A Randomised Controlled Trial Investigating the Use of PuraBond® (3-D Matrix) in Transoral Resections of Primary Oral or Oropharyngeal Mucosal Lesions
Phase: NA
Conditions: Pain, Hemorrhage, Hemostatics, Oropharynx, Oral Cavity
Sponsor: University of Liverpool

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PuraBondÒ PROOF Study 
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Full Title: A randomised controlled trial investigating the use of 
PuraBondÒ (3-D Matrix) in transoral resections of primary oral or 
oropharyngeal mucosal lesions 
 
 
Short Title: PuraBondÒ and Pain following Resection of Oral or 
Oropharyngeal mucosal lesions (PuraBondÒ PROOF) 
 
 
IRAS 322447 
NCT05773781  
 
 

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Full Title: A randomised controlled trial investigating the use of PuraBondÒ 
(3-D Matrix) in transoral resections of primary oral or oropharyngeal mucosal 
lesions 
 
Short Title: PuraBondÒ and Pain following Resection of Oral or 
Oropharyngeal mucosal lesions (PuraBondÒ PROOF) 
 
 
 
 
 
 
Clinical Trial Protocol  
Version: 0.7 
Date: 26th October 2023  
IRAS Number: 322447 
Funder: 3-D Matrix  
Funder No: TBC 
Name of Sponsor: University of Liverpool  
Sponsor No: UoL001737 
 
 
 

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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 Sponsor’s 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. 
 
Authorised by: 
 
Mrs Karen Jennings-Wilding 
 
 
 
 
Mr Jason Fleming 
Senior Clinical Research Governance Manager  
 
Chief Investigator 
 
 
 
Date:  
 
 
 
 
 
Date: 
 
 
 
 

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General Information  
This protocol describes the PuraBondÒ PROOF clinical trial and provides information about the 
procedures for entering participants into the trial, study processes, safety reporting and 
governance requirements The protocol should not be used as a guide, or as an aide-memoire for 
the treatment of other patients. Every care has been taken in drafting this protocol; however, 
corrections or amendments may be necessary. These will be circulated to the known 
Investigators in the trial following receipt of required approvals. Problems relating to the trial 
should be referred, in the first instance, to the chief investigator. 
 
Compliance 
This trial will adhere to the conditions and principles of Good Clinical Practice which apply to all 
clinical trials. It will adhere to the principles outlined in the UK Policy Framework for Health and 
Social Care Research. It will be conducted in compliance with the protocol, the Declaration of 
Helsinki (South Africa, 1996), the Data Protection Act 2018 and the UK GDPR as amended from 
time to time and any successor legislation in the UK and any other directly applicable regulation 
relating to data protection and privacy as well as any other regulatory requirements as 
appropriate. 
Funding  
The trial is being funded by 3-D Matrix, UK. 
 
Key Study Contacts 
Chief Investigator 
Mr Jason Fleming 
 
Senior Clinical Lecturer, University of Liverpool, Liverpool, UK. 
Consultant ENT/ Head and Neck Surgeon, Aintree University Hospital, LUHFT, Liverpool. 
 
Jason.fleming@liverpoolft.nhs.uk; Jason.fleming@liverpool.ac.uk;  
0151 529 5259 
Study                    
Co-investigators 
Dr Randa Ghazal Asswad 
Clinical Research Fellow, Aintree University Hospital, LUHFT Liverpool.  
Randa.Ghazal-Asswad@liverpoolft.nhs.uk; R.ghazalasswad@doctors.org.uk;  
0151 529 5259 
 
Mr Andrew Schache 
Reader/Hon Consultant Oral & Maxillofacial (Head & Neck) Surgeon, Liverpool Head and 
Neck Centre, Department of Molecular and Clinical Cancer Medicine and Liverpool 
University Hospital NHS Foundation Trust. 
schache@liverpool.ac.uk 
0151 529 5283 
Sponsor 
The University of Liverpool is the research Sponsor for this Study. It is recognised that 
as an employee of the University the Chief Investigator has been delegated specific 
duties, as detailed in the Sponsorship Approval letter. 
For further information regarding the sponsorship conditions, please contact: 
Mrs Karen Jennings-Wilding 
Senior Clinical Research Governance Manager 
Sponsor@liverpool.ac.uk  
 
 

