The Personalised Antibiotic Duration for Cellulitis (PAD-C) Cohort Study
Conditions: Cellulitis, Cellulitis of Leg, Antibiotic Duration
Sponsor: University of Sussex

 
 
 
The Personalised Antibiotic Duration for Cellulitis (PAD-C)  
Cohort Study 
 
This protocol has regard for the HRA guidance 
 
IRAS NUMBER: 295690 
 
VERSION 1.7 DATED: 06-January-2023 
 
SPONSOR: University of Sussex 
 
CHIEF INVESTIGATOR: Dr Elizabeth Cross  
Signature: 
    Date: 06/01/2023 
 
 
 

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KEY STUDY CONTACTS 
 
Chief Investigator 
Dr Elizabeth Cross 
Elizabeth.Cross2@nhs.net 
Tel: 07919207783 
 
Temporary absence cover: 
Professor Martin Llewelyn 
Brighton & Sussex Medical School 
Medical Research Building, Room 1.08 
University of Sussex 
Falmer, Brighton 
BN1 9PS 
M.J.Llewelyn@bsms.ac.uk 
Sponsor 
University of Sussex 
Sussex House 
Brighton 
East Sussex 
BN1 9RH 
Email: researchsponsorship@sussex.ac.uk 
Funder 
National Institute for Health Research 
Key Protocol Contributors 
Professor Martin Llewelyn 
Brighton & Sussex Medical School 
Medical Research Building, Room 1.08 
University of Sussex 
Falmer, Brighton 
BN1 9PS 
M.J.Llewelyn@bsms.ac.uk 
 
Professor Gail Hayward 
NIHR Community Healthcare MIC 
Nuffield Department of Primary Care Health Sciences 
Radcliffe Primary Care Building 
Radcliffe Observatory Quarter 
Woodstock Road, Oxford 
OX2 6GG 
gail.hayward@phc.ox.ac.uk 
 
Professor (Ann) Sarah Walker 
Nuffield Department of Medicine 
University of Oxford 
Microbiology Department 
John Radcliffe Hospital, Level 7 
Headington 
Oxford 
OX3 9DU 
sarah.walker@ndm.ox.ac.uk 
Statistician 
Professor (Ann) Sarah Walker 
Nuffield Department of Medicine 
University of Oxford 
Microbiology Department 
John Radcliffe Hospital, Level 7 

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Headington 
Oxford 
OX3 9DU 
sarah.walker@ndm.ox.ac.uk 
 
 
 
 

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i. LIST of CONTENTS 
 
 
KEY STUDY CONTACTS ....................................................................................................................................... 2 
I. LIST OF CONTENTS ........................................................................................................................................... 4 
II. LIST OF ABBREVIATIONS ................................................................................................................................ 6 
III. STUDY SUMMARY ............................................................................................................................................ 7 
IV. FUNDING ........................................................................................................................................................... 8 
V. KEYWORDS: ...................................................................................................................................................... 8 
VI. STUDY OVERVIEW .......................................................................................................................................... 9 
1 
BACKGROUND & RATIONALE ................................................................................................................... 10 
2 
OBJECTIVES AND OUTCOME MEASURES .............................................................................................. 11 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................ 11 
2.2 
SECONDARY OBJECTIVES ......................................................................................................................... 11 
2.3 
OUTCOME MEASURES/ENDPOINTS ............................................................................................................. 11 
3 
STUDY DESIGN AND SETTING .................................................................................................................. 12 
4 
PARTICIPANT ELIGIBILITY CRITERIA ....................................................................................................... 12 
4.1 
INCLUSION CRITERIA ................................................................................................................................ 12 
4.2 
EXCLUSION CRITERIA ............................................................................................................................... 13 
5 
STUDY PROCEDURES ................................................................................................................................ 13 
5.1 
RECRUITMENT ......................................................................................................................................... 13 
5.2  
CONSENT ................................................................................................................................................ 13 
5.3 
STUDY ASSESSMENTS .............................................................................................................................. 14 
5.4 
LONGER-TERM FOLLOW-UP ASSESSMENTS ................................................................................................ 18 
5.5 
WITHDRAWAL OF PARTICIPANTS ................................................................................................................ 19 
5.6 
DEFINITION OF END OF STUDY .................................................................................................................. 19 
6 
STATISTICS & DATA ANALYSIS ................................................................................................................ 19 
6.1 
SAMPLE SIZE CALCULATION ...................................................................................................................... 19 
6.2 
STATISTICAL ANALYSIS PLAN ..................................................................................................................... 20 
7 
DATA MANAGEMENT ................................................................................................................................. 21 
7.1 
SOURCE DATA ......................................................................................................................................... 21 
7.2 
CASE REPORT FORMS ............................................................................................................................. 22 
7.3 
DATA HANDLING AND RECORD-KEEPING ..................................................................................................... 22 
7.4 
ACCESS TO DATA .................................................................................................................................... 22 
8 
MONITORING, AUDIT & INSPECTION ........................................................................................................ 22 

