Measurement of Mucus Plugging With Computer Tomography Before and Following Implementation of the AffloVest in Adults With Bronchiectasis - a Feasibility Study'
Phase: NA
Conditions: Bronchiectasis
Sponsor: Papworth Hospital NHS Foundation Trust

 
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 ‘Measurement of mucus plugging with computer 
tomography before and following implementation of the 
AffloVest in adults with bronchiectasis – a feasibility study’ 
 
 
 
 
STUDY PROTOCOL – AFFLO Study 
 
DATE 09/09/2019 
 
 
CHIEF INVESTIGATOR 
Dr Charles Haworth 
 
List Investigators 
Siobhan Singh 
Andres Floto 
Nicholas Screaton 
Timothy Baird 
 
 
Investigation Sites:  
Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Papworth Road, 
Cambridge, CB2 0AY, UK 
 
 
Protocol Identification Number:  
P02552 
 
Date of Protocol:  
09/09/2019 
 
Protocol Version Number: 
2 
 
Trial Sponsor:  
Royal Papworth Hospital NHS Foundation Trust

 
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Contents 
 
TRIAL OVERVIEW 
 
1. 
Trial Overview 
Primary Research Question 
Study Design 
Primary Outcome 
Secondary Outcome 
Rationale 
 
2. 
Patient Recruitment 
Study Population 
Inclusion Criteria 
Exclusion Criteria 
Recruitment Strategy 
 
3. 
Data Analysis  
          Sample Size 
Statistical Analysis 
 
4.       Consent Process and Visit Schedule 
Visit 1 
Follow-up Visit 
Informed Consent Procedure 
Table 2: Visit Schedule  
Table 3: Trial Specific Procedures versus Routine Procedures 
 
5. 
Follow up Visits, Travel Expenses and Other Costs 
 
6. 
Data Collection, Auditing and Retention of Documents 
Data Collection Form Completion 
Source Documentation 
Errors and Correcting 
Storage of Documents 
Retention of Documents 
Monitoring and Auditing 
Labelling of Source Documentation 
 
7. 
Adverse and Serious Adverse Events 
Recording & Reporting 
 
8. 
Amendments 
Amendment log 
 
9. 
References 
 

 
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TRIAL OVERVIEW 
 
1. 
Trial Overview 
 
Principal Objective: 
 
The principal objective is to test the feasibility of using computer tomography and the modified Brody 
score to measure the amount of mucus plugging within the lungs of adults with bronchiectasis at 
baseline and after six weeks treatment with the AffloVest. The study outcomes will facilitate the design 
of a future study to test treatment efficacy. 
 
Study Design: 
 
This is a feasibility study using computer tomography to measure the amount of mucus within the 
lungs of adults with bronchiectasis before and following implementation of the AffloVest. The aims of 
the study include assessing the feasibility of the study protocol and estimating the size and variability 
of the treatment effect with the AffloVest to facilitate the design of a future study to test treatment 
efficacy. 
 
30 adult subjects (male and female) who have a known diagnosis of bronchiectasis and who attend 
the Cambridge Centre for Lung Infection (CCLI) at the Royal Papworth Hospital will be recruited. 
 
Subjects will be recruited through convenience sampling and must demonstrate stability during a 2-
week period prior to enrolment. Stability is defined as no change in medical treatment. 
 
Participants will be asked to use the AffloVest for 30 minutes twice daily (in addition to their standard 
airway clearance regimen where possible) for six weeks, with clinical review and tests performed at 
baseline, three and six weeks. 
 
Tests to be performed at baseline, after three and six weeks of treatment with the AffloVest include: 
computer tomography (CT) at full inspiration and full expiration; spirometry (FEV1 and FVC); and the 
patient reported outcomes Visual Analogue Scale for ease of sputum clearance (VAS), St George’s 
Respiratory Questionnaire (SGRQ) and Quality of Life–Bronchiectasis (QOL-B). 
 