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Table of Contents 
1 Trial Schema ......................................................................................................................................................... 6 
2 Trial synopsis ........................................................................................................................................................ 7 
3 Background, rationale and objectives .................................................................................................................. 8 
3.1 Background and rationale ................................................................................................................................. 8 
3.2 Study objectives ................................................................................................................................................ 9 
4 Study design ......................................................................................................................................................... 9 
4.1 Study setting ..................................................................................................................................................... 9 
5 Trial entry ........................................................................................................................................................... 10 
5.1 Identification of participants ........................................................................................................................... 10 
5.2 Screening procedures ..................................................................................................................................... 10 
5.3 Inclusion criteria ............................................................................................................................................. 10 
5.4 Exclusion criteria ............................................................................................................................................. 10 
6 Surgery ............................................................................................................................................................... 11 
7 Registration and randomisation ........................................................................................................................ 11 
8 Trial endpoint assessments ................................................................................................................................ 12 
8.1 Baseline (pre-operative assessments) ............................................................................................................ 12 
8.2 Intra-operative assessments ........................................................................................................................... 12 
8.3 Post-operative assessments ........................................................................................................................... 12 
8.3.1 Post-operative discharge ............................................................................................................................. 12 
8.3.2 Post-operative follow up .............................................................................................................................. 12 
8.4 Schedule of trial assessments ......................................................................................................................... 14 
9 Adverse effects and safety reporting ................................................................................................................. 15 
9.1 Definitions ....................................................................................................................................................... 15 
9.2 Reporting procedures ..................................................................................................................................... 15 
9.2.1 Adverse Events (AE) ..................................................................................................................................... 15 
9.2.2 Serious Adverse Events (SAE) ....................................................................................................................... 16 
10 Data management ........................................................................................................................................... 16 
10.1 Data collection and study database .............................................................................................................. 16 
10.2 Training ......................................................................................................................................................... 16 
10.3 Patient data ................................................................................................................................................... 17 
11 Trial management ............................................................................................................................................ 17 
11.1 Trial committees ........................................................................................................................................... 17 
11.1.1 Patient and public involvement group ....................................................................................................... 17 
11.1.2 Trial oversight ............................................................................................................................................ 17 
11.2 Risk assessment ............................................................................................................................................ 17 
11.3 Participant withdrawal .................................................................................................................................. 18 
11.4 Lost to follow up ........................................................................................................................................... 18 
11.5 Protocol/ GCP non-compliance ..................................................................................................................... 18 
11.6 End of trial ..................................................................................................................................................... 18 
11.7 Archiving ....................................................................................................................................................... 18 
12 Statistical considerations ................................................................................................................................. 19 
12.1 Randomisation .............................................................................................................................................. 19 
12.2 Outcome measures ....................................................................................................................................... 19 
12.2.1 Primary outcome measures ....................................................................................................................... 19 
12.2.2 Secondary outcome measures ................................................................................................................... 19 
12.3 Sample size calculation ................................................................................................................................. 19 
12.4 Statistical analysis ......................................................................................................................................... 20 
13 Informed consent, ethical and regulatory considerations ............................................................................... 21 
13.1 Informed consent .......................................................................................................................................... 21 
13.2 Ethical approval ............................................................................................................................................ 21 
13.3 Confidentiality and data protection .............................................................................................................. 21 
14 Publication ....................................................................................................................................................... 22 
15 References ....................................................................................................................................................... 23 
APPENDIX 1: Abbreviations and glossary .............................................................................................................. 24 
APPENDIX 2: TSC members ................................................................................................................................... 25 
 
 
 

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1 Trial Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All adults undergoing planned elective tumour/ lesion excision of either oropharyngeal or oral 
mucosal pathology who are: Aged ³18 years, able to provide written informed consent and 
willing to complete study questionnaires up to 1-month post-surgery. 
Patient eligible for study 
Patient not 
eligible for study 
Patient approached during pre-operative clinic/ 
pre-operative assessment/ pre-operative wards. 
Study information provided. 
Patient agrees to participate 
Patient declines 
to participate 
Patient treated with 
usual standard of care. 
Written informed consent obtained 
Pre-surgical baseline assessments completed (including baseline VAS). 
Randomisation 1:1 ratio to surgery with PuraBondÒ application or surgery without PuraBondÒ 
application to surgical field 
Operating surgeon informed of group allocation. 
Surgery with PuraBondÒ 
application 
Surgery without PuraBondÒ 
application 
Follow up of patient’s pain VAS scores at days 1, 2, 4, 7, 14 and 30 

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2 Trial synopsis 
Study title 
A randomised controlled trial investigating the use of PuraBondÒ (3-D 
Matrix) in transoral resections of primary oral or oropharyngeal lesions 
Study acronym 
PuraBondÒ PROOF 
Funder 
3-D Matrix, UK 
Chief investigator 
Mr Jason Fleming 
Sponsor 
University of Liverpool 
Trial design 
Non-CTIMP 
Single site, parallel group randomised controlled trial 
Study participants 
64 suitable patients 
Setting 
Aintree University Hospital LUHFT at Liverpool Head and Neck Centre, 
UK. A large tertiary UK centre with a track record of successful 
recruitment to clinical trials and significant head and neck case load. 
Main eligibility criteria 
Inclusion: 
• 
Patient and disease factors are deemed suitable for transoral 
surgery under general anaesthetic. 
• 
Decision to treat with primary transoral resection or local 
excision biopsy. 
• 
Aged 18 or over. 
• 
Written informed consent provided. 
• 
Clinically suspected or histologically confirmed primary 
dysplasia or malignancy of the oral cavity or oropharynx OR 
histologically confirmed diagnosis of squamous cell carcinoma 
in a cervical lymph node of unknown primary. 
• 
Patient considered fit for surgery. 
 
Exclusion: 
• 
Lesions undergoing incisional or punch biopsy only. 
• 
Surgery with planned primary closure or local/ distant flap 
reconstruction. 
• 
Inability to provide written informed consent. 
• 
Medical contraindication to a general anaesthetic or to 
PuraBondÒ use. 
 
Interventions 
Two existing operative techniques:  
i) 
PuraBond Ò application to surgical field  
ii) 
No PuraBond Ò application to surgical field. 
Follow up duration 
1 month 
Planned Study Period 
TBD 
Objectives 
To test the hypothesis that in adult patients undergoing surgical 
excision procedures for mucosal pathology of the oral cavity or 
oropharyngeal subsites, the use of PuraBond Ò intraoperatively on 
the surgical bed significantly reduces acute pain at 30 days post 
randomisation. To compare the effectiveness of its use on the 
incidence of post-operative complications and important clinical 
outcomes. 

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3 Background, rationale and objectives 
 
3.1 Background and rationale 
Head and Neck Cancer (HNC) describes a host of different malignancies originating from various 
anatomical sites including the oral cavity, pharynx and larynx, with 90% of tumours being squamous 
cell carcinomas. In the UK, HNC is the eighth most common cancer type accounting for an estimated 
12,422 new cases annually [1]. 
 
One particular subtype of HNC is oropharyngeal squamous cell carcinoma which relates to the 
structures of the oropharynx including the tonsils, base of tongue (BOT), soft palate and walls of the 
oropharynx. In 2018, the global incidence of oropharyngeal cancer (OPC) was just over 92,000 new 
cases [2]. Both premalignant oral lesions and OPC are treated with surgical excision and healing by 
secondary intention [3]. Surgery within this anatomical area means pain is an important side effect 
and as with all surgical procedures, intra-operative and post-operative bleeding is also a known 
consequence. 
 