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9  
ETHICAL & REGULATORY CONSIDERATIONS ........................................................................................ 22 
9.1  
DECLARATION OF HELSINKI ...................................................................................................................... 22 
9.2  
GUIDELINES FOR GOOD CLINICAL PRACTICE ............................................................................................. 23 
9.3  
RESEARCH ETHICS COMMITTEE (REC) APPROVALS ................................................................................... 23 
9.4  
REPORTING ............................................................................................................................................. 23 
9.5  
DATA PROTECTION AND PATIENT CONFIDENTIALITY .................................................................................... 23 
9.6  
PUBLIC AND PATIENT INVOLVEMENT .......................................................................................................... 23 
9.7 
PAYMENTS .............................................................................................................................................. 24 
9.8  
FINANCIAL AND OTHER COMPETING INTERESTS .......................................................................................... 24 
9.9  
INDEMNITY ............................................................................................................................................... 24 
10  
DISSEMINATION & PUBLICATION POLICY .......................................................................................... 24 
10.1  DISSEMINATION POLICY ............................................................................................................................ 24 
10.2  PUBLICATION POLICY ................................................................................................................................ 25 
11 
REFERENCES .......................................................................................................................................... 26 
12.  
APPENDICES ........................................................................................................................................... 28 
12.1 
APPENDIX 1 – AMENDMENT HISTORY ........................................................................................................ 28 
12.2 
APPENDIX 2 – SAMPLE SIZE STATA PROGRAM ............................................................................................ 30 
 
 
 

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ii. LIST OF ABBREVIATIONS 
 
AMR 
Antimicrobial Resistance 
ANOVA 
Analysis of variance 
CSS 
Cellulitis severity score 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GP 
General Practitioner 
HRA 
Health Research Authority 
ICF 
Informed Consent Form 
ICMJE 
International Committee of Medical Journal Editors 
IV 
Intravenous 
NHS R&D 
National Health Service Research & Development   
NIHR 
National Institute for Health Research 
PIS 
Participant Information Sheet 
QoL 
Quality of Life 
REC 
Research Ethics Committee 
SF-12 
Medical Outcomes Study Short Form 12-Item Health Survey 
STROBE 
Strengthening the Reporting of Observational Studies in Epidemiology 
SCR 
Summary Care Record 
TTO 
To Take Out 
 

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iii. STUDY SUMMARY 
Trial Title 
The Personalised Antibiotic Duration for Cellulitis (PAD-C) Cohort Study 
Internal ref. no. (or 
short title) 
PAD-C Cohort 
Study Design 
Prospective cohort study with nested technology comparison 
Trial Participants 
Patients with lower limb cellulitis receiving antibiotic treatment in a hospital or 
another service based outside of the hospital, which will conduct ongoing 
follow-up regardless of location.  
Planned Sample 
Size 
Up to 240 
Follow up duration 
90 – 180 days 
Planned Study 
Period 
3 years 3 months 
 
Objectives 
Outcome Measures 
Primary 
 
To understand what features of 
individual patients predict how likely 
they are to make a sustained 
recovery from cellulitis. This 
information will be used to test and 
refine a previously developed risk 
score that predicts clinical outcomes 
of patients with cellulitis. 
 
