BIOSYM - A Feasibility Randomised Controlled Trial Comparing Biological Matrices With Synthetic Meshes in Women Undergoing One Stage Implant Based Breast Reconstruction
Phase: NA
Conditions: Breast Cancer
Sponsor: University Hospitals of Derby and Burton NHS Foundation Trust

 
 
 
 
 
 
 
 
 
 
 
 
 
FULL TITLE OF THE STUDY 
BIOSYM - A Feasibility Randomised Controlled Trial Comparing Biological 
Matrices with Synthetic Meshes in Women Undergoing One Stage Implant Based 
Breast Reconstruction 
SHORT TITLE/ ACRONYM 
Randomised trial comparing Biological Matrices with Synthetic Meshes  
Version and Date of 
Protocol: 
 
V5 28/February/2025 
Sponsor:  
University Hospitals of Derby and Burton NHS 
Foundation Trust 
Chief Investigator: 
Associate Professor Amit Goyal 
Sponsor Reference: 
UHDB/2020/078 
IRAS Project ID: 
 
315581 
 
 
ClinicalTrials.gov: 
 
 
ClinicalTrials.gov: NCT05449691 
Funder(s): 
University Hospitals of Derby and Burton NHS 
Foundation Trust  
This protocol has regard for the HRA guidance 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
 

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This document contains confidential information that must not be disclosed to anyone other 
than the Sponsor, the Investigator Team, host NHS Trust, regulatory authorities, and 
members of the Research Ethics Committee. 
 
 
TABLE OF AMENDMENTS: 
The following amendments and/or administrative changes have been made to this protocol since the 
implementation of the first approved version 
 
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Type of 
amendment  
Summary of amendment 
1 
11/08/2023 
3.0 
Substantial 
The study will be multicentre and 
supported by Derby CTSU. Addition of 3 
centres to achieve sample size of 60. 
2 
21/09/2023 
NA 
Non 
Substantial 
Addition of new sites and mNCA added to 
study. No protocol updates. 
3 
01/11/2024 
NA 
Non 
substantial 
New PI at Derby site, no protocol updates 
4 
03/06/2024 
4.0 
Non 
Substantial  
Addition of remote consent. Clarification 
surrounding participant withdrawals. 
Addition of two new centres.  
5.0 
04/02/2025 
5.0 
Non 
Substantial 
Amendment to progression criteria 
wording and inclusion of new study logo. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SIGNATURE PAGE 
 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the study in compliance with the approved protocol and will adhere to 
the principles outlined in the Declaration of Helsinki, the collaborators’ SOPs, and other regulatory 
requirements. 
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. 
 
BIOSYM Trial Protocol version 5.0 28 February 2025 
 
This protocol has been approved by:  
  
Name:  
Associate Professor Amit Goyal  
Trial Role:  
Chief Investigator  
Signature:  
_________________________  
Date:  
DD / MON / YYYY  
 

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KEY STUDY CONTACTS 
 
Chief Investigator: 
Amit Goyal 
Consultant Oncoplastic Breast Surgeon & Associate Professor  
Royal Derby Hospital, Derby, DE22 3NE 
Tel: 01332 785538 
Email: amit.goyal@nhs.net 
Sponsor’s 
representative: 
Teresa Grieve 
Assistant Director of Research and Development  
University Hospitals of Derby & Burton NHS Foundation Trust 
Royal Derby Hospital 
Derby, DE22 3NE 
Tel: 01332 724639 
Email: uhdb.sponsor@nhs.net 
Trial Statistician 
Jacqueline Beckhelling 
Derby Clinical Trials Support Unit 
University Hospitals of Derby & Burton NHS Foundation Trust 
Derby, DE22 3NE 
Email : jacqueline.beckhelling@nhs.net 
Trial Management 
Supported by Derby Clinical Trials Support Unit 
University Hospitals of Derby & Burton NHS Foundation Trust 
Royal Derby Hospital 
Derby, DE22 3NE 
Email: uhdb.derbyctsu@nhs.net 
PPI representative 
Janice Rose 
Patient advocate 
NCRI Breast CSG 
Email: jan.rose3012@outlook.com 
Co-Investigators: 
Emanuele Garreffa 
Consultant Oncoplastic Breast Surgeon, Royal Derby Hospital, Derby, DE22 
3NE 
Email: emanuele.garreffa@nhs.net 
 
Monika Kaushik 
Consultant Oncoplastic Breast Surgeon, University Hospitals of Leicester NHS 
Trust, Leicester, LE3 9QP 
Email: monika.kaushik@uhl-tr.nhs.uk 
 
Fiona Tsang-Wright 
Consultant Oncoplastic Breast Surgeon,Wycombe Hospital,High Wycombe, 
HP11 2TT  
 
Email: fiona.tsangwright@nhs.net 
 
 
Hazem Khout 
Consultant Oncoplastic Breast Surgeon,Nottingham University Hospitals, 
Hucknall Road, Nottingham NG5 1PB 
Email: hazem.khout@nuh.nhs.uk 
 
 
Kartikae Grover 
Consultant Oncoplastic Breast Surgeon, Castle Hill Hospital, Hull, HU16 5JQ 
Email: Kartikaegrover@nhs.net 
Funder: 
 Derby & Burton Hospital’s Charity (registered charity number 1061812). 
 

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STUDY SUMMARY 
 
Study Title: 
BIOSYM - A Feasibility Randomised Controlled Trial Comparing 
Biological Matrices with Synthetic Meshes in Women 
Undergoing One Stage Implant Based Breast Reconstruction 
Sponsor Study Reference: 
UHDB/2020/078 
Study Design: 
A phase III feasibility randomised controlled trial in which 
participants will be randomised in a 1:1 ratio. 
Study Participants: 
Women undergoing mastectomy for breast cancer or risk 
reduction and immediate one-stage mesh assisted implant 
breast reconstruction as standard care. 
Planner Number of Sites: 
5 
Planned Sample Size: 
60 women (30 per arm) 
Randomisation: 
Participants will be randomised to biological matrix or synthetic 
mesh 
Blinding: 
Participants will be blinded to the type of mesh (biological or 
synthetic mesh). 
Follow Up Duration: 
6 months 
Planned Recruitment Start 
Date: 
01 November 2023 
Planned Recruitment End Date: 
30 November 2025 
Planned Study End Date: 
30 May 2026 
Research Question/ Aims: 
To assess patient and clinician acceptance, recruitment rate, 
compliance with randomly allocated type of mesh and data 
completeness.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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FUNDING AND SUPPORT IN KIND 
 
Funder(s) 
 
Financial and Non-Financial Support Given 
Derby & Burton Hospital’s Charity (registered 
charity number 1061812). 
Financial support 
Consultant Oncoplastic Breast Surgeons and 
trainees 
Surgeons and trainees participating in the study 
will undertake research activities. 
 

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ROLES & RESPONSIBILITIES 
 
Sponsor 
The Sponsor, University Hospitals of Derby & Burton NHS Foundation Trust, take on overall 
responsibility for appropriate arrangements being in place to set up, run and report the research project. 
The sponsor is not providing funds for this study but has taken on responsibility for ensuring finances 
are in place to support the research.  
 