The CT images will be scored by two independent expert thoracic radiologists using the modified 
Brody Scoring System which is sensitive and reproducibe.12 Both radiologists will be blinded to the 
time point of the CT scans being analysed and if there is disagreement in scores, an average will be 
taken. 
 
We hypothesize that there will be a reduction in the amount of mucus plugging and an improvement in 
patient reported outcomes following implementation the AffloVest in adults with bronchiectasis. 
 
Primary Outcome 
 
The primary outcome of this study is to test the feasibility of using computer tomography and the 
modified Brody score to measure the amount of mucus plugging within the lungs of adults with 
bronchiectasis at baseline and after six weeks of treatment with the AffloVest. The study outcomes will 
facilitate the design of a future study to test treatment efficacy. 
 
Secondary Outcome(s) 
 
Secondary outcomes include the full modified Brody score, lung function, quality of life scores and a 
visual analogue score for ease of sputum expectoration measured at baseline, after 3 weeks of 
intervention and after 6 weeks of intervention. There will also be a sub-group analysis excluding 
patients that have a pulmonary exacerbation during the study. 
 
Rationale 
 
Bronchiectasis is a chronic inflammatory suppurative respiratory disease associated with poorer 
quality of life, increased admissions and increased mortality.1,2 The disease is characterised by a 

 
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clinical syndrome of cough, sputum production and recurrent respiratory infection, with radiological 
evidence of abnormal and permanent dilation of the bronchi.1,4 In the United Kingdom, incidence and 
prevalence rates are increasing with recent reports suggesting a current prevalence of 566 and 485 
per 100000 patient years in women and men respectively.5 
 
A major strategy in the management of patients with bronchiectasis is to optimise airway clearance 
and thereby reduce the inflammatory and infective burden in the lung.  Several guidelines for airway 
clearance techniques have been created including the European Respiratory Society Guidelines for 
the management of adult bronchiectasis1, and Guidelines for the physiotherapy management of the 
adult, medical, spontaneously breathing patient.5 However, no one technique has consistently been 
shown more effective than others and all the studies discussed in the guidelines were of poor quality. 
Furthermore, none of these guidelines evaluated High Frequency Chest Wall Oscillation (HFCWO). 
 
First described in 1966 by Beck, HFCWO uses percussive forces, transmitted to the lungs to mobilise 
secretions to mimic effects or percussion and vibration without the need of a physiotherapist or 
caregiver.7 Traditional HFCWO machines use single waveforms delivered by large volumes of air at 
high amplitudes to rapidly inflate and deflate an air bladder. Conversely, the AffloVest uses 
mechanically generated pressure waveforms from 8 dynamic oscillating motors inside a vest. Current 
evidence for HFCWO has focused on cystic fibrosis (CF) and suggests that it is at least as effective as 
conventional physiotherapy in clearing secretions with improved patient adherance.7  
 
Additionally, studies in asthma and chronic obstructive pulmonary disease (COPD) have shown that 
HFCWO may be beneficial for hospitalised patients through leading to reduced Borg dyspnoea scores, 
improved FEV1, increased sputum expectoration and reduced exacerbation frequency.8,9  Finally, 
HFCWO has been used by over 50,000 patient’s suggesting it is safe and effective intervention in a 
number of airway diseases and is now recognised as standard of care in individuals with CF in North 
America.10  
 
However, to date, there have been no studies of HFCWO in adult patients with bronchiectasis utilising 
CT to measure the amount of mucus within the lungs before and after implementation of this 
intervention. This study aims to assess the feasibility of the protocol and to estimate the size and 
variability of the treatment effect with the AffloVest to facilitate the design of a future study to test 
treatment efficacy in adults with bronchiectasis. 
 
Schedule of Events 
 
Day -21 to Day -1 
 
Informed consent and review of inclusion & exclusion criteria 
 
Day 1 – Start of intervention 
 
CT scan; FEV1 and FVC; PROs (VAS for ease of sputum clearance, SGRQ & QOL-B). 
 
Participants will be shown how to use the AffloVest and will complete a skills checklist for 
home use. 
 