To investigate whether early 
response to antibiotic treatment (e.g. 
reduction in skin temperature and 
patient-reported symptoms) 
improves the predictive ability of a 
previously developed risk score. 
Sustained recovery, defined as no 
initiation of new antibiotic treatment for 
cellulitis at the same site through to 90 
days. 
Secondary 
 
Recovery at 28 days, defined as the 
absence of warmth and tenderness at 
the site, with improvement in swelling 
and acute colour change, that did not 
require new antibiotic treatment. 
 
Patient-reported time to resolution of 
cellulitis and symptoms of pain and 
swelling, using a numeric and verbal 
marked scale. 
 
Patient-reported time to return to 
work/normal activities and quality of life 
at 90 days (+/- 180 days on a subset of 
patients in whom there is >180 days 
available before the study ends). 
 
Patient-report on whether the cellulitis 
has exacerbated their other medical 
conditions collected at day 28. 
 
Cellulitis-related readmission and 
mortality within 90 days (+/- 180 days 

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on a subset of patients in whom there 
is >180 days available before the study 
ends). 
 
Antibiotic usage and antibiotic-related 
adverse events collected daily until 
discharge or completion of hospital 
antibiotic treatment. 
Nested technology comparison 
Nested technology 
comparison 
To identify the best technological 
device for measuring affected skin 
temperature change (as an objective 
measure of early response) in 
patients with cellulitis. 
Comparison of: 
Repeatability coefficient (repeatability 
of the measurements taken by the 
temperature measurement devices) 
 
Agreement between the methods 
quantified by estimating the limits of 
agreement. 
 
Mean time taken to measure skin 
temperature. 
 
Failure rates in obtaining a 
measurement of skin temperature. 
 
iv. FUNDING 
 
The National Institute for Health Research is the funder of the study. 
v. KEYWORDS: 
 
Cellulitis; antibiotics; treatment duration; treatment length 
 
 
 
 
 

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vi. STUDY OVERVIEW 
 
D0
D1
D2
D3
D4 to 
Discharge
D28
D90
D180
If joins on D0 
Physical 
assessments
If joins on D1
Skin temperature 
measurements 
& physical 
examination
Skin temperature 
measurements 
& physical 
examination
Patient-reported
QoL
Pain & 
swelling 
scores 
until self-
reported 
recovery 
or 28-day 
follow-up
Skin temperature 
measurements 
& physical 
examination
Skin temperature 
measurements 
& physical 
examination
Physical 
examination to 
assess recovery 
at 28 days
Recurrence of symptoms 
within 90 days
QoL & return to normal
Data at 90 days also collected at 180 days for the 
subset of patients recruited within the first year
Medical & laboratory 
records
Demographics & 
medical history
Vital signs 
daily to 
day 3
Routine 
laboratory 
results
Antibiotic 
use & 
related 
adverse 
events 
until end of 
treatment 
or 
discharge
+ / -
Recurrence of symptoms 
Antibiotic adverse events
Exacerbation of other 
medical conditions
Antibiotic 
use for 
cellulitis at 
same site
Cellulitis-
related re-
admission 
& mortality
Admission 
details 
+ / -
+ / -
If joins on D2

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1 
BACKGROUND & RATIONALE 
 
Cellulitis is a bacterial infection of the skin characterised by pain, swelling and loss of mobility, usually 
affecting the legs.1 Cellulitis is the commonest form of acute skin and soft tissue infection and is one of 
the commonest infections leading to hospitalisation.1,2 Treatment is with either oral or intravenous (IV) 
antibiotics depending on severity and the first-line recommended agent in the UK is flucloxacillin.3  
 
