And CRF in accordance with the protocol  
 
Is the event specified as an adverse event which does not require immediate reporting as an SAE?  
Record in medical records, CRF (and AE Log if 
required)  
Complete an SAE report form 

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15.5. Reporting Urgent Safety Measures 
If any urgent safety measures are taken the PI shall immediately and in any event no later than 
3 days from the date the measures are taken, give written notice to the relevant REC and 
Sponsor of the measures taken and the circumstances giving rise to those measures. 
15.6. Protocol deviations and notification of protocol violations 
 
A deviation is usually an unintended departure from the expected conduct of the study 
protocol/SOPs, which does not need to be reported to the sponsor.   The PI will monitor 
protocol deviations. 
 
 A protocol violation is a breach which is likely to effect to a significant degree – 
(a) the safety or physical or mental integrity of the participants of the study; or 
(b) the scientific value of the study. 
The PI and sponsor will be notified immediately of any case where the above definition applies 
during the study conduct phase.   
15.7. Reporting incidents involving a medical device  
Any adverse incident involving a medical device should be reported to the manufacturer of the 
device.  
This is especially important where the incident has led to or, was it to occur again could lead to 
an event classified as serious (see section 9.1 for definition of SAE). Other minor safety or 
quality problems should be reported along with incidents that appear to be caused by human 
error.  
All adverse incidents must be reported to Smith’s Medical International via 
globalcomplaints@smiths-medical.com. 
Incidents should be reported within 24 hours.  
15.8. Trust incidents and near misses 
An incident or near miss is any unintended or unexpected event that could have or did lead to 
harm, loss or damage that contains one or more of the following components: 
a. It is an accident or other incident which results in injury or ill health. 
b. It is contrary to specified or expected standard of patient care or service. 
c. It places patients, staff members, visitors, contractors or members of the public at 
unnecessary risk. 
d. It puts the Trust in an adverse position with potential loss of reputation. 
e. It puts Trust property or assets in an adverse position or at risk. 
Incidents and near misses must be reported to the Trust through DATIX as soon as the 
individual becomes aware of them. 
A reportable incident is any unintended or unexpected event that could have or did lead to 
harm, loss or damage that contains one or more of the following components: 

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a) It is an accident or other incident which results in injury or ill health. 
b) It is contrary to specified or expected standard of patient care or service. 
c) It places patients, staff members, visitors, contractors or members of the public at 
unnecessary risk. 
d) It puts the Trust in an adverse position with potential loss of reputation. 
e) It puts Trust property or assets in an adverse position or at risk of loss or damage. 
 
16. 
MONITORING AND AUDITING 
The PI will ensure there are adequate quality and number of monitoring activities conducted 
by the study team. This will include adherence to the protocol, procedures for consenting and 
ensure adequate data quality.  
 
The PI will inform the sponsor should he/she have concerns which have arisen from 
monitoring activities, and/or if there are problems with oversight/monitoring procedures. 
 
17. 
TRAINING 
The Principle Investigator will review and provide assurances of the training and experience of 
all staff working on this study.  Appropriate training records will be maintained in the study 
files 
 
18. INTELLECTUAL PROPERTY 
All intellectual property rights and know-how in the protocol and in the results arising directly 
from the study, but excluding all improvements thereto or clinical procedures developed or 
used by each participating site, shall belong to UCLH. Each participating site agrees that by 
giving approval to conduct the study at its respective site, it is also agreeing to effectively 
assign all such intellectual property rights (“IPR”) to UCLH and to disclose all such know-how to 
UCLH with the understanding that they may use know-know gained during the study in clinical 
services and teaching to the extent that such use does not result in disclosure of UCLH 
confidential information or infringement of UCLH IPR.  
19. INDEMNITY ARRANGEMENTS 
UCLH will provide NHS indemnity cover for negligent harm, as appropriate and is not in the 
position to indemnify for non-negligent harm. NHS indemnity arrangements do not extend to 
non-negligent harm and NHS bodies cannot purchase commercial insurance for this purpose; it 
cannot give advance undertaking to pay compensation when there is no negligence 
attributable to their vicarious liability. The Trust will only extend NHS indemnity cover for 
negligent harm to its employees, both substantive and honorary, conducting research studies 
that have been approved by the R&D Department. The Trust cannot accept liability for any 
activity that has not been properly registered and Trust approved. Potential claims should be 
reported immediately to the Joint Research Office. 
 

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20. ARCHIVING 
UCLH and each participating site recognise that there is an obligation to archive study-related 
documents at the end of the study (as such end is defined within this protocol). The study 
master file will be archived at UCLH in accordance with the UCLH Standard Operating 
Procedure 10 Archiving of Investigator Site File (ISF) and Pharmacy Site File (PSF).  It will be 
archived for a minimum of 5 years from the study end, and no longer than 30 years from study 
end.  
21. PUBLICATION AND DISSEMINATION POLICY 
It is anticipated that the results for this study will be disseminated via publication in a peer-
reviewed journal, such as the Journal of Voice. 
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