3 weeks of AffloVest for 30 minutes twice a day (10 minutes each of percussion, vibrations 
and drainage at an intensity tolerable by each individual participant) in addition to their 
standard airway clearance regimen (where possible). 
 
Day 21 – Midpoint of intervention 
 
CT scan; FEV1 and FVC; PROs (VAS for ease of sputum clearance, SGRQ & QOL-B); 
adherence check. 
 
3 further weeks of AffloVest for 30 minutes twice a day (10 minutes each of percussion, 
vibrations and drainage at an intensity tolerable by each individual participant) in addition to 
their standard airway clearance regimen (where possible). 
 
Day 42 – End of intervention 
 
CT scan; FEV1 and FVC; PROs (VAS for ease of sputum clearance, SGRQ & QOL-B), 
adherence check. 
 
 
 
 

 
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2. 
Patient Recruitment Criteria 
 
Study Population 
 
Participant number: n = 30 
 
Population group: Adults (males and females) with bronchiectasis who attend the Cambridge 
Centre for Lung Infection, Royal Papworth Hospital NHS Foundation Trust 
 
Time in study: A total of 63 days from enrolment 
 
Inclusion 
 
Adult male and females ≥18 years 
 
Current diagnosis of bronchiectasis (see above definition) 
 
Productive of sputum on a daily basis 
 
Clinical stability over a 2-week period prior to enrolment (see above definition) 
 
Exclusion 
 
Cystic fibrosis 
 
Severe obstructive airways disease (defined as FEV1 < 25%) 
 
Predominant lung disease is not bronchiectasis in the opinion of the investigator (e.g. 
asthma; COPD; pulmonary fibrosis) 
 
Bronchiectasis in only 1 lobe 
 
Currently treated non-tuberculous mycobacterial lung disease 
 
Acute congestive cardiac failure 
 
Contra-indication or unable to perform HRCT imaging, including pregnancy 
 
Contra-indication to using AffloVest including lung malignancy, recent rib fractures, 
radiological evidence of lung cavitation, and recent significant haemoptysis (in the opinion 
of the investigator) 
 
History of poor adherence to physiotherapy treatment 
 
Cognitive or memory problems affecting ability to follow instructions or give informed 
consent 
 
Recruitment 
The planned recruitment target is 30 participants. No strategies for promoting or boosting 
recruitment are deemed necessary, other than ‘in-house’ referral from respiratory physicians and 
physiotherapists working at the Cambridge Centre of Lung Infection, Royal Papworth Hospital. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Section 3. 
Sample Size and Data analysis  
  
Sample Size: 
 
N = 30.  
 
There are currently no data on which to base an estimation of treatment effect following 
implementation of high frequency chest wall oscillation, nor what the minimal clinically significant 
change in CT parameters might be. Thus feasibility data are required to guide the design and power 
calculation of a future larger study to test treatment efficacy. In these circumstances, we have 
suggested a sample size of 30 patients, as we anticipate that this will allow sufficiently precise 
estimation of the size and variability of the treatment effect. Furthermore, if we encounter a drop out 
rate of 15%, a cohort size of 30 would generate 95% confidence intervals 2.2% and 27.8%. 
 
 
Statistical Analysis: 
To analyse the primary outcome, the CTs will be reviewed by two independent radiologists blinded to 
the time point for each scan and quantified using the "mucus component" of the modified Brody 
scoring system. If there is discrepancy on the score for an individual participant at one time point, the 
two scores will be averaged. After the modified Brody score for each patient is determined we will 
calculate summary statistics including group mean, standard deviation, standard error and confidence 
intervals at baseline and after 6 weeks of treatment. Other feasibility measures such as participant 
dropout rate will also be calculated. 
Secondary outcome summary statistics including the full modified Brody score, FEV1, FVC, SGRQ, 
QOL-B, VAS score and adherence to treatment will be calculated at baseline, after 3 weeks of 
treatment and after 6 weeks of treatment. Any participants who suffer an exacerbation of their 
bronchiectasis during the trial will continue in the study and will be included in the analysis of the 
primary endpoint. However, an additional sub-group analysis will be undertaken excluding this 
population as a secondary outcome. 
Finally, we will also carry out paired t-tests to assess change in CT, lung function and symptom 
parameters following implementation of the AffloVest. However, this is not the primary aim of this 
feasibility study and the study may be significantly underpowered to properly address this point. In any 
case, data generated by the study will inform the design of a larger trial to fully investigate efficacy. A 
p-value of 0.05 will be interpreted as statistically significant unless otherwise stated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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4. 
Consent Process and Visit Schedule  
 