Developed by the company 3-D Matrix, PuraBondÒ (also known as PuraStatÒ; 3-D Matrix Ltd, Tokyo, 
Japan) is a novel haemostatic agent [4]. It utilises RADA16, a synthetic peptide normally viscous in 
consistency, that is organised in β-sheet nanofibers in acidic environments. However, upon exposure 
to biological fluids such as blood these sheets cross-link creating a stable interwoven transparent 
hydrogel 3-D matrix. This hydrogel acts as a barrier to prevent further blood flow from the operative 
wound site. Thus, its use controls local surgical haemorrhage and prevents post-operative re-
bleeding. Its use as a haemostatic agent has been demonstrated in various surgical fields including 
endoscopic resection of gastrointestinal lesions, cardiac surgery and laparoscopic colorectal 
operations [5,6,7]. These studies confirmed PuraBondÒ as an effective operative haemostat. 
Packaged in a prefilled syringe, use of PuraBondÒ is thus practical within busy operating theatres. It 
was approved for use in the European Union (EU) in 2014 (with the United Kingdom a member state 
at this time) as a CE marked class III medical device. It is currently actively being used within routine 
head and neck cancer operations in Liverpool University Hospital Foundation Trust (LUHFT), although 
current use is variable and largely depends on surgeon preference. 
 
Transoral approaches in head and neck surgery have become more common given they offer a 
minimally invasive approach to surgery, thus removing the need for external incisions in the neck. 
This surgical approach can involve using either a carbon dioxide laser or a robotic approach. A recent 
UK case series from Birmingham reported on the use of PuraBondÒ in thirteen oropharyngeal cancer 
cases treated with Transoral Robotic Surgery (TORS) [8]. No cases of primary or secondary 
haemorrhage post-operatively were recorded and all patients resumed oral diet on day one post 
operatively. The authors also alluded to better patient outcomes including swallowing, pain and 
length of stay in hospital. Although, the use of PuraBondÒ as a haemostatic agent is well 
documented, its impact on pain management is a clinically important factor of interest as pain directly 
impacts patient recovery. Yet this factor has not been studied within the parameters of a randomised 
control trial. The formation of the hydrogel barrier insulates the wound bed thus it may also reduce 
pain stimulus to the operative site. A clinical trial such as PuraBondÒ PROOF is needed to provide 
gold-standard evidence to support such findings and impact clinical management. This will provide 
real world evidence of PuraBondÒ use on pain outcomes in head and neck surgery. 
 

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3.2 Study objectives 
The aim of this study is to assess whether intraoperative use of the haemostatic agent PuraBondÒ is 
associated with decreased levels of pain postoperatively following wide local excision procedures for 
oral or oropharyngeal mucosal lesions. We hypothesise that patients treated with such agents will 
have better post-operative pain scores compared to those treated without. 
 
4 Study design 
PuraBondÒ PROOF is a prospective, single centre, parallel group randomised controlled trial (RCT). 
Patients eligible for the study must have clinically suspected or histologically confirmed dysplasia or 
malignancy in the oral cavity or oropharyngeal subsites. Their primary lesion must be considered 
resectable via a transoral approach. After informed consent, patients will undergo baseline 
assessment of pain levels prior to surgery and demographic data will be collected. Surgery may or 
may not involve laser use to the primary site. 
 
Suitable patients will be stratified prior to randomisation by lesion site (oral cavity or oropharynx) 
and whether or not the surgical technique will involve laser resection. Depending on which arm the 
participant is allocated to, PuraBondÒ may or may not be applied to the surgical bed intraoperatively. 
It is important to note that both treatments are routinely used in these operations and PuraBondÒ 
use will fall completely within its license in this study.  
 
Using surgical site and technique to clinically stratify patients is important as standard post operative 
analgesia management differs between these groups (see table below). It is important that data 
collected from this trial represents real world evidence and thus, pre and post operative analgesia 
agents used will be recorded by analysing patient’s prescriptions rather than. restricting analgesia 
prescriptions and changing current standard of care. This means this trial will not lack generalisability 
and will not limit the relevance of its results to real world practice. 
 
Medication 
Oropharyngeal surgery 
Oral cavity surgery 
TOLR 
No laser used 
Paracetamol 
✓ 
✓ 
✓ 
Ibuprofen 
✓ 
✓ 
✓ 
Codeine 
✓ 
✓ 
✓ 
Morphine 
✓ 
Not routinely used 
Not routinely used 
Oxycodone 
X 
Not routinely used 
Not routinely used 
Chlorhexidine 
X 
X 
✓ 
GelclairÒ* 
✓ 
X 
✓ 
Benzydamine 0.15% solution 
✓ 
✓ 
✓ 
Pregabalin 
✓ 
X 
X 
*Please note: Patients enrolled in PuraBondÒ PROOF will not be prescribed GelclairÒ post 
operatively. GelclairÒ is a viscous gel used orally that may confound any results of PuraBond use. 
It is a product licensed for treatment of oral mucositis in in oncology, hence use in our patient 
cohort is considered off label. 
 
4.1 Study setting 
This will be a single centre study undertaken at Liverpool University Hospitals NHS Foundation 
Trust (LUHFT) in Liverpool Head and Neck Centre. LHNC is the largest UK NHS/ University head 
and neck collaboration delivering research-driven high-quality patient care. It has developed a 

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large clinical trial portfolio with multiple international and national clinical trials supported at the 
centre. Thus, it provides an ideal clinical setting to ensure adequate patient recruitment into the 
study due to the large number of surgical head and neck operations conducted daily as well as 
research expertise. 
 
Suitable patients will be identified by screening both daily operative lists at the centre as well as 
head and neck outpatient clinic lists and MDT. Suitable patients will then be approached by a 
member of the research team to confirm eligibility as well as discuss and provide information on 
the study and potential participation. All trial procedures including identification, recruitment, 
surgery and follow up will be undertaken within LUHFT. 
 