Funder 
 Derby & Burton Hospital’s Charity (registered charity number 1061812). Feasibility study results will be 
used to apply for NIHR HTA funding for the main study.  
 
Study Management Committees 
 
Trial Management Group (TMG) 
The TMG will meet regularly to oversee the day-to-day management of the trial, including all aspects 
of the conduct of the trial. Any problems with study conduct will be raised and addressed during TMG 
meetings.  
 
The TMG will review recruitment, retention, compliance and data quality to ensure efficient trial conduct 
according to the research timeline. They will report to the independent Trial Steering Committee (TSC). 
 
Trial Steering Committee (TSC) 
The TSC will oversee and supervise the progress of the trial and ensure that it is being conducted 
according to the protocol and the applicable regulations. The TSC is an independent body that includes 
a majority of members who are not involved with the running of the trial. They will meet prior to 
commencement of the study, and then at regular intervals until completion (at least annually). The 
responsibilities of the TSC are outlined in the TSC Charter which will be signed by all members. 
 
Data Monitoring and Ethics Committee (DMEC) 
This is a small feasibility study and therefore will not require a DMEC.  
 
 
Protocol Contributors 
 
A number of protocol contributors have been involved in the development of this protocol, these include; 
Chief Investigator, Co-Investigators (including patient and public representatives) and the Trial 
Management team. Protocol contributors are responsible for inputting into the design of the study, 
ensuring that it is designed transparently and efficiently.  
 
 
 
 
 
 
 
 
 
 
 
 
 

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CONTENTS 
SIGNATURE PAGE .............................................................................................................................. 3 
KEY STUDY CONTACTS ....................................................................................................................... 4 
STUDY SUMMARY.............................................................................................................................. 5 
FUNDING AND SUPPORT IN KIND ...................................................................................................... 7 
ROLES & RESPONSIBILITIES ................................................................................................................ 8 
LIST OF ABBREVIATIONS .................................................................................................................. 11 
STUDY FLOW CHART ........................................................................................................................ 12 
1. 
BACKGROUND ......................................................................................................................... 13 
1. 
RATIONALE .............................................................................................................................. 13 
2. 
AIMS, OBJECTIVES AND OUTCOME MEASURES/ ENDPOINTS.................................................... 14 
2.1. Objectives ............................................................................................................................ 14 
2.2. Outcomes ............................................................................................................................ 14 
2.2.1. 
Feasibility study primary outcomes: ......................................................................... 14 
2.2.2. 
Feasibility study secondary outcomes: ...................................................................... 14 
3. 
STUDY DESIGN ......................................................................................................................... 15 
4. 
ELIGIBILITY CRITERIA ................................................................................................................ 15 
4.1. Inclusion Criteria .................................................................................................................. 15 
4.2. Exclusion Criteria ................................................................................................................. 15 
5. 
STUDY PROCEDURES ................................................................................................................ 15 
5.1. Screening and Consent......................................................................................................... 15 
5.1.1. 
Participant Identification .......................................................................................... 15 
5.1.2. 
Patient Information Sheet (PIS)................................................................................. 15 
5.1.3. 
Informed Consent ..................................................................................................... 15 
5.1.4. 
Screening/Enrollment Log ........................................................................................ 16 
5.2. Trial Entry ............................................................................................................................ 17 
5.2.1. 
Pathway for Trial Entry ............................................................................................. 17 
5.3. EnrollmentRegistration and Randomisation Procedure ........................................................ 18 
5.3.1. 
Method of Implementing the Treatment Arm Allocation .......................................... 18 
5.4. Interventions ....................................................................................................................... 18 
5.4.1. 
Surgery ..................................................................................................................... 18 
5.4.2. 
Pathology ................................................................................................................. 18 
5.5. Study assessments ............................................................................................................... 18 
5.5.1. 
Randomised participants .......................................................................................... 18 
5.6. Withdrawal Criteria.............................................................................................................. 19 
5.7. End of Study ........................................................................................................................ 20 
6. 
ADVERSE EVENT MANAGEMENT .............................................................................................. 20 
6.1. Definitions ........................................................................................................................... 20 
6.2. Reporting Requirements ...................................................................................................... 21 
6.2.1. 
Adverse Events and Adverse Device Events .............................................................. 21 
6.2.2. 
Serious Adverse Events and Serious Adverse Device Events ...................................... 22 
6.2.3. 
Reporting Procedure ................................................................................................ 22 
6.2.4. 
Reporting Period ...................................................................................................... 23 
6.2.5. 
Reporting Urgent Safety Measures ........................................................................... 23 
7. 
DATA HANDLING...................................................................................................................... 23 
7.1. Data Collection Tools ........................................................................................................... 23 
7.2. Source Data ......................................................................................................................... 24 
7.3. Data handling and reporting ................................................................................................ 24 
7.4. Access to Data ..................................................................................................................... 24 

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7.5. Archiving .............................................................................................................................. 24 
8. 
STATISTICS AND DATA ANALYSIS .............................................................................................. 25 
8.1. Sample Size Calculation ........................................................................................................ 25 
8.2. Statistical Analysis ................................................................................................................ 25 
8.3. Criteria for the Premature Termination of the Study ............................................................ 25 
8.4. Progression criteria to main trial .......................................................................................... 26 
9. 
MONITORING, AUDIT & INSPECTION........................................................................................ 26 
10. ETHICAL AND REGULATORY CONSIDERATIONS ......................................................................... 26 
10.1. Public and Patient Involvement ........................................................................................ 26 
10.2. Research Ethics Committee (REC) & Regulatory Considerations........................................ 27 
10.3. Protocol Compliance ........................................................................................................ 27 
10.4. Notification of Serious Breaches to GCP and/or the Protocol ............................................ 27 
10.5. Data Protection and Patient Confidentiality...................................................................... 28 
10.6. Financial and Other Competing Interests .......................................................................... 28 
10.7. Indemnity ........................................................................................................................ 28 
10.8. Amendments ................................................................................................................... 28 
10.9. Access to Final Study Dataset ........................................................................................... 28 
10.10. Data Sharing Statement ................................................................................................... 28 
11. DISSEMINATION POLICY ........................................................................................................... 29 
11.1. Policy for Publication and Authorship ............................................................................... 29 
12. REFERENCES ............................................................................................................................ 30 
 
 
 

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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
CI 
Chief Investigator 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DMEC 
Data Monitoring and Ethics Committee 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical requirements for 
registration of pharmaceuticals for human use. 
ICPV 
ICJME 
Independent Cancer Patient’s Voice  
International Committee of Medical Journal Editors  
IRAS 
Integrated Research Application System 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised Controlled Trials  
NCRI 
National Cancer Research Institute 
NICE 
National Institute for Health Care Excellence  
NHS R&D 
National Health Service Research & Development 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
PPI 
Patient Public Involvement 
QA 
Quality Assurance 
QALY 
Quality-adjusted Life Year  
QoL 
Quality of Life 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure  
SSDL 
Site Signature and Delegation Log  
TMG 
Trial Management Group 
TMF 
Trial Master File 
TNO 
Trial Number 
TSC 
Trial Steering Committee 
UHDB 
University Hospitals of Derby and Burton NHS Foundation Trust  
 