Visits 
 
 
Subjects will be approached about the study by the CCLI Research team, physiotherapy team 
or CCLI consultant team at an outpatient appointment, during a day case / inpatient visit or via 
postal invitation (if known to the service and deemed appropriate for the study).  Once seen, 
and if deemed to be eligible for the study, they will be consented and enrolled.   
 
 
Each participant will be assigned a study number; the study numbers will be allocated 
sequentially starting at 10. 
 
 
Participants will then be arranged to undergo first visit testing with treatment and follow up 
according to the schedule below. 
 
 
Visits will be scheduled and performed according to table 1. 
 
 
Trial specific procedures versus routine procedures are detailed in table 2.  The trial specific 
procedures will only be performed after written informed consent has been obtained.  
 
Table 1 
Visit Schedule 
 
Visit Number 
Screening 
Visit 1 
Visit 2 
Visit 3 
Time interval of Visit 
Day -21 to 
day -1 
Day 1 
Day 21 
Day 42 
Informed consent 
X 
 
 
 
Review of inclusion 
& exclusion criteria 
X 
X 
 
 
Medical history and 
examination 
 
X 
X 
X 
Size for AffloVest 
X 
 
 
 
Fit AffloVest, teach 
how to use it, check 
tolerance of settings 
 
X 
 
 
AffloVest skills 
checklist of 
participant 
competency 
 
X 
X 
X 
AffloVest adherence 
tracking 
 
 
X 
X 
Spirometry (FEV1 
and FVC) 
 
X 
X 
X 
Pregnancy test if 
appropriate (urine 
dipstick) 
 
X 
X 
X 
Patient reported 
outcomes (VAS, 
SGRQ & QOL-B) 
 
X 
X 
X 
CT scan 
 
X 
X 
X 
 
 
Informed Consent Procedure  
 
 
Subjects will receive written and verbal information about the trial. 
 
Written informed consent will be obtained by a member of the trial team using the Patient 
Information and Consent Form (PICF).  Consent will only be obtained after a suitable time has 
elapsed during which the subject has had ample time to read the information sheet, consider 

 
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the trial and ask any questions.  The Investigator or appropriate delegate will explain to each 
subject the nature of the study, its purpose, the procedures involved, the expected duration, the 
potential risks and benefits involved and any discomfort it may entail.  The signed PICF will be 
scanned and uploaded electronically onto the hospital’s secure electronic medical records.  
 
The ultimate responsibility for obtaining written informed consent lies with the Investigator but 
this responsibility may be delegated to a suitably trained and experienced person. 
 
Prior to the subject’s participation in the study, the written informed consent form will be signed 
and personally dated by the subject and by the clinician who conducted the informed consent 
discussion.  Each box at the end of each statement on the consent form will be signed by the 
subject. 
 
Each subject will be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment. 
 
A copy of the informed consent document will be given to the participant.  One copy will be filed 
in the participant’s hospital case notes and uploaded on the password locked hospital electronic 
medical records.  
 
The Principle Investigator or research delegate will ensure that the subject does not have any 
trial specific procedures prior to giving informed consent. 
 
If a participant withdraws their consent a line will be drawn diagonally through the consent form 
and labelled ‘consent withdrawn’ and signed and dated by a member of staff and uploaded into 
the electronic medical record. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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5. 
Follow-up Visits, Travel Expenses and Other Costs 
 
 
Follow up Visits: 
 
The follow up visits will be in accordance with the visit schedule outlined in table 1. Participants will be 
seen at each visit by one of the principal investigators. 
 