5 Trial entry  
 
5.1 Identification of participants 
Patients will be identified directly from clinical lists of patients undergoing a predetermined list 
of surgical procedures involving either the oral cavity or oropharyngeal sites (see section 6). 
Patients will be identified by members of their normal clinical team or study team. Patients who 
appear to fulfil the inclusion criteria will be referred to the research team for confirmation. 
Eligibility will be formally confirmed by the CI, site PI, study co-investigators or delegates, who 
have access to, and a full understanding of, the patient’s medical history. Once eligibility is 
confirmed the patient will be approached by a suitably delegated member of the trial team who 
will inform them of the trial. This may occur in a variety of settings e.g., in surgical clinics, pre-
operative clinics and on pre-operative wards. 
 
5.2 Screening procedures  
Patients are eligible for the trial if they are undergoing surgical excision of either suspected or 
confirmed dysplasia or malignancy of an oral or oropharyngeal subsite, all inclusion criteria are 
met (see section 5.3) and none of the exclusion criteria apply (see section 5.4). The patient`s 
written informed consent must be obtained before registration and any trial related procedures 
are undertaken (see section 12). 
 
5.3 Inclusion criteria  
Patients are eligible for the trial if all of the following criteria are met: 
• 
Patient and disease factors are deemed suitable for transoral surgery under general 
anaesthetic. 
• 
Decision to treat with primary transoral resection or local excision biopsy. 
• 
Aged 18 or over. 
• 
Written informed consent provided. 
• 
Clinically suspected or histologically confirmed primary dysplasia or malignancy of the 
oral cavity or oropharynx OR histologically confirmed diagnosis of squamous cell 
carcinoma in a cervical lymph node of unknown primary. 
• 
Patient considered fit for surgery. 
 
5.4 Exclusion criteria  
Patients are not eligible for the trial if any of the following criteria apply:  
• 
Lesions undergoing incisional or punch biopsy only. 
• 
Surgery with planned primary closure or local/ distant flap reconstruction. 
• 
Inability to provide written informed consent. 

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• 
Medical contraindication to a general anaesthetic or to PuraBondÒ use. 
 
6 Surgery 
Surgery should only be carried out through the transoral route. Depending on the lesion subsite, 
suitable procedures include: 
 
Oral cavity  
Excision of a lesion from free oral mucosal surfaces with planned healing by secondary 
intention. 
 
Oropharynx: 
- 
Tonsillectomy 
- 
Tongue base mucosectomy 
- 
Lateral oropharyngectomy 
- 
Tongue base resection 
- 
Soft palate excision 
 
It is important to note that all surgical procedures undertaken will be standard of care and agreed 
on before and regardless of trial participation. PuraBondÒ is already in use in head and neck 
surgery at LUHFT depending on the operating surgeon’s preference and is currently on the 
recognised supplier list for the trust. 
 
7 Registration and randomisation 
Following clinical assessment, participants will be randomised to one of two trial arms using the 
method of minimisation. Randomisation will be performed centrally by the LCTC. Patient eligibility 
must be established prior to randomisation (see section 5.1) and patients must confirm their 
consent by providing a signed informed consent form (see section 12.1). Details of the trial 
enrolment will be recorded in the participant’s electronic patient record. This will include 
confirmation of eligibility and the date of enrolment into the trial. 
 
At registration the participant will be given a unique participant trial number. At randomisation 
the participant will be allocated to a treatment arm. To register or randomise a patient the 
relevant registration or randomisation case report form (CRF) should be completed and the LCTC 
contacted. Participants will be randomised centrally by a computer in a 1:1 ratio to either have 
PuraBondÒ applied to the surgical field or not intraoperatively. A minimisation algorithm will be 
used within the online randomisation system to ensure balance in the treatment allocation over 
the three following clinical variables: 
 
- 
Surgical subsite: oral cavity or oropharynx 
- 
Surgical operation: concurrent neck procedure (yes or no) 
- 
Surgical technique: laser use (yes or no) 
 
The operating surgeon will be informed by LCTC regarding the patient’s treatment arm allocation. 
Due to the packaging of PuraBondÒ within pre-filled and labelled syringes, attempts to 
completely blind clinicians intraoperatively are not feasible. However, the patient, the assessors 
of postoperative outcomes and the study co-investigators will be blinded. 
 

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8 Trial endpoint assessments 
The aim of the PuraBondÒ PROOF trial is to determine whether PuraBondÒ application 
intraoperatively on the surgical field significantly reduces postoperative pain in head and neck 
transoral operations. Assessment of secondary clinical outcomes such as hospital stay and time 
till oral intake alongside post operative complications are also important points to record 
consequently. The study will also briefly consider any health economic benefits of PuraBondÒ 
use. 
 
Details of the assessments required are included in the CRF and are outlined below in the schedule 
of trial assessments (see section 8.4). With regards to the timing of assessments, the date of 
transoral surgery and thus whether PuraBondÒ is applied or not is classified as day 0. 
 
8.1 Baseline (pre-operative assessments) 
Pre-operative clinical investigation and preparation will be as per trust guidelines. Upon obtaining 
informed patient consent for participation in the study, the following data will be recorded: 
 
- 
Informed Consent (written) 
- 
Compliance to inclusion/exclusion criteria 
- 
Assignment of unique patient ID 
- 
Sex and age in years (on the day of surgery) 
- 
Height in centimetres  
- 
Weight in kilograms 
- 
Diagnosis and indication for surgery 
- 
Surgical plan  
 
8.2 Intra-operative assessments 
On the day of the operation (day 0), the following data will be recorded: 
 
- 
Baseline VAS pain score 
- 
Surgical plan 
- 
WHO performance score 
- 
Surgeon’s survey 
 
8.3 Post-operative assessments 
8.3.1 Post-operative discharge 
On discharge day, the following data will be recorded: 
 
- 
Length of stay in hospital (days) 
- 
Intraoperative complications 
- 
Time till commencement of oral intake 
 
8.3.2 Post-operative follow up 
A patient phone call may be conducted on days 1,2,4,7,14 and 30 to remind them to fill in their 
VAS pain scores. A scheduled patient phone call on day 30 will collect the following data: 
 
- 
Reoperation within 30 days 
- 
Post operative complications 

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- 
Readmission to hospital within 30 days 
 
They will be asked to return their VAS pain CRF to the study team via a pre-paid envelope provided. 