It is not known what the optimal duration of antibiotic treatment for cellulitis is. Recommendations vary 
from 51,4 to 10-143,5 days but, in practice, patients often receive over 14 days of therapy.6-12 Clinical 
evaluation of patients is complicated by the fact that local inflammation can persist for several days 
even when patients are making a good response.13 Clinicians often prolong treatment in the hope of 
ensuring cure, but consequently overtreat many patients.14 Unnecessary antibiotic use accelerates the 
development of antimicrobial resistance (AMR), which is an urgent threat to human health.15,16 
 
For several common bacterial infections there is now good evidence that shorter courses of antibiotics 
are as effective as longer courses for most patients.14,17,18 The benefits of reducing antibiotic exposure 
include reducing the risks of antibiotic-associated adverse events and subsequent antibiotic-resistant 
infections.19,20 However, there is still uncertainty about which patients with cellulitis can be safely 
treated with a shorter duration of antibiotic therapy.21 
 
A recent systematic review and meta-analysis of trials comparing a longer to a shorter duration of 
antibiotics for cellulitis found no evidence of a difference in clinical response for patients followed up to 
one month.22 However, the most recent trial, which compared 6 to 12 days of treatment and followed 
patients up to 90 days, found more recurrences in the short treatment group (24% versus 6%, 
P=0.045).21 The trial failed to show non-inferiority of short-duration treatment but crucially three-
quarters of patients treated for 6 days did achieve sustained cure to 90 days. This study sets out to 
address how to identify these patients so that they can avoid the harms of prolonged antibiotics. 
 
Observational studies have also found no relationship between antibiotic duration and clinical recovery 
or recurrence in cellulitis.22 Instead, they demonstrate that important predictors of outcomes are pre-
existing patient factors (e.g. prior episodes of cellulitis23 and other medical conditions10,24,25) and illness 
severity26 (e.g. sepsis10,23). Early response to treatment at 48-72 hours is another potentially important 
predictor, but the evidence is sparse and inconsistent.27,28 This study will determine whether early 
response to treatment predicts how well patients with cellulitis fully recover.  
 
Current methods of measuring early response, such as assessing a reduction in the area of affected 
skin, are hard to evaluate objectively and consistently by visual observation alone.29,30 Devices to 
directly measure skin temperature are now available and a handful of small studies have recently 
begun to examine their use in cellulitis.29,31-33 Skin temperature measurement has shown promise as 
an objective marker of early response in cellulitis and could potentially support personalisation of 
treatment, but more evidence is needed. This study will also help to identify the best technological 
device for measuring affected skin temperature change (as a measure of early response) in patients 
with cellulitis. 
 

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2 
OBJECTIVES AND OUTCOME MEASURES 
 
2.1 
Primary objective 
 
To understand what features of individual patients predict how likely they are to make a sustained 
recovery from cellulitis. This information will be used to test and refine a previously developed risk 
score that predicts clinical outcomes of patients with cellulitis. 
 
2.2 
Secondary objectives 
 
To investigate whether early response to antibiotic treatment (e.g. reduction in skin temperature and 
patient-reported symptoms) improves the predictive ability of a previously developed the risk score. 
 
To identify the best technological device for measuring affected skin temperature change in patients 
with cellulitis. 
 
Occurring separately but parallel to this study, a large-scale retrospective analysis of electronic health 
records will be undertaken to develop a risk score to predict clinical outcome in patients with cellulitis. 
Only limited information on early response to antibiotic treatment will be available, a limitation that the 
current study overcomes. The desired outcome of these two pieces of research is to develop an 
algorithm based on the risk score and clinical response, which prescribers can use to tailor decisions 
about antibiotic treatment duration for patients with cellulitis and could be tested in a future trial. 
 