If the participants choose to consent to it, the study organisers may contact participants after the study 
has completed to request feedback regarding the longer-term experience of using the AffloVest. 
 
 
 
Travel Expenses: 
 
Reasonable travel expenses will be reimbursed for each study visit. 
 
 
 
Study Costs: 
 
 
30 HFCWO AffloVests (provided by International Biophysics) 
 
90 inspiratory and expiratory CT scans (3 per participant) with reporting by two independent 
 
radiologists – £437 each (Total = £39,330) 
 
90 FEV1 measurements (3 per participant) – £45 per time point per patient (Total = £4,050) 
 
Pregnancy test – covered by Royal Papworth Hospital where applicable 
 
Physiotherapist time (£177 per patient) – £5,310 
 
CI time – £1,962 
 
R&D overheads (20%) - £10,130 
 
Total – £60,782 
 
Total costs (Travel and Study Costs): £65,28230  
 

 
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6. 
Data Collection, Auditing and Retention of Documents 
 
Data Collection Form Completion 
 
 
The Investigator will ensure the accuracy, completeness, legibility and timeliness of the data 
recorded and in all required reports to e.g. the Sponsor, Funder, R&D, REC. 
 
Source Documentation 
 
 
The investigator/clinical research nurses will maintain electronic clinical case notes on the 
hospital’s secure electronic medical record system.  This will include all demographic and 
clinical information. A copy of the patient information and consent form will also be uploaded 
electronically in the patient’s case notes (see above section on consent). All information will be 
traceable to and consistent with the participant’s hospital electronic case notes. 
 
Errors and Corrections 
 
 
Any change or correction will be dated, initialled, and explained (if necessary) and will not 
obscure the original entry (i.e. an audit trail will be maintained). 
 
Storage of Documents 
 
 
Electronically uploaded forms and electronic clinical case notes will be stored securely on the 
hospital’s password locked electronic medical records.   
 
Retention of Documents 
 
 
All study specific documentation will be stored for 12 months after the last patient has 
completed their last visit. 
 
Monitoring and Audit 
 
 
Upon request of the monitor, auditor, Sponsor, R&D, REC, MHRA or other regulatory authority, 
the Investigator will make available for direct access all requested study-related records. 
 
The project data will monitored by an appointed member of the R&D department at the Royal 
Papworth Hospital NHS Foundation Trust.  

 
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Section 7. 
 Adverse and Serious Adverse Events  
 
The definition of an adverse event is: ‘Any untoward medical occurrence in a patient which does not 
necessarily have a causal relationship with this treatment’. This includes ‘any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated 
with the study drug’. This may include, for example, a cold or an accident. 
 
The definition of a serious adverse event is one that fulfils at least one of the following criteria: 
 
Is fatal- results in death  
 
Is life threatening 
 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 
Results in persistent or significant disability/incapacity 
 
OR 
 
Is a congenital anomaly/birth defect 
 
The definition of a suspected unexpected serious adverse reaction (SUSAR) is a serious adverse 
event that is thought to be possibly or definitely related to the study drug. 
 
Recording and Reporting 
 
 
Studies have shown HFCWO to be safe. There are however risks involved with HFCWO and  
FEV1 including haemoptysis, rib fractures, tenderness, bronchospasm, breathlessness and 
fainting. These occur rarely and supervision and guidance throughout testing procedures will 
also minimise the chance of risks occurring. There is equal chance of these risks occurring 
during patient’s normal medical care and airway clearance treatments.  
 
Additional ionising radiation exposure via 3 low dose HRCT’s over the 28-day period will occur.  
The estimated radiation dose per scan is 3.6mSv. The total research protocol dose is therefore 
11mSv, which is equivalent to that received, on average in the UK, from natural sources of 
background radiation in approximately 5 years. For adults in the general population, this dose is 
estimated to correspond to a cancer risk of around 1 in 2,500. This can be compared with the 
natural lifetime risk of cancer in the UK of about 1 in 2 and it should be noted that the latency 
period for radiation induced cancer is about 5 years for leukaemia and decades for solid 
tumours. 
 