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8.4 Schedule of trial assessments 
 
Assessment/ Procedure 
Screening and 
baseline 
Surgery (Day 0) 
Day of 
discharge 
Follow up  
POD 1 
POD 2 
POD 4 
POD 7 
POD 14 
POD 30 
Eligibility (inclusion/ exclusion criteria) 
x 
 
 
 
 
 
 
 
 
Written informed consent 
x 
 
 
 
 
 
 
 
 
Registration 
x 
 
 
 
 
 
 
 
 
Assignment of a unique participant 
identification number 
x 
 
 
 
 
 
 
 
 
WHO performance score 
x 
X 
 
 
 
 
 
 
 
Randomisation 
 
x 
 
 
 
 
 
 
 
Pain VAS score 
 
x 
x 
x 
x 
x 
x 
x 
x 
Participant demographics – age, gender etc. 
x 
 
 
 
 
 
 
 
 
Diagnosis and proposed surgery 
x 
x 
 
 
 
 
 
 
 
TOLR/ transoral surgical excision 
 
x 
 
 
 
 
 
 
 
Surgeon’s survey 
 
x 
 
 
 
 
 
 
 
Return to theatre within 24 hours 
 
 
 
x 
 
 
 
 
 
Length of hospital stay 
 
 
x 
 
 
 
 
 
 
Readmission to hospital within 30 days 
 
 
 
 
 
 
 
 
x 
Return to theatre within 30 days 
 
 
 
 
 
 
 
 
x 
Intra operative complications 
 
 
x 
 
 
 
 
 
 
Post operative complications 
 
 
 
x 
x 
x 
x 
x 
x 
Time till oral intake 
 
 
x 
x 
 
 
 
 
x 
 

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9 Adverse effects and safety reporting 
 
9.1 Definitions 
PuraBondÒ PROOF is a non-CTIMP study as defined by the MHRA due to PuraBondÒ being a 
class III CE marked medical device not a drug. Thus, the following definitions are applicable to 
this study: 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical study 
subject, including unfavourable and unintended signs, including 
abnormal laboratory results, symptoms or a disease associated with 
treatment. 
Serious Adverse Event 
(SAE) 
Any AE that: 
• Results in death 
• Is life-threatening 
• Requires hospitalisation, or prolongation of existing inpatients’ 
hospitalisation 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect. 
Suspected Unexpected 
Serious Adverse Event 
(SUSAE) 
Any SAE, the nature and severity of which is not consistent with the 
Reference Safety Information (RSI) for the trial treatments – transoral 
surgery or PuraBondÒ application to the surgical field. 
 
Medical judgement should always be exercised in deciding whether an AE is serious in other 
situations. Important AEs that are not immediately life-threatening or do not result in death or 
hospitalisation but may jeopardise the subject or may require intervention to prevent one of the 
other outcomes listed in the definition above, should also be considered serious. 
 
9.2 Reporting procedures 
Any questions concerning adverse event reporting should be directed to the CI in the first 
instance. 
 
9.2.1 Adverse Events (AE) 
An AE has been defined above (see section 9.1). It may or may not be related to the transoral 
surgical procedure or PuraBondÒ application to the surgical field. Any AE should be recorded, this 
can be done on the designated CRF and in the patient electronic hospital medical records. 
 
A list of expected complications of transoral surgery include: 
- 
Teeth, lip, gum injury  
- 
Cutaneous or intraoral laser injury 
- 
Pain 
- 
Haemorrhage 
- 
Surgical site infection 
- 
Velopharyngeal insufficiency 
- 
Difficulty swallowing 
- 
Lingual or hypoglossal nerve injury 

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- 
Pharyngocutaneous fistula 
 
A list of expected complications of PuraBondÒ application include: 
- 
Irritation/inflammation, or disruption of blood components, due to the low pH of the product. 
- 
Thromboembolism following migration of thrombus resulting from haemostatic effect. 
- 
Embolization of gelled product following migration into blood vessels before or after gelation. 
 
The above listed complications can be used as the RSI when assessing the expectedness of SAEs 
causally to the trial treatments. 
 
9.2.2 Serious Adverse Events (SAE) 
All SAEs (see section 9.1) must be reported immediately with 24 hours of knowledge of the event 
apart from a hospitalisation because of expected complications of transoral surgery or 
PuraBondÒ application as defined above (see section 9.2.1) which will not require expediated 
reporting. 
 
A SAE form should be completed and sent to either the CI or study co-investigators (see SAE 
reporting form). All SAEs should also be reported to the relevant NHS research ethics committee 
where in the opinion of the CI, the event was both related to the study (it resulted from the 
administration of any of the research procedures) and unexpected (an event that is not listed in 
the protocol as an expected occurrence). These should be sent within 15 days of the CI becoming 
aware of the event. The CI should also inform the sponsor regarding any SAE. 
 
10 Data management 
 
The University of Liverpool, as Sponsor, has overall responsibility for the security, maintenance, 
and integrity of the study. The study’s CI and study co-investigators are responsible for data held 
locally at LUHFT and for ensuring all data provided is subject to written informed consent. 
 