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STUDY FLOW CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROs, patient reported outcomes; BCN, breast care nurse, QoL, quality of life 
 
Women undergoing mastectomy (removal of whole 
breast) for cancer or risk reduction + one-stage mesh 
assisted implant breast reconstruction 
Eligible, consent, and register 
•
Record baseline data 
•
Baseline PRO questionnaires  
RANDOMISATION 1:1 n=60 
 
Biological matrix 
n=30 
Follow-up 3 months post-surgery 
Routine clinic visit or telephone or hospital records 
Record complications - Take action as appropriate 
Questionnaires–Postal/clinic PROs (Breast Q, EQ-5D-5L) 
Primary feasibility outcomes: 
Clinician acceptance: Proportion of eligible women offered the trial  
Patient acceptance: Proportion of those offered the trial who consent & are randomised 
Recruitment rate - average per year  
Compliance with allocated type of mesh  
Completeness of data collection 
After surgery, women will receive routine treatment for 
breast cancer, as appropriate.  
Synthetic mesh 
n=30 
Follow-up 6 months post-surgery 
Routine clinic visit or telephone or hospital records 
Record complications – Take action as appropriate  
Questionnaires–Postal/clinic PROs (Breast Q, EQ-5D-5L) 

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1. 
BACKGROUND 
 
Immediate breast reconstruction in women undergoing removal of the whole breast (mastectomy) for 
cancer or risk reduction is most commonly performed using breast implants[1]. A sheet of mesh is 
used as standard treatment in majority of implant reconstructions[2] to cover the implant partially or 
completely like an internal bra to support the weight of implant and re-create a natural looking breast. 
The mesh enables one-stage breast reconstruction and avoids a second procedure for the patient[3].  
 
Two types of meshes that are used routinely in the NHS are – biological and synthetic. Biological 
matrices are derived from animal tissue e.g. pig or cow, treated to remove animal cells and are costly 
(around £2500 per sheet). Synthetic meshes are made from net-like absorbable or non-absorbable 
fabric with open spaces between the strands and cost less (around £500 per sheet). The two types of 
meshes have different acceptability issues amongst women because of personal beliefs and concerns 
on animal welfare. 
 
The UK iBRA audit[4] has collected information on the use and outcomes of different meshes at 3-
months. The audit showed that use of mesh does not put patients at any higher risk of adverse post-
operative outcomes, and both meshes may be equally safe. The quality of data is poor as it was an 
audit that did not directly compare the two types of meshes. It did not assess the long-term safety, 
lacks patient reported outcomes and suffers from numerous selection (e.g. women undergoing 
reconstruction using synthetic meshes may have been healthier and different before surgery than 
those who had biological meshes) and other biases (e.g. incomplete reporting and differences in 
surgical experience between surgeons contributing data). In contrast to iBRA, US and Canadian 
MROC study[5] showed significantly higher major complications with some biological matrices that 
has led FDA to issue a safety warning[6]. There are no trials directly comparing the two types of 
meshes. We do not know how safe each type of mesh is beyond 3-months. This is important as there 
can be side-effects that only appear in the long-term as they have for some other types of surgery.  
 
A randomised study directly comparing the two types of meshes is needed to address the long-term 
safety, clinical effectiveness and cost effectiveness of the biological and synthetic meshes. It would 
allow women and surgeons make shared informed decisions on breast reconstruction.  
 
Before starting a large study, we will run a feasibility study to find out whether women and surgeons 
are willing to take part in such a study. Women undergoing reconstruction will be randomly allocated 
to receive biological or synthetic mesh and followed up-to 6-months initially. Feasibility study will 
establish whether random allocation of type of mesh is acceptable to women and clinicians and 
explore what outcomes are important to capture. This will help us design the follow-on main trial that 
will measure women’s satisfaction with reconstructed breasts, quality of life (QoL), complications and 
costs over 5 years. 
 
 
2. 
RATIONALE 
 
Breast and cosmetic implant registry data shows that in 2019, 2885 implant reconstructions were 
performed and 2075 meshes were implanted in England &Scotland[2]. This is an underestimate as 
figures from Hospital Episodes Statistics and the Private Healthcare Information Network suggests 
that half of all people that had breast implant surgery in 2019 are not recorded in the registry[2]. 
Women are living longer with more effective cancer treatment. Reconstruction is a part of cancer 
treatment and women have to live with the outcome for the rest of their lives. National Mastectomy 
and Reconstruction Audit[1] and iBRA audit[4] show that 9% women suffer implant loss at 3-months. 
The number of women requiring repeat surgery for complications has increased from 5%[1] to 18%[4] 
in the last few years. The complications can be serious and unpleasant to women trying to adapt to 
life after breast cancer and are costly to NHS in terms of hospital related and primary care costs.  
 
Although mesh assisted implant breast reconstruction has become standard treatment and the most 
widely used procedure[4], we do not know patient outcomes and how safe each type of mesh is in the 
long-term to guide patient choices or surgeon decision-making. The choice of mesh is currently 
guided by surgeon preference and availability.  
 

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Mesh surgery for urinary incontinence and vaginal prolapse has seen many women complain of 
devastating side effects. The NICE (National Institute for Health and Care Excellence) guidelines 
have been revised and advise mesh surgery as the last resort for these symptoms and recommend 5 
year follow-up[7].  
 
Therefore, it is important to conduct a study comparing the two types of meshes in breast 
reconstruction and generate long-term patient outcome and safety data. The BIOSYM research 
question has been identified as a key research gap by Association of Breast Surgery[8]. The research 
output will reduce the risk of avoidable harm in the future as recommended by the independent review 
report ‘First do no harm’[9] and inform specialist and NICE guidelines.  
 
The NCRI Living With and Beyond Cancer Initiative highlights what is important to cancer patients to 
live better with and beyond cancer. The number one priority concerns looking at long-term side effects 
of cancer treatment, confirming the importance of this study to women[10]. 
 
 
3. 
AIMS, OBJECTIVES AND OUTCOME MEASURES/ ENDPOINTS 
3.1. Objectives 
To assess patient and clinician acceptance, recruitment rate, and compliance with randomly allocated 
type of mesh. We will explore views of women and healthcare professionals about the study; evaluate 
appropriateness and completeness of data on proposed future main study outcomes. The standard 
deviation (SD) of patient reported ‘satisfaction with breasts’ score on Breast Q questionnaire will 
inform sample size calculations for the main study. 
 
Feasibility study will assess: 
 
• 
Clinician acceptance: Proportion of eligible women offered the trial  
• 
Patient acceptance: Proportion of women offered the trial who participate in the trial 
• 
Recruitment rate (average per year ) 
• 
Completeness of data on proposed definitive trial study outcomes 
• 
Compliance with allocated type of mesh 
 
The follow-on main study will assess long-term (5 years) patient reported ‘satisfaction with breasts’ 
measured using Breast Q questionnaire, quality of life measured using Breast Q and EQ-5D-5L 
questionnaires, complications and economic evaluation. 
 