2.3 
Outcome measures/endpoints 
 
2.3.1 Primary endpoint/outcome 
 
Sustained recovery, defined as no initiation of new antibiotic treatment for cellulitis at the same site 
through to 90 days. 
 
While appropriate antibiotic therapy of cellulitis is associated with early cure rates of up to 96%, a 
recent trial highlighted the major risk of short antibiotic treatment to be recurrence assessed at 90 
days (24% in the short-duration arm).21 It is also the most frequently identified outcome that is 
important to patients and healthcare professionals,34,35 and there is a striking lack of data around 
outcomes beyond 30 days in cellulitis.22 
 
2.3.1 Secondary endpoints/outcomes 
 
Cohort study 
Recovery at 28 days, defined as the absence of warmth and tenderness at the site, with improvement 
in swelling and acute colour change, that did not require new antibiotic treatment.  
 

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Patient-reported time to resolution of cellulitis and symptoms of pain and swelling, using a numeric 
and verbal marked scale. 
 
Patient-reported time to return to work / normal activities and quality of life assessed using the Medical 
Outcomes Study Short Form 12-Item Health Survey (SF-12). This will be collected on all patients at 
baseline, 90 days +/- 180 days. 
 
Patient-report on whether the cellulitis has exacerbated their other medical conditions collected at day 
28. 
 
Cellulitis-related readmission and mortality within 90 days (from electronic healthcare records) +/- 180 
days. 
 
Antibiotic usage events (from medical notes daily until discharge or completion of hospital antibiotic 
treatment) and antibiotic-related adverse events (from medical notes, laboratory records and patient-
reported). 
 
Nested technology comparison 
Comparison of:  
- 
Repeatability coefficient (repeatability of the measurements taken by the temperature 
measurement devices). 
- 
Agreement between the methods quantified by estimating the limits of agreement. 
- 
Mean time taken to measure skin temperature. 
- 
Failure rates in obtaining a measurement of skin temperature. 
 
3 
STUDY DESIGN AND SETTING 
 
This study is an observational study with a nested technology comparison of three temperature 
measurement devices. The study is based at University Hospitals Sussex NHS Foundation Trust (a 
merger between Brighton and Sussex University Hospitals NHS Trust and Western Sussex Hospitals 
NHS Foundation Trust from 1st April 2021), at up to four hospital sites where participants will be 
recruited. The expected duration of participant involvement is under 2.5 hours in total: that includes 
the consent process, in-study assessments, patient-reported outcomes and follow-up appointments.  
 
4 
PARTICIPANT ELIGIBILITY CRITERIA 
 
4.1 
Inclusion criteria 
 
Adults (age ≥18 years) will be eligible for inclusion if they are identified by their treating clinician as 
having lower limb cellulitis that requires IV or oral antibiotic treatment either from the hospital or 
another service based outside of the hospital, which will conduct ongoing follow-up regardless of 

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location. The clinicians' diagnosis of cellulitis (or change to an alternate diagnosis) will apply from days 
0-3. 
 
4.2 
Exclusion criteria 
 
The exclusion criteria are patients: 
• 
who have already received 3 or more calendar days of antibiotics from the hospital for cellulitis. 
• 
who have been treated for a previous episode of cellulitis in the preceding 28 days. 
• 
receiving antibiotic therapy for another indication that is anticipated to continue for longer than 
the antibiotic treatment for cellulitis and that, in the judgement of the investigator, would impact 
the study assessments. 
• 
for whom a surgical procedure to treat their cellulitis is planned (i.e. debridement of suspected 
necrotising skin / soft tissue infection). 
• 
who, in the judgement of the investigator, do not have a clear diagnosis of cellulitis (to enable 
the exclusion of infections, such as severe/deep diabetic foot infection, which may be loosely 
labelled as cellulitis, but treated with different guideline antibiotic agents and durations) 
• 
lack capacity to give informed consent to participate. 
• 
are receiving end-of-life care. 
• 
are already involved in a CTIMP of relevance to the treatment of their cellulitis. 
• 
are unlikely, in the opinion of the investigator, to comply with study procedures. 
5 
STUDY PROCEDURES  
 
5.1 
Recruitment 
 
5.1.1    Participant identification 
 
Members of the clinical team responsible for the patient’s care will contact the research team to notify 
them of potential participants. The research team will maintain close liaison with the clinical team (e.g. 
through handover meetings) and refer to Trust systems for managing acute admissions. Eligibility will 
be confirmed by an appropriately trained member of the research team. 
 