10.1 Data collection and study database 
Data will be collected according to the study protocol and by approved, delegated members of 
the study team only. Data will be recorded on the designated CRF and then transcribed over onto 
a specifically designed electronic data capture system. The REDCap (Research Electronic Data 
Capture) database that will be used in this study is encrypted and password protected. Only 
approved and delegated study team members will be given access to the study’s REDCap 
database for data insertion. Access to this database is controlled by means of user identifiers and 
passwords, thus an audit trail will be available. Participants will be assigned a unique study 
identification number on registration, and this will be used on subsequent CRFs and database 
reporting, thus maintaining the strictest patient confidentiality. 
 
10.2 Training 
All members of the study team will be educated on the trial protocol at a departmental meeting.  
This will allow members of staff the opportunity to ask questions to ensure they are confident 
and comfortable with all aspects of the study protocol. Furthermore, the CI and study co-
investigators will confirm surgeon credentialing through prior experience with PuraBondÒ before 
any surgery is performed. Study team members that are approved to use REDCap will undergo 
further training on how to use this database. 
 

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10.3 Patient data 
All data collected for the study will be pseudonymised using unique identification numbers. Thus, 
a master patient identification list will be created and held securely on the password-protected 
encrypted NHS servers at LUHFT, ensuring it is securely and confidentially stored on site. Direct 
access to patient identifiable data, including access to the master patient identification list to 
enable reversal of pseudonymisation, will be granted to specific individuals or authorised 
representatives, and regulatory authorities only on request for monitoring, audit and inspection 
purposes. 
 
11 Trial management 
 
11.1 Trial committees 
11.1.1 Patient and public involvement group 
Patient involvement and advice will be sought from some members of the Merseyside regional 
head and neck cancer patient and carer support group. This includes patients who have previously 
undergone head and neck surgery at the study setting. Their input on key study elements will be 
incorporated into the study protocol. Furthermore, their involvement in reviewing the study PIS 
is vital. 
 
11.1.2 Trial oversight 
The Trial Management Group (TMG) will consist of the CI, study co-investigators and 
representatives from LCTC. This group will be responsible for the daily running of the trial. A small 
independent Trial Steering Committee will be convened for this study on the basis that the 
surgery performed and PuraBondÒ intervention are already in routine clinical use and both 
treatment arms are considered standard of care (see appendix 2). No Independent Data 
Management Committee (IDMC) is being proposed for this study. 
 
11.2 Risk assessment 
Given both treatment arms are already used throughout the UK and in head and neck surgical 
operations at the study site of LUHFT, the risk to all the study participants is no higher than that 
of standard care. In fact, a case series on PuraBondÒ use in transoral surgery reported no 
significant adverse events. A higher evidence study, such as PuraBondÒ PROOF, is needed to 
prove efficacy. A trial risk assessment will be performed to identify the potential hazards 
associated with the trial and their likelihood of occurring. 
 
PuraBondÒ is a class III CE marked medical device not a drug, it is being used within its license for 
this study. The following risks have been identified for PuraBondÒ use: 
- 
Irritation/inflammation, or disruption of blood components, due to the low pH of the product. 
- 
Thromboembolism following migration of thrombus resulting from haemostatic effect. 
- 
Embolization of gelled product following migration into blood vessels before or after gelation. 
 
It is important to stress that such side effects would be the same for participants enrolled onto 
the study as for those patients not enrolled in the study but are treated with PuraBondÒ routinely 
as per the operating surgeon’s preference. The level of risk that a trial participant would be 
exposed to is the same of that they would encounter outside of the trial as its use is standard of 
care. 
 

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11.3 Participant withdrawal 
By consenting to this trial, participants are accepting of the trial interventions, assessments and 
follow up data collection requirements. However, at time of informed consent, patients will be 
reminded that their participation is voluntary, and they retain the right to withdraw from the 
study without reason and without prejudicing any further treatment. The sample size calculation 
accounts for some participant withdrawal, so it is not anticipated that it will be necessary to 
replace participants who decide to withdraw. 
 
If a participant does decide to withdraw from this study, they can do so at any time by informing 
the CI or any other member of the research study team by calling 0151 529 5259. The contact 
details of the study team are recorded on the PIS. The investigator will need to clarify whether 
the participant wishes to withdraw from all or only particular trial components. If the latter is 
requested, then follow up data collection for which the participant previously consented to may 
continue. Should any participant wish to withdraw fully from the study, any data collected prior 
to withdrawal may be retained and used in trial analysis as specified by the study protocol. If 
following randomisation, the participant does not go on to have their surgery they should be 
withdrawn from the trial. 
 
11.4 Lost to follow up 
If a participant is lost to follow up, the study team will attempt to contact the participant to obtain 
information on their status in the first instance. Otherwise, the patient will be considered 
withdrawn from the study (see section 11.3).  
 
11.5 Protocol/ GCP non-compliance 
The CI should report any non-compliance to the trial protocol or the conditions and principles of 
GCP to the sponsor as soon as they become aware of it. 
 
11.6 End of trial 
The end of the trial is defined as the date of final data capture to meet the trial endpoints. 
 
11.7 Archiving 
The Trial Master File (TMF) will be held in a secure locked personal office of the CI which itself is 
located in a secure staff only access department area at LUHFT. Essential documents pertaining 
to the trial shall not be destroyed without permission from the Sponsor. Electronic copies of the 
study documents will also be archived on the password-protected encrypted NHS server at LUHFT 
for a minimum of 10 years. 
 
 

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12 Statistical considerations 
 
12.1 Randomisation 
After confirmation of eligibility, randomisation will take place by contacting LCTC. Participants will 
be randomised using minimisation to ensure balanced treatment allocation by several clinically 
important stratification factors including lesion site and surgical technique. A randomisation 
allocation ratio of 1:1 will be used. 
 