3.2. Outcomes 
3.2.1. Feasibility study primary outcomes: 
• 
Clinician acceptance: Proportion of eligible women offered the trial  
• 
Patient acceptance: Proportion of women offered the trial who consent & are randomised in 
the trial 
• 
Recruitment rate (average per year) 
• 
Compliance with allocated type of mesh 
• 
Completeness of data on proposed definitive trial study outcomes 
 
3.2.2. Feasibility study secondary outcomes: 
• 
Sample size estimation: Estimate the sample size for the main study. 
• 
Completeness of data on proposed definitive trial study outcomes 
a. Surgical complications such as infection, wound breakdown, readmission, 
reoperation, unplanned surgery, skin flap necrosis, implant loss, seroma, pain, 
capsular contracture and haematoma recorded at routine NHS clinic visits (or by 
nurse led telephone call or from hospital records) at 3- and 6-months post-surgery. 

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b. Patient reported outcomes (PROs) questionnaires: Breast Q and EQ-5D-5L 
completed at randomisation in the clinic or at home, 3- and 6-month post-surgery 
(postal or clinic). 
 
4. 
STUDY DESIGN 
Pragmatic phase III randomised, feasibility trial with of biological matrices compared with synthetic 
meshes in women undergoing immediate one-stage mesh assisted implant breast reconstruction as 
standard care. 
 
5. 
ELIGIBILITY CRITERIA 
5.1. Inclusion Criteria 
Eligible participants will be/should have: 
• 
Female age ≥ 18 
• 
Women undergoing mastectomy and immediate one-stage mesh assisted implant breast 
reconstruction as standard treatment 
5.2. Exclusion Criteria 
Participants will be excluded if they have any one of the following: 
• 
Revision reconstruction surgery 
• 
Delayed reconstruction surgery, i.e. when reconstruction surgery is NOT performed at the 
same time as mastectomy. 
 
6. 
STUDY PROCEDURES 
6.1. Screening and Consent 
 
6.1.1. Participant Identification 
The target population are women undergoing mastectomy for breast cancer or risk reduction and 
immediate one-stage mesh assisted implant breast reconstruction as standard care. 
 
Potential trial participants will be identified at the routine multi-disciplinary meetings and reconstruction 
clinics, where patients’ eligibility will be assessed. The trial will be introduced and discussed with the 
patient by the treating clinician at the clinic appointment. Screened patients will be entered onto the 
screening log which will record whether they were eligible for the trial or not and the reasons why non-
eligible patients were not eligible.  Eligible patients will be approached by their treating clinician.  If a 
treating clinician decides not to approach an eligible patient, the reasons for not approaching them must 
be recorded in the screening log. 
6.1.2. Patient Information Sheet (PIS) 
The aim of the PIS is to provide information about the research study to potential BIOSYM participants  
Patients will be encouraged to take the information sheet home and discuss the trial with their family 
ahead of making an informed decision. Patients will be given sufficient time to consider the information 
and reach a decision, this may include coming back to the centre for another clinic visit.  
6.1.3. Informed Consent  
If a patient has read the PIS, and is happy to participate in the trial, they will be consented and enrolled 
in the study. The patient must be given the opportunity to ask questions and to be satisfied with the 
responses, prior to written consent being given. Patients can refuse consent without giving a reason, 
but if they do say why they do not want to take part this should be recorded in the screening log. Consent 
may be taken remotely using the same version of the consent form. Participants should be provided 

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with a PIS and the consent form should be completed by a delegated individual via a telephone or video 
conference call. The delegated individual will mark that the consent was taken remotely. At the next 
routine visit to the hospital, , the same consent form should be countersigned by the participant and a 
copy given to them for their record.  
6.1.3.1 
Responsibilities  
It is the responsibility of the Principal Investigator (PI) at each site, or trained delegate, to obtain 
informed consent for each participant, prior to performing any trial related procedure. The PI may 
delegate responsibility for obtaining informed consent to other appropriate members of the site research 
team, for example Clinical Nurse Specialists and Research Nurses, who must be appropriately trained 
in obtaining informed consent and in Good Clinical Practice (GCP).  Delegation of responsibility for 
obtaining informed consent must be indicated appropriately on the Site Signature and Delegation Log 
(SSDL). Participant eligibility should be confirmed by the PI or Investigator(s) who are delegated this 
task on the SSDL. Other members of the Research Team (e.g. Research Nurse) may assist with this 
process but responsibility remains with the PI. 
6.1.3.2 
Process for obtaining informed consent 
Full consent can be obtained in writing at a face to face clinic visit or remotely.  
The local PI, or designee receiving consent, must countersign the consent form.  
 
If a participant is not available to consent face to face, consent may be taken remotely via a 
teleconference or video call. The same consent form will be used by the delegated individual who will 
sign the form and document on the form that consent was completed remotely. At the next routine visit 
to the hospital, the participant will be requested to sign the same consent form.   
 
A patient cannot be randomised to the trial without informed consent (remote consent is acceptable for 
randomisation). Completed informed consent forms should be kept at site. 
 
A copy of the fully signed consent form must be given to the patient. The site must ensure that the 
patient’s participation in the trial is recorded in the patient notes and is communicated to the patient’s 
GP.   
Original ICFs must be retained on site (the original should be retained in the trial site file, with a copy 
filed in the relevant participant’s hospital notes and a copy given to the participant).  
If the PIS and/or ICF are modified during the course of the trial, sites will be notified of the procedure to 
follow for participants already consented and for prospective participants.  
6.1.4. Screening Log 
Participating sites will be expected to maintain an electronic screening log of all potential study 
candidates. This log will include limited information about the potential candidate (e.g. date of birth and 
initials), the date and outcome of the screening process (e.g. enrolled into study, reason why not 
approached for consent, reason why candidate declined to participate).  
 
As part of the screening process, the participant will be assigned a unique trial number (TNO) generated 
sequentially by the EDC system that should be used to identify the participant and be recorded on all 
eCRFs and on any correspondence. 
 
No identifiable information about patients who are not eligible or who do not consent will go out of the 
clinical team. 

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6.2. Trial Entry 
6.2.1. Pathway for Trial Entry 
Eligible participants will be approached prior to surgery. If patients give their informed consent to 
participate, they will be enrolled and randomised on to the study.   
 
 
Women underoing 
immediate mesh assisted 
one-stage implant breast 
reconstruction
Meets eligibility criteria
Consent and register
Complete baseline 
questionnaires
RANDOMISE 1:1
Biological matrix n=30
Synthetic mesh n=30

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6.3. Enrollment and Randomisation Procedure 
Before randomising a participant, written informed consent must have been obtained and confirmation 
of trial eligibility documented in the patient’s medical notes. Following consent, participants will be 
enrolled and complete the baseline Breast Q and EQ-5D-5L questionnaires. They will be randomised 
to biologic matrix or synthetic mesh to allow sufficient days to order the allocated mesh for surgery. 
Participants will be blinded to the type of mesh (biological or synthetic mesh).  
 