5.2  
Consent  
 
Potential participants will be approached by a member of their clinical team and offered the Participant 
Information Sheet (PIS). The PIS has been designed to fit onto two sides of A4 paper along with the 
Informed Consent Form (ICF) and should take less than 10 minutes to read. The participant will be 
given sufficient time to read the PIS (a minimum of 10 minutes) before a member of the research team 
will approach them. They will be given the opportunity to ask any questions and discuss anything they 
wish to explore further. The participant does not need to decide at the time they are first approached 
and will be offered more time as required, up to the point at which they cease to be eligible (i.e. 2 
calendar days after the day they received their first dose of antibiotics for cellulitis from the hospital). 

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An appropriately trained member of the research team will explain to potential participants the 
rationale for the study, why they have been invited and what it will involve. Participants will be 
informed: 
• 
that their participation is voluntary 
• 
that they may withdraw consent to participate at any time 
• 
that choosing not to participate will not affect the medical care they receive 
• 
that if they lose capacity their active participation in the research will stop but we will continue 
to gather information from their health records to answer the study questions 
• 
that the data collected during the study may be looked at by individuals from the Sponsor, NHS 
Trust and regulatory authorities to check that the study is being carried out correctly 
• 
that anonymous information may be used to support other research in the future and shared 
with the companies that make the temperature measurement devices, so they can improve the 
use of their device for cellulitis 
• 
that their General Practitioner (GP) will be contacted about their participation in the study and 
information about antibiotics prescribed by their GP will be accessed 
• 
that they agree to being sent a summary of the results of the study. 
 
If they agree to join, they will sign and date the consent form. There will be an optional point regarding 
whether they consent to the photographs of their leg being used for future teaching and research 
purposes. After having received consent, the original ICF will be filed in the medical notes, a copy 
given to the participant, and a copy filed in the researcher site file. All members of the research team 
seeking informed consent will have up to date Good Clinical Practice (GCP) training. If verbal 
translation is needed this will occur via a hospital interpreter by phone. 
 
After receiving informed consent potential participants will be asked if they would like to provide contact 
details for a family member, friend, carer or other suitable person to assist in providing their patient-
reported symptoms and other information on their behalf where necessary. This is not a requirement for 
participation but may help to facilitate the participation of participants who are frailer.  
 
5.3 
Study assessments 
 
The following assessments will be undertaken as soon as possible after the participant has provided 
their consent to participate in the study. Baseline is referred to as day 0, see Table 1 Schedule of 
Assessments. If patients are not recruited to the study on day 0 then data for most assessments will 
still be available and can be collected retrospectively for the day 0 timepoint. However, day 0 skin 
surface temperature measurement and physical examination of affected skin cannot be collected 
retrospectively and data will be missing for that timepoint. According to the exclusion criteria, the latest 
timepoint at which a patient will be eligible for recruitment is the end of day 2. Similarly, for patients 
recruited on a Friday, only day 0 and day 3 skin surface temperature measurement and physical 
examination of affected skin can be taken. 
 