12.2 Outcome measures 
12.2.1 Primary outcome measures 
The primary outcome of this study will be pain following procedure. This will be measured using the 
visual analogue scale (VAS) which is a validated pain rating scale first used by Hayes and Patterson in 
1921 [9]. Self-reported pain severity is recorded by marking a point on a 10cm line that represents a 
continuum between ‘no pain’ at one end and ‘worst pain’ at the other. VAS pain scores preoperatively 
and on days 1, 2, 4, 7, 14 and 30 postoperatively will be recorded.  
 
12.2.2 Secondary outcome measures  
This will include data on: 
- 
Post-operative analgesia usage (including drug used, dose, route and frequency) 
- 
Post-operative complications by Clavien Dindo Classification including wound infection and 
bleeding rates 
- 
Length of stay in hospital 
- 
Readmission to hospital within 30 days post operatively 
- 
Bleeding events including primary (24 hours post operatively) and secondary (day 1 to 30 
post operatively) haemorrhage 
- 
Return to operating room within 24 hours post operatively 
- 
Return to operating room within 30 days post operatively 
- 
Surgeon survey regarding ease of PuraBondÒ use 
- 
Time taken to normal oral dietary intake (days) 
- 
Any health economic benefits of PuraBondÒ use. 
 
12.3 Sample size calculation 
To achieve a power of 80% with a significance level of 0.05, 32 patients will be needed in each 
treatment arm. A comparative study looking at pain scores following corticosteroid use in 
transoral robotic surgery reported a standard deviation in VAS pain scores of 2.0 [10]. A 1.2-point 
difference in VAS pain scores between intervention and control groups would be significant 
[10,11]. Analysis will be conducted using analysis of Covariance techniques which include pre-
surgical pain scores. 
 
The following sample size calculation was conducted for our continuous pain VAS outcome 
measure: 
! = 2 [(' + ))!],!
-!
 
 
Where: n = the sample size in each group arm, a = the conventional multiplier for alpha (1.96 for 
5% alpha), b =the conventional multiplier for power (0.84 for 80% power), s = standard deviation 
and d = the difference you wish to detect. 

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! = 2 [(1.96 + 0.84)!]2!
1.2!
 
! = 62.72
1.96 = 43.5 8'9:;!9< 8;= >?;='@@ 
 
= 87 8'9:;!9< :! 9>9'@ 
 
To account for the study using pre-surgical pain scores in the final analysis, the sample size is 
adjusted using a design factor based on the correlation between pre- and post-surgical pain 
scores. Here a conservative estimate of 0.3 is used. A final sample size, including 5% inflation for 
patient attrition is then given by: 
 
87*(1-0.3)*1.05 = 64 patient (32 per treatment group) 
 
12.4 Statistical analysis 
All data will be collected using the trial CRF and will be included in the final analysis. A detailed 
statistical analysis plan will be developed before the analyses are conducted. The following 
statistical considerations will be used in this study: 
 
Data Summaries: 
Continuous data are summarised as median (inter-quartile ranges) and categorical data are 
summarised as frequencies of counts (percentages). All VAS pain scores will be recorded to 1 
decimal point. 
 
Missing Data: 
Missing data are assumed to be rare given the study methodology and short follow up period, 
and analyses are thus planned on a complete case basis. 
 
Levels of Significance: 
Statistical significance will be determined using the p<0.05 significance level with all results 
presented alongside two-sided 95% confidence intervals. 
 
Patient groups for analysis: 
All analysis will be carried out on an intention to treat basis, retaining patients irrespective of any 
protocol violations. 
 
Analysis of the primary outcome: 
Analysis of the primary outcome will be carried out using Analysis of Covariance (ANCOVA) 
techniques. Here the post-operative pain score will be analysed as the primary outcome with the 
pre-surgical pain score being included as an adjusting covariate. Results will be presented in terms 
of the difference in means (95% confidence) intervals between the two groups. 
 
 

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13 Informed consent, ethical and regulatory considerations 
 
13.1 Informed consent 
Before any trial related procedures are undertaken, the patient’s written informed consent must 
be obtained using the PuraBondÒ PROOF trial Informed Consent Form (ICF), which follows the 
PIS. Please note, only when written informed consent has been obtained from the patient and 
they have been registered into the trial can they be considered a trial participant. 
 
The patient’s consent to participate in the trial should be obtained by those delegated to do so 
such as members of the study team, research nurses or qualified members of their direct clinical 
team, all after a full explanation has been given. All patients must be informed of the objectives 
of the study, the trial design, the possible adverse events, the procedures, and personal 
implications of study participation. They will be informed of the strict confidentiality of their 
patient data, but that their medical records may be reviewed for trial purposes by authorised 
individuals other than their treating physician. 
 
Patients will be provided with adequate time after being given the trial PIS to consider and discuss 
participation and have the opportunity to ask questions. This will be defined using patient and 
public involvement and engagement (PPIE) data (see PPIE survey). The study team will conduct a 
PPIE exercise with previous head and neck surgery patients that are part of the Merseyside & 
Cheshire Head & Neck Cancer Support Group. During the consent process, the investigator should 
determine that the patient is fully informed of the trial and their participation, in accordance with 
the principles of Good Clinical Practice. Patients should always be asked to sign a consent form. 
One copy should be given to the participant, but the original copy should be kept in the 
investigator site file and a further copy should be kept with the participant’s hospital notes. At 
the time of signing the ICF, each participant must be given the names and contact details of study 
site staff for reporting adverse events and medical emergencies. 
 
The right of the patient to refuse to participate in the trial without giving reasons will be respected 
and participants are free to withdraw from the study at any time before the last trial data 
collection point, that takes place at one-month postoperatively, without giving reasons and 
without prejudicing any further treatment. 
 
13.2 Ethical approval 
The relevant ethical approval will be obtained from the research ethics committee (REC) for the 
study and all associated documents before any activity commences on the study. All study 
amendments must be reviewed by the sponsor to assess if they are substantial or non-substantial. 
All substantial amendments to the protocol will be submitted to the relevant bodies and approval 
received before implementation. Informed written consent will be obtained from all participants. 
The right of a patient to refuse participation or withdraw from the study without giving reasons 
must and will be respected. 
 