6.3.1. Method of Implementing the Treatment Arm Allocation  
Participants will be randomly allocated using permuted block randomisation stratified by site via a web-
based randomisation form in the Electronic Data Capture (EDC) system. Access to the EDC system 
will be via personal username and password, and specific to role. 
 
Patients will be randomly allocated to the techniques in a 1:1 ratio. Women undergoing bilateral surgery 
will receive the same mesh on both sides.  
6.4. Interventions 
Participants will undergo ALL treatments as per standard local practice.  
6.4.1. Surgery 
Breast surgery will be performed as per standard local practice.  
 
Surgery quality assurance (QA): The use of mesh for implant breast reconstruction has embedded 
into surgical practice[2]. For QA, only surgeons who have performed at least 25 mesh assisted 
implant reconstructions previously with implant loss of <10% will be eligible to participate.  
6.4.2. Pathology 
The histology specimens should be examined and reported according to standard local practice.  
6.5. Study assessments 
6.5.1. Randomised participants  
Participant demographics, medical history, and indication for surgery will be collected at randomisation. 
Operative details such as procedure time, placement of implant under or over the muscle, and hospital 
stay will be collected during the in-patient stay for surgery. Details of any treatment given after surgery 
will also be collected during follow-up. We are using validated questionnaires for participant reported 
outcomes that have been used previously.  
 
 
Study Assessments 
Baseline 
visit 
 
Surgery 
admission 
Month 
3 post 
surgery 
Month 
6 post 
surgery 
Consent 
X 
 
 
 
Randomisation 
X 
 
 
 

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Participant Demographics 
X 
 
 
 
Medical History 
X 
 
 
 
Indication for Surgery 
X 
 
 
 
Operative Details 
 
X 
 
 
Post-Surgery Histology 
 
 
X 
 
Post-Surgery Treatment Details  
 
 
 
X 
Questionnaires (Breast Q, EQ-5D-
5L) postal or clinic 
X 
 
X 
X 
Follow-Up (Surgical Complications 
data collection;  via clinic, 
telephone or hospital records)  
 
 
X 
X 
 
 
Complications: such as infection, wound breakdown, readmission, reoperation, unplanned surgery, 
skin flap necrosis, implant loss, seroma, pain, capsular contracture and haematoma recorded at routine 
NHS clinic visits (or by nurse led telephone call or from hospital records) at 3 and 6 months post-surgery. 
 
Patient reported outcomes (PROs) questionnaires: Patient-reported outcome data will also be 
collected in this feasibility study. We will assess aesthetic outcome and QoL with the widely used and 
validated reconstruction module of the Breast-Q questionnaire[11, 12]. This questionnaire has become 
the gold-standard measure of QoL for breast surgery, and was used in the National Mastectomy and 
Breast Reconstruction Audit[1]. It is comprised of independently functioning scales that measure 
outcomes and patient’s experience of care (i.e. satisfaction with the surgeon, information and medical 
team). The QoL domain consists of three subdomains: physical, psychosocial and sexual wellbeing. 
The satisfaction with outcome domain also consists of three subdomains: satisfaction with breasts, 
satisfaction with overall outcome and satisfaction with care. A total Breast-Q score will be calculated 
(ranging from 0-100), with higher scores indicating greater satisfaction or better QoL. A minimum 
difference score of 4 points on the transformed 0 to 100 scale is clinically important when assessing an 
individual patient’s outcome using the reconstruction module of the Breast-Q[13].  
 
The EQ-5D-5L questionnaire is recommended to estimate utility values and quality-adjusted life years 
(QALYs) in economic evaluations in the UK[14]. This is a validated generic QoL tool and the responses 
to this questionnaire administered at randomisation, 3- and 6-months post-surgery will be summarised 
by randomised arm as completion rates and descriptive statistics (mean and median with their 
associated measure of uncertainty). QALYs will be estimated using the area under the curve 
approach[15] and summarised descriptively. 
 
If the scores suggest any concerns, we will arrange rapid access back to the patient’s breast care nurse. 
 
Patient Photographs:  
Patient photographs, both before and after surgery, will be recorded in accordance with routine local 
guidelines. Patients will be asked to provide consent for the use of these photographs for publication 
purposes, as per routine NHS practice. 
 
6.6. Withdrawal Criteria 
In the event of a participant’s decision to withdraw from the trial, the Investigator should ascertain from 
which aspects of the trial the participant wishes to withdraw and record the details on the eCRF. For 
participants withdrawing from all aspects of the trial, the investigator should ascertain from the 
participant if they continue to consent to collecting routine information from hospital records. 
 

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Participants may withdraw from the allocated trial treatment only; this may be at the discretion of the 
investigator due to safety concerns. If a participant is withdrawn from the allocated trial treatment prior 
to surgery, they must be followed-up in accordance with the protocol and standard of care.  
 
Participants who are randomised, but subsequently found not to meet the eligibility criteria, should be 
withdrawn from the trial, continue with standard care and a replacement patient should be recruited.  
 
For patients who are lost to follow-up, follow-up data should continue to be collected from hospital or 
GP records, these patients should not be automatically withdrawn from the trial. 
 
Participants who withdraw prior to randomisation will be replaced. Participants who withdraw from the 
study after randomisation will not be replaced.  
 
6.7. End of Study 
The end of study will be defined as last data capture for the last participant, allowing 1 month after the 
last visit to upload data and answer data queries. The CI will notify the Sponsor, participating site/s and 
REC within 90 days of the end of study, or within 15 days if the study is ended prematurely (please see 
Section 9.6 for the criteria for premature study termination). The clinical study report will be written 
within 12 months of the end of study.  
7. 
ADVERSE EVENT MANAGEMENT 
7.1. Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in 
subjects, users or other persons, where or not related to the 
investigational medical device and whether anticipated or 
unanticipated. 
Adverse Device 
Effect (ADE) 
 
An adverse event related to the use of an investigational medical 
device. 
 
NOTE: this definition includes: 
• 
AEs resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any 
malfunction of the investigational medical device.  
• 
Any event resulting from use error or from intentional misuse of the 
investigational medical device. 
• 
‘Comparator’ if the comparator is a medical device. 
Serious Adverse 
Event (SAE) 
An adverse event that led to any of the following: 
• death 
• serious deterioration in the health of the subject, users, or other persons 
as defined by one of more of the following 
o a life-threatening illness or injury, or 

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o a permanent impairment of a body structure or a body 
function including chronic diseases, or  
o in-patient of prolonged hospitalisation, or 
o medical or surgical intervention to prevent life-threatening 
illness or injury, or permanent impairment to a body structure 
of a body function, 
• foetal distress, foetal death, a congenital abnormality, or birth defect 
including physical or mental impairment. 
 
NOTE: Planned hospitalisation for a pre-existing condition, or a 
procedure required by the CIP without a serious deterioration in health, 
is not considered a SAE. 
Serious Adverse 
Device Effect (SADE) 
 
An adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
Unanticipated 
Serious Adverse 
Device Effect 
(USADE) 
 
A serious adverse device effect which by its nature, incidence, severity or 
outcome has not been identified in the current risk assessment. 
 