 
 

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Study assessments are as follows: 
 
Data from medical and laboratory records: 
• 
Demographics for day 0 only 
• 
Medical history (including previous episodes of cellulitis) for day 0 only 
• 
Admission details (admitting and discharging specialty, intensive care stay, length of stay) 
• 
Vital signs (e.g. heart rate, temperature) daily on days 0-3 
• 
Antibiotic data: Total IV and oral antibiotic use as inpatient and to take out (TTO) on day 0 and 
daily until discharge or completion of antibiotic treatment, antibiotic use immediately prior to 
admission, antibiotic allergies 
• 
Antibiotic-associated adverse events on day 0 and daily until discharge or completion of hospital 
antibiotic treatment 
• 
Microbiology, haematology & biochemistry results will be extracted from laboratory records on 
days 0-3. 
 
Physical assessments: 
• 
Skin surface temperature measurement daily on days 0-3 (see 5.3.1 Skin surface temperature 
measurements) 
• Physical examination of affected skin daily on days 0-3 (see 5.3.2 Physical examination of 
affected skin) 
 
Table 1. Schedule of Assessments 
Assessment 
Day 0 
D1 to D3 
post-
antibiotic 
treatment 
initiation 
D1 to 
discharge 
Day 28  
(+/- 3 days) 
post-
antibiotic 
treatment 
initiation 
Day 90  
+/- 180 
(+/- 5 days) 
post-antibiotic 
treatment 
initiation † 
Setting 
Trust (inpatient / ambulatory care) 
Trust (clinic) 
or virtual 
Telephone-
based 
Informed consent 
X 
 
 
 
 
Medical and laboratory records 
Demographics 
  X * 
 
 
 
 
Medical history 
  X * 
 
 
 
 
Vital signs 
  X * 
  X * 
 
 
 
Antibiotic use 
  X * 
  X * 
  X * 
  X * 
  X *† 
Antibiotic-related adverse 
events 
  X * 
  X * 
  X * 
X 
 
Routine microbiology, 
haematology & biochemistry 
  X * 
  X * 
 
 
 
Admission details 
 
 
 
  X * 
 
Readmission and mortality 
 
 
 
 
  X *† 
Physical assessments 
Skin surface temperature 
measurement (includes time 
  X ^ 
X   
 
 
 

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taken to measure and failed 
measurements) 
Physical examination of 
affected skin 
  X ^ 
X 
 
X 
 
Patient-reported 
Symptoms of pain & swelling 
  X 
X 
 X # 
X 
 
Recurrence of symptoms 
 
 
 
X 
X † 
Exacerbation of other 
medical conditions 
 
 
 
X 
 
Quality of life 
X 
 
 
 
X † 
Return to normal activities 
 
 
 
 
X † 
* Information available as part of routine care. 
^ Day 0 data for these assessments needs to be collected at actual day 0, not retrospectively. 
# Patient-reported symptoms will continue to be recorded daily until either they feel they have recovered or they 
reach their 28-day follow-up. 
†Measured at 180 days for the subset of patients in whom there is >180 days available before the study ends. 
 
       Patient-reported: 
• 
Symptoms - patients will report the severity of their pain and swelling due to cellulitis on a 10-point 
verbal and numerical scale. They will also report on whether they feel recovered from their 
cellulitis. Responses will be recorded from day 0 until either they feel they have recovered or 
reach their day 28 follow-up appointment. They will be given access to an online symptom diary, 
but a paper-based option will be available if the participant does not have access to a computer or 
smartphone. If participants have not filled in their online symptom diary for one or more days and 
they have not reported that they feel recovered, they can be sent a reminder to do so (text/email, 
phone call, depending on their preference). Participants with paper diaries will be reminded to 
complete their diary on alternate days from either the date of discharge or day 4 (whichever is 
earliest) to day 7 (+/- 1 day to account for weekends). They will then receive reminders each week 
until their 28-day appointment. If they are still an inpatient and cannot be contacted by other 
means they can be reminded in-person. 
• 
Recurrence of symptoms of cellulitis at 28, 90 +/- 180 days. 
• 
Whether the cellulitis has exacerbated their other medical conditions. 
• 
Whether they experienced any antibiotic adverse events (e.g. diarrhoea or rashes). 
• 
Quality of life - assessed using the SF-12 at day 0, 90 days +/- 180 days. 
• 
Return to normal activities - assessed at day 90 days +/- 180 days. 
 