13.3 Confidentiality and data protection 
All information collected during this study will be kept strictly confidential. Information will be 
held anonymously and securely on an electronic data capture system. A REDCap database will be 
created and utilised to collect study data. This will be compliant with the relevant data protection 
laws and any data published will be anonymous. 
 
 

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14 Publication  
The study team is committed to transparent communication of findings. Thus, data will be 
analysed and published as soon as possible. The results of this trial will be disseminated through 
presentations at scientific meetings, and in scientific articles in peer-reviewed medical journals. 
 
 

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15 References 
1. UK, 
Cancer 
Research. 
Head 
and 
neck 
cancers 
statistics. 
https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-
bycancertype/head-and-neck-cancers, (accessed 20th August 2022) 
2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal, A. (2018) Global cancer 
statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 
185 countries. CA: a cancer journal for clinicians. 68, 394-424 
3. Mehanna H, Evans M, Beasley M, Chatterjee S, Dilkes M, Homer J, O'Hara J, Robinson M, Shaw 
R, Sloan P. Oropharyngeal cancer: United Kingdom National Multidisciplinary Guidelines. J 
Laryngol Otol. 2016 May;130(S2):S90-S96. 
4. 3-D 
Matrix 
Medical 
Technology, 
PuraBond 
haemostatic 
agent. 
https://3dmatrix.com/products/purabond, (accessed 20th August 2022) 
5. Subramaniam S, Kandiah K, Thayalasekaran S, Longcroft-Wheaton G, Bhandari P. Haemostasis 
and prevention of bleeding related to ER: The role of a novel self-assembling peptide. United 
European Gastroenterol J. 2019 Feb;7(1):155-162. 
6. S. Giritharan, K. Salhiyyah, G. Tsang, et al. Feasibility of a novel, synthetic, self-assembling 
peptide for suture-line haemostasis in cardiac surgery J. Cardiothorac. Surg., 13 (2018), p. 68 
7. Ortenzi M, Haji A. Safety and feasibility of PuraStat® in laparoscopic colorectal surgery 
(Feasibility study). Minim Invasive Ther Allied Technol. 2021 Dec;30(6):363-368. 
8. Gupta K, Garas G, Idle M, Germain S, De M. Evaluating the role of the self-assembling topical 
haemostat PuraBond® in Transoral Robotic Surgery (TORS) for oropharyngeal cancer: A case 
series. Annals of Medicine and Surgery. https://doi.org/10.1016/j.amsu.2022.104302 
9. Couper M, Tourangeau R, Conrad F, et al.: Evaluating the effectiveness of visual analog scales: 
A web experiment. Soc Sci Comput Rev2006;24:227-245. 
10. Clayburgh D, Stott W, Bolognone R, Palmer A, Achim V, Troob S, Li R, Brickman D, Graville D, 
Andersen P, Gross ND. A randomized controlled trial of corticosteroids for pain after transoral 
robotic surgery. Laryngoscope. 2017 Nov;127(11):2558-2564. 
11. Delgado DA, Lambert BS, Boutris N, McCulloch PC, Robbins AB, Moreno MR, Harris JD. 
Validation of Digital Visual Analog Scale Pain Scoring With a Traditional Paper-based Visual 
Analog Scale in Adults. J Am Acad Orthop Surg Glob Res Rev. 2018 Mar 23;2(3). 
 
 
 

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APPENDIX 1: Abbreviations and glossary 
 
PuraBondÒ PROOF 
PuraBondÒ and Pain following Resection of Oral or Oropharyngeal lesions 
AE 
Adverse Event 
AR 
Adverse Reaction 
AUH 
Aintree University Hospital 
CI 
Chief Investigator 
CRF 
Case Report Form 
CTIMP 
Clinical Trial of an Investigational Medical Product 
GCP 
Good Clinical Practice 
HNC 
Head and Neck Cancer 
ICF 
Informed Consent Form 
IDMC 
Independent Data Management Committee 
LCTC 
Liverpool Clinical Trials Centre 
LHNC 
Liverpool Head and Neck Centre 
LUHFT 
Liverpool University Hospital Foundation Trust 
MDT 
Multidisciplinary Team 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NHS 
National Health Service 
PIS 
Participant Information Sheet 
PPIE 
Patient and Public Involvement and Engagement 
RCT 
Randomized control Trial 
REC 
Research Ethics Committee 
REDCap 
Research Electronic Data Capture 
RSI 
Reference Safety Information 
SAE 
Serious Adverse Event 
SUSAE 
Suspected Unexpected Serious Adverse Event 
TLM 
Transoral Laser Microsurgery 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TOLR 
Transoral Laser Resection 
TORS 
Transoral Robotic Surgery 
TSC 
Trial Steering Committee 
VAS 
Visual Analogue Scale 
 
 
 

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APPENDIX 2: TSC members 
 
Chairman: 
Mr Dejo Olaleye  
Consultant ENT/ Head and Neck Surgeon, University Hospitals Leicester. 
 
Panel members: 
• 
Mrs Pippa Mather 
Principal Head and Neck Oncology Dietician, Guy’s Hospital London. 
• 
Mr Jason Fleming 
CI of PuraBondÒ PROOF. Consultant ENT/ Head and Neck Surgeon, Aintree University Hospital, 
LUHFT, Liverpool. Senior Clinical Lecturer, University of Liverpool. 
• 
Mr Michael McGovern  
Lay member who is a patient representative of the Merseyside regional head and neck cancer 
patient and carer support group. 
• 
Mr Richard Jackson 
Medical statistician. Senior Lecturer at the department of Health Data Science, University of 
Liverpool 
 
Invited attendees: 
• 
3D Matrix representative. 
• 
Sponsor/ LCTC representative.