NOTE: Anticipated serious adverse device effect (ASADE) is an effect which by 
its nature, incidence, severity or outcome has been identified in the risk 
assessment. 
Device Deficiency 
Inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, usability, safety or performance. 
 
NOTE: This definition includes: 
• 
Malfunctions, use errors, and inadequacy in the information supplies 
by the manufacturer including labelling.  
• 
Device deficiencies related to the investigational medical device or the 
comparator.  
Serious Health 
Threat 
Signal from any adverse event or device deficiency that indicates an imminent 
risk of death or a serious deterioration in the health in subjects, users or other 
persons, and that requires prompt remedial action for other subjects, users or 
other persons.  
 
NOTE: this would include events that are of significant and unexpected nature 
such that they become alarming as a potential serious health hazard or 
possibility of multiple deaths occurring at short intervals.  
 
7.2. Reporting Requirements 
7.2.1. Adverse Events and Adverse Device Events 
Data about relevant AEs or adverse device events are collected through routine data capture (i.e. on 
the Follow-up Form and through participant reported outcomes on questionnaires). Recurrence of 
and/or death from breast cancer and the diagnosis of new cancers in participants are outcome 

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measures of the trial that will be collected via the CRF and are treated as expected events. Further 
separate collection of adverse event data is not required for trial analysis.  
7.2.2. Serious Adverse Events and Serious Adverse Device Events 
Whilst it is not anticipated there will be any serious adverse events or serious adverse device events 
directly related to the study, it is important that this protocol includes a process for dealing with any 
serious adverse events in the unlikely event they occur. All participants in this study will receive standard 
NHS treatment. Both types of meshes – biologic matrix and synthetic mesh are used routinely in the 
NHS. This protocol does not contain investigational agent(s). Therefore, events related to the natural 
course of the disease and its treatment are expected  and not required to be reported as outlined below. 
 
For the purpose of this study, the following are regarded as expected SAEs and should not be recorded 
as an SAE. 
• 
Haematoma, wound infection, seroma or other surgical complication of breast surgery  
• 
SAEs relating to radiotherapy  
• 
SAEs relating to breast reconstruction  
• 
SAEs relating to adjuvant treatment for breast primary cancer or recurrence  
• 
SAEs relating to lymphoedema events 
 
For the purposes of this study, the following events also constitute expected SAEs and should not be 
reported to Research ethics.  
• 
Hospitalisations for:  
• 
Surgical complications related to breast reconstruction, as this information is captured 
elsewhere in the CRF 
• 
Pre-planned elective procedures unless the condition worsens.  
• 
Treatment for progression of the patient’s cancer  
• 
Progression or death as a result of the patient’s cancer. 
 
For medical devices that are CE marked and being used for their intended use(s) all USADEs must be 
reported to the REC and the manufacturer. 
7.2.3. Reporting Procedure 
Site  
Events that meet the criteria for a SAE or SADE per the protocol, should be reported on the SAE form 
on the Electronic Data Capture (EDC) system by the investigator or a member of the research team. 
When completing the form, the Investigator will be asked to confirm the following information:  
• 
full details in medical terms and case description 
• 
event duration (start and end dates and times, if applicable) 
• 
action taken 
• 
outcome 
• 
grade of severity  
• 
causality (i.e. relatedness to type of mesh), in the opinion of the investigator 
• 
expectedness 
 
On becoming aware that a patient has experienced a SAE, the Investigator (or delegate) must 
complete, electronically sign and date the SAE Form on EDC.  
 
Patients should be followed up until resolution or stabilisation of the event. Follow-up information should 
be provided on a new SAE form. 
 
Trial Office  

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On receipt of an SAE Form, the Chief Investigator will perform an independent assessment of 
relatedness. The Chief Investigator will also assess all related SAEs for expectedness. If the event is 
deemed unexpected (i.e. is not defined as an expected event in Section 7.2.2) it will be classified as 
an Unexpected and Related SAE.  
      
Reporting to the REC        
The Chief Investigator/Trial co-ordinator will report all events that are categorised as 
Unexpected and Related SAEs to the REC within 15 days of receipt. Details of all Unexpected and 
Related SAEs and USADEs will also be reported to Principal Investigators at recruiting sites.  
 
All related and unexpected SAEs must be reported by the investigator using the ‘non-CTIMP 
safety report to REC form’ from the HRA website. The completed form should be submitted to 
the Sponsor and REC within 15 days of the CI becoming aware of the event. Safety information 
will be reviewed during trial management group meetings.  
 
 
 
UHDB contact information: 
Email: uhdb.randdsae@nhs.net 
 
7.2.4. Reporting Period  
The PI is responsible for checking for SAEs and SADEs when participants attend for treatment and 
follow-up. Details of all related SAEs (except those listed in Section 7.2.2) will be documented and 
reported from randomisation until 6 months post randomisation.  This reporting period should be 
sufficient to capture all SAEs associated with the trial protocol however, if a related SAE is identified 
after this period, the event should be reported to the Trial Office.  
 
7.2.5. Reporting Urgent Safety Measures 
If any urgent safety measure is taken the research team should inform the Sponsor with 24 hours using 
the Sponsors safety incident reporting form. The Sponsor will inform the REC and participating sites of 
the measures taken and the circumstances giving rise to those measures within 3 days on 
implementation of the urgent safety measure. 
8. 
DATA HANDLING 
8.1. Data Collection Tools  
Study data will be entered at site into electronic case report forms (eCRF) directly by study personnel. 
The study will use an electronic data capture (EDC) system to store all data securely. The database will 
be a cloud-based EDC hosted by a fully validated 3rd party vendor. The database will be compliant with 
ICH-GCP and MHRA guidelines for computerised systems. Derby CTSU will be responsible for 
database design, build and data validation while the provider of the software will be responsible for 
hosting and storage of the study data. Access to the EDC will be assigned based on study roles. 
 
After data entry is performed, validation checks will be applied to the data to ensure accuracy and 
consistency according to the data validation plan. All data queries generated as a result of these checks 
will be available online for resolution by the site. Processing of study data and monitoring for 
consistency, validity and quality will be undertaken by study statisticians, data and trial manager on an 

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ongoing basis during recruitment.  After data entry is complete and all data queries have been resolved, 
the database will be locked and released for statistical analysis. 
 
Participants will be identified only by their unique study number assigned by the Electronic Data Capture 
system. The NHS numbers will be linked to the study numbers and this information will be stored 
securely locally at each hospital with restricted access. 
 
 
Participant reported outcomes will be captured via a series of participant questionnaires (outlined in 
Section 3.2). Paper questionnaires will be issued to participants at the required time points by site staff 
in clinic or posted to the participants. Participants will complete their responses within the questionnaire 
booklet, and return the completed document to site, for entry onto the trial database. 
8.2. Source Data 
Source documents are where data are first recorded, and from which participants’ CRF data are 
obtained. These include, but are not limited to, hospital records (from which medical history and 
previous and concomitant medication may be summarised into the eCRF), and correspondence. 
 