5.3.1 Skin surface temperature measurements 
 
Temperature measurement devices will be compared for measuring skin surface temperature on days 0-
3. For settings outside of the hospital in which access to and storage of all three devices may not be 
feasible (e.g., Outpatient Parenteral Antibiotic Therapy), skin temperature measurements may be taken 
with device A or C only: 
 

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Device A - The Extech® IR200 non-contact infrared thermometer.36 Non-contact infrared thermometers 
have previously been used to monitor clinical response in cellulitis.29,37 This device can measure 
temperature over areas of the body other than the forehead and the temperature range is larger than that 
of other noncontact infrared thermometers.36,38 
 
Device B - The FLIR One Generation 3 thermal camera for smartphones.39 Thermal imaging cameras 
have previously been used in studies investigating the diagnostic utility of skin surface temperature in 
cellulitis (Generation One; FLIR Systems).31,32 Benefits over non-contact infrared thermometers include 
easier determination of the point of the maximum temperature of the lesion. 
 
Device C - The Thermofocus® 0800 is a non-contact infrared thermometer similar to device A that has 
been extensively evaluated in settings other than cellulitis. 40,41 A recent study found that the device has 
good reproducibility of measurements, with very small differences between the first and the second 
readings.40 
 
Skin surface temperature measurement daily on days 0-3: 
• 
All patients will have their skin temperature measured but at least the first 50 patients recruited will 
have the first measurement repeated (twice for device A and C) by the same member of research 
staff in order to calculate repeatability of the measurements, interim analyses of variability will be 
used to determine whether repeated measurements continue or not (see section 6.2.2 
Technology comparison analysis for justification of sample size). The measurement will be taken 
at the point of maximal temperature on the affected limb and at the corresponding point on the 
non-affected limb to allow for calculation of temperature difference: 
- 
For device A and C, determination of the point of maximal temperature will not be exact 
and will involve taking up to 3-5 ‘test’ measurements at different points of the lesion. 
Device A should be held approximately 5 cm and 3cm from the skin, respectively. 
- 
For device B, the point of maximal temperature on the affected lesion will be determined 
by localising the warmest point on the live thermal image. 
• 
In patients in whom both legs are affected, the unaffected skin surface temperature of an arm will be 
taken. 
• 
The time taken to measure and record skin surface temperature using each device will be 
measured (including the time taken for test measurements using device A) to provide 50 
comparisons, this serves to provide an estimate of the average resource use required. 
• 
Each time a device fails to obtain a temperature measurement will also be recorded. 
 
5.3.1 Physical examination of affected skin 
 
A physical examination of the affected skin will be performed on days 0-3: 
• 
The area of the affected lesion will be measured (i.e. acute colour change, oedema, or induration, 
whichever is largest) with a flexible disposable tape measure, by multiplying the longest head-to-
toe length of the lesion with the widest width perpendicular to that length. 
 

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• 
A cellulitis severity score (CSS) will also be measured. This is a descriptive symptom score, 
with 7 items (colour change, oedema, warmth, pain, ulceration, discharge and fluctuance) 
being scored on a 4-point scale (none = 0, mild = 1, moderate = 2, severe = 3), creating a total 
score between 0 and 21. 
- 
To minimise inter-observer variation for the CCS, the Chief Investigator will perform this 
assessment in addition to another member of the research team until assessments 
performed independently match consistently. 
 
5.4 
Longer-term follow-up assessments 
 
Day 28 follow-up 
All participants will be seen at 28 days (+/- 3 days) post-treatment initiation for follow-up. A physical 
examination of the leg affected by cellulitis will take place to assess recovery, defined as the absence 
of warmth and tenderness at the site, with improvement in swelling and acute colour change, that did 
not require new antibiotic treatment. While in-person assessments will be attempted there is a 
possibility, given