All research staff in contact with participants will be responsible for noting adverse events that 
are reported by the patient and making them known to the Principal Investigator.  All AE’s will 
be documented in the participant’s electronic clinical case notes, as per usual standard of care.   
 
At each visit or study assessment, adverse events that have occurred since the previous visit 
will be elicited from the patient. The event will be detailed in the participant’s electronic clinical 
case notes, as source document verification, including the start date (if known) and end date.  
 
The action taken regarding the study procedure will be documented. 
 
Any treatment/medication given for the event, including the dates the treatment/medication was 
commenced and the date it was stopped/changed, if applicable, will be documented. 
 
Documenting of adverse events will be the responsibility of the Principle Investigator, Co-
Investigator and Clinical Research Nurse/Assistant 
 
Events, which are ongoing at the final study visit, will be followed up as clinically indicated. 
 
All serious adverse events (SAEs) and suspected unexpected serious adverse reactions 
(SUSARS) will be documented as above. 
 
SUSARS will be reported to the Sponsor within 48 hours of the Chief / Principle 
Investigator/Clinical Research Nurse being aware. 
 
All Unexpected SAEs and SUSARs will be reported to the hospital R&D department and may be 
require analysis through the hospital incident reporting system.  
 
Expected SAEs will be reported to the Main REC in the annual REC report; the REC who 
performed the locality assessment does not need to be informed. 
 
All completed SAE forms will be uploaded to the participant’s electronic medical record. 

 
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8. 
Amendments 
 
Substantial amendments will be submitted to the Health Research Authority and Research Ethics 
Committee for review and approval. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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9. 
References 
 
 
 
1. Polverino E, Goeminne PC, McDonnell MJ et al. European Respiratory Society guidelines for 
the management of adult bronchiectasis. Eur Respir J. 2017;50:1700629. 
DOI:10.1183/13993003.00629-2017. 
 
2. Pasteur MC, Bilton D, Hill AT. British Thoracic society guideline for non-CF bronchiectasis. 
Thorax. 2010;65:i1ei58. DOI:10.1136/thx.2010.136119. 
 
3. Bhalla M. Turcios N. Aponte V et al. Cystic fibrosis: scoring system with thin-section CT. 
Radiology. 1991;179(3):783-8. 
 
4. Koser U and Hill A. What’s new in the management of adult bronchiectasis? 
F1000Research. 2017;6:527. DOI:10.12688/f1000research.10613.1. 
 
5. Quint JK, Millett ER, Joshi M, et al.: Changes in the incidence, prevalence and mortality of 
bronchiectasis in the UK from 2004 to 2013: a population-based cohort study. Eur Respir 
J. 2016;47(1):186–93. 
 
6. Bott, J, Blumenthal, S, Buxton, M et al. Guidelines for the physiotherapy management of the 
adult, medical, spontaneously breathing patient. Thorax, 2009;64:1-i52. 
DOIhttp://dx.doi.org/10.1136/thx.2008.110726 
 
7. Jones, R., Lester, R., Brown, N. Effects of high frequency chest compression on respiratory 
system mechanics in normal subjects and cystic fibrosis patients. Can Respir J 1995;2(1):40-
46. 
 
8. Pisi, G., Chetta, A. The role of airway clearance therapy in reducing pulmonary complications 
in cystic fibrosis patients. Eur Respir Dis. 2008:36-37 
 
9. Krishnan, J., Ridge, A., Walker Harris, V et al. Early treatment of acute asthma or chronic 
obstructive pulmonary disease with high frequency chest wall oscillation in hospitalized 
patients. Chest. 2009;136(4):96-100. 
 
10. Diette, G., Rand, C., Thompson, K et al. A pilot study of high frequency chest wall oscillation 
(HFCWO) to reduce acute exacerbation of COPD (AE-COPD). Chest. 2007;132(4):531a 
 
11. Bravermann, J., Nozzarella, M. High-frequency chest compression: Advanced therapy for 
obstructive lung disease. Respiratory therapy. 2007;2(2)48-51