Outcome 
Source 
Participant Demographics 
Patient case records 
Medical History 
Patient case records 
Indication for Surgery 
Patient case records 
Operative Details 
Operation notes 
Post-Surgery Histology 
Histology report 
Post-Surgery 
Treatment 
Details  
Patient case records 
Questionnaires (Breast Q, 
EQ-5D-5L)  
Paper or scanned 
questionnaires 
 
 
eCRF entries will be considered source data if the CRF is the site of the original recording (e.g. there is 
no other written or electronic record of data).  All documents will be stored safely in confidential 
conditions. On all trial-specific documents, other than the signed consent, the participant will be referred 
to by the trial participant number, not by name.  
 
Investigators should keep records of all participating patients andall original signed informed consent 
forms. It is necessary for investigators to provide access to source document for monitoring and audit 
purposes to Sponsor, any monitoring or regulatory authorities as deemed necessary.  
8.3. Data handling and reporting 
Data will be collected and retained in accordance with the Caldicott Principles, UK Data Protection Act 
2018 and General Data Protection Regulation (GDPR). 
8.4. Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit study-related monitoring, audits and inspections. 
8.5. Archiving 
At the end of the study, following completion of the end of study report, UHDB will securely archive all 
centrally held study related documentation for a minimum of 10 years. At the end of the defined archive 
period arrangements for confidential destruction will be made. It is the responsibility of each PI to ensure 

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that data and all essential documents relating to the study are retained securely for a minimum of 10 
years after the end of study, and in accordance with national legislation. All archived documents must 
continue to be available for inspection by appropriate authorities upon request.  
 
 
9. 
STATISTICS AND DATA ANALYSIS 
9.1. Sample Size Calculation 
The sample size is 60. Sample sizes between 30 and 50 are recommended for a feasibility study[16, 
17]. By recruiting 60 (out of 120) we will be able to estimate a participation rate of 50% of women 
offered the trial to within a 95% confidence interval of +/-9% and a completion rate of 90% (54 of 60) 
within a 95% confidence interval of (80%, 95%).  
 
9.2. Statistical Analysis 
Descriptive statistics will be presented to summarize the distribution of demographic and baseline 
variables across each of the randomisation groups. A Consolidated Standards of Reporting Trials 
(CONSORT) flow diagram will be produced, showing the frequency of patients/ participants: 
• 
Assessed for eligibility and reasons for not eligible, 
• 
Approached and reasons for not approached 
• 
Confirmed as eligible 
• 
Consented and reasons for not consented 
• 
Excluded before randomisation (and the frequency of each reason for exclusion), 
• 
Randomised, 
• 
Allocated to each randomisation group, 
• 
That received each allocated type of mesh, 
• 
That did not receive each allocated type of mesh, 
• 
Lost to follow-up (and the frequency of each reason for loss to follow-up) for each randomisation 
group, 
• 
Analysed for each randomisation group, 
• 
Not analysed (and the frequency of each reason for not being analysed) for each randomisation 
group. 
 
Primary analysis will be intention-to-treat. Clinician acceptance (proportion of eligible women offered 
the trial), patient acceptance (proportion of women offered the trial who participate in the trial), 
randomisation rate and recruitment rate (average per year) will be presented overall as proportions 
along with 95% confidence intervals. Compliance with allocated type of mesh and completeness of data 
(primary and secondary endpoints) will be presented overall and by study group using summary 
statistics along with 95% confidence intervals.  
 
Secondary outcome measures will be presented overall and by study groups, as summary statistics at 
each assessment point. The standard deviation and effect size of Breast Q will be estimated using an 
Independent T-Test. Safety outcomes (AEs, SAEs, complications) will be presented with summary 
statistics by the treatment that has been received. 
 
Missing data will be excluded from analysis and will not be imputed. 
9.3. Criteria for the Premature Termination of the Study 
The Sponsor may suspend or prematurely terminate either the entire study, or the study at an individual 
site, for significant reasons that must be documented (e.g. an unacceptable risk to participants or 
serious repeated deviations from the protocol/ regulations). If this occurs the Sponsor shall justify its 

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decision in writing and will promptly inform any relevant parties (i.e. participants, investigators, 
participating sites, REC, regulatory bodies).  
9.4. Progression criteria to main trial 
The feasibility study will identify the challenges with study implementation and delivery. This will help 
us design the main trial that will measure women’s satisfaction with reconstructed breasts, quality of life 
(QoL), complications and costs over 5 years. We will progress to writing the grant application for the 
main trial if ALL the criteria below are met: 
o 
Clinician acceptance (proportion of eligible women offered the trial) - 50% and above 
o 
Patient acceptance (proportion of those offered the trial who consent & are randomised) - 20% 
and above 
o 
Average recruitment rate, 30 per year (overall) 
o 
Compliance with allocated treatment (treatment acceptability) – 80% and above 
 
10. 
MONITORING, AUDIT & INSPECTION 
 
The Investigator(s) must ensure that source documents and other documentation for this study are 
made available to study monitors or the Research Ethics Committee (REC). Authorised representatives 
of the Sponsor may visit the participating sites to conduct audits/ inspections.  
 
 
11. 
ETHICAL AND REGULATORY CONSIDERATIONS 
11.1. Public and Patient Involvement 
Patient & Public Involvement (PPI) has been key in the planned research for the BIOSYM trial. Patient 
representatives were approached for collaboration and involvement in the trial design from the outset. 
An extensive consultation process was undertaken across a number of patient advocate groups, 
including Independent Cancer Patient’s Voice (ICPV) and the National Cancer Research Institute 
(NCRI) Consumer Forum. 
Jan Rose (NCRI) has joined the research team as lay co-investigator. She was involved in the 
development of the trial design and the protocol. Their feedback underlined that there is currently a lack 
of involvement of breast cancer patients in the decision making regarding the type of mesh used in their 
reconstructive surgery. They also highlighted that to make an informed decision, more information 
should be available to those diagnosed with breast cancer on outcomes for patients, quality of life and 
the long-term safety of the different types of mesh. The patient representatives further contributed to 
the development of the proposal by advising and reviewing the plain English summary of the study 
protocol to ensure that the study rationale and procedures were explained in an accessible language. 
 
A Patient & Public Involvement (PPI) group will be formed to ensure that the BIOSYM trial remains 
centred on patients’ needs. This is important so that they can engage better and they’ve got somebody 
else there with them that they can connect with, and they don’t feel like they're there by themselves. 
We will follow the ‘outreach’ model of PPI, in which the named lay representatives will be linked to 
patient advocates from breast cancer charities or support groups.  
Representatives of the above group will be members of the protocol development group and (after the 
trial has launched) the trial management group. They will provide advice at different stages of the 
planned research. Main activities will involve:- 
a.) Contributing to and reviewing of the study protocol; (we will also ask members of Independent 
Cancer Patient’s Voice (ICPV) to review the study protocol); 
b.) Reviewing the content of the patient information leaflet to protect patient rights and ensure that the 
research rationale, procedures and risks will be fully explained and in an accessible language. (we will 
also ask members of ICPV to advise on the patient information leaflet); 

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c.) Providing insight in the ethical approval application, and assisting with communications with the NHS 
Research Ethics Committee; 
d.) Assisting with the dissemination of the planned research, including advising on conference 
proceedings and how to share the research findings to a wide audience in a way the public can 
understand; 
e.) Contributing to the trial design, agreeing which outcomes would be most important to measure and 
the grant application of the main study.  
The PPI group will engage throughout the study with the other members of the research team via email, 
remote video meetings (MS Teams/Zoom) and teleconferences. 
11.2. Research Ethics Committee (REC) & Regulatory Considerations 
The study will be conducted in compliance with the approved protocol, GCP, the Declaration of Helsinki 
and the Sponsor SOPs. The protocol and all related documentation (e.g. ICF, PIS, and questionnaires) 
will be reviewed and receive approval by a REC. The investigator will not begin any participant activities 
until approval from the HRA and REC has been obtained and documented. All documentation and 
correspondence must be retained in the trial master file/investigator site file. Substantial amendments 
that require HRA and REC (where applicable) review will not be implemented until the HRA and REC 
grants a favourable opinion (with the exception of those necessary to reduce immediate risk to 
participants).  
 
It is the responsibility of the CI to ensure that an annual progress report (APR) is submitted to the REC 
within 30 days of the anniversary date on which the favourable opinion was given, annually until the 
study is declared ended. The CI is also responsible for notifying the REC of the end of study within 90 
days. Within one year of the end of study, the CI will submit a final report with the results, including any 
publications/abstracts to the REC. 
 
The CI is also responsible for ensuring that the publicly available databases on which the trial is 
registered (i.e. ISRCTN or clinicaltrials.gov) are updated with the results of the trial.  
 
Before any site can enrol a participant into the study confirmation of capacity must be sought from the 
site’s research and development (R&D) department. In addition, for any amendment that will potentially 
affect the site’s permission, the research team must confirm with the site’s R&D department that 
permission is ongoing. 
11.3. Protocol Compliance 
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures described in this protocol. Prospective, planned deviations and/or waivers to the protocol 
are not acceptable. Accidental protocol deviations (known as non-compliances) may happen and as 
such these must be reported within the eCRF via a non-compliance form on the EDC by the PI or a 
delegated staff member.  Within this form the non-compliance will be categorized and classified as 
minor, major, or a serious breach, and will be reviewed by the trial manager and the TMG to identify 
any trends. Corrective and preventative actions will be identified and actioned. 
11.4. Notification of Serious Breaches to GCP and/or the Protocol 
A “serious breach” is a departure from the protocol, Sponsor procedures (i.e. SOPs), or regulatory 
requirements which is likely to effect to a significant degree – 
(a) The safety or physical or mental integrity of the subjects of the study; or 
(b) The scientific value of the study. 
If a serious breach is confirmed by clear and unequivocal evidence, the study Sponsor must notify the 
REC within 7 days of the matter coming to their attention.  

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11.5. Data Protection and Patient Confidentiality 
The study will be conducted in accordance with the General Data Protection Regulation (GDPR). The 
investigator must ensure that participant’s anonymity is maintained throughout the study and following 
completion of the study. Participants will be identified on all study specific documents (except for the 
informed consent form and enrolment log) by only the participants study specific identifier (and initials 
if deemed necessary). This identifier will be recorded on documents and the database. The Investigator 
Site File will hold an enrolment log detailing the study specific identifier alongside the names of all 
participants enrolled in the study.  
 
All documents will be stored securely with access restricted to study staff and authorised personnel.  
 
To preserve the participants’ anonymity, only their allocated trial number and initials will be required on 
the eCRFs. Participants should be assured that their confidentiality will be respected at all times 
 
UHDB will act as data controller of the data generated in the study.  
11.6. Financial and Other Competing Interests 
At the time of protocol writing, there are no known financial or other competing interests of the Chief 
Investigator or their team.  
11.7. Indemnity 
As UHDB is acting as the research Sponsor for this study, NHS indemnity applies. NHS indemnity 
provides cover for legal liabilities where the NHS has a duty of care. Non-negligent harm is not covered 
by the NHS indemnity scheme. UHDB, therefore, cannot agree in advance to pay compensation in 
these circumstances. In exceptional circumstances an ex-gratia payment may be offered. 
11.8. Amendments 
Changes to the protocol will be documented in written protocol amendments; the Sponsor is responsible 
for deciding if an amendment should be deemed substantial or non-substantial. Substantial 
amendments will be submitted to the relevant regulatory bodies (REC, HRA) for review and approval. 
The amendments will only be implemented after approval and a favourable opinion has been obtained. 
Non-substantial amendments will be submitted to the HRA for their approval/ acknowledgment. 
Amendments will not be implemented until all relevant approvals are in place. 
11.9. Access to Final Study Dataset 
Access to the trial datasets will be limited to the CI and to the trial statisticians. The datasets will be 
provided to the sponsor at the end of the trial for archiving purposes.  
 
Access to all data at site will be restricted to personnel approved by the local Principal Investigator and 
recorded on a delegation log. Access will also be given to the sponsor and regulatory authorities.   
11.10. Data Sharing Statement 
Any requests for access to the trial data should be sent to the CI who will inform the data custodians 
and agreement will be made through the data access committee which will comprise of the 
principal investigators from the trial management group. For each data sharing request, it is essential 
that a proforma is completed which will describe the purpose, scope, data items requested, analysis 
plan and acknowledgment of the trial management team. Requestors who are granted access to the 
data will be required to complete a data sharing agreement which will be signed by the requester, 
sponsor and principal investigator(s). We anticipate that data sharing will be possible after the 
publication of the primary endpoint of the trial. 
 

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12. DISSEMINATION POLICY 
 
The dissemination of the study results will be via a study report and research papers for publication in 
peer reviewed journals, and presentation at relevant conferences. Reporting will be in compliance with 
CONSORT recommendations. Publication of the results will be based on outcomes at least 6 months 
following the last recruited participant. No interim publication of results is planned. 
  
A summary of the results will be publicised through Independent Cancer Patients’ Voice, Cancer 
Research UK and Breast Cancer Now.   
12.1. Policy for Publication and Authorship  
Authors and Contributors will be defined as per The International Committee of Medical Journal Editors 
(ICJME) recommendations. The publication and authorship policy shall be agreed with the 
collaborators. The first author will be the CI of the study. Authorship will be named authors on behalf of 
a collaborative group; the named authorship is for those who have made a significant contribution. 
Additional authors will be those who have contributed to the overall success of the study. These will 
include team members who have randomized at least 10 participants to the study.    
 
Citable collaborators: Citable collaborators will have made a considerable contribution to the study but 
will not have met the ICMJE criteria for authorship (non-author contributors). All citable collaborators 
will be listed at the end of the paper and their roles identified.   
 
Acknowledged collaborators: Acknowledged collaborators will include team members and trainees who 
have made a lesser contribution to patient recruitment and data collection than that required for citable 
collaborator status. Trainees who are acknowledged contributors will also receive a certificate of 
participation for inclusion in their portfolios.   
   

 
 
 
13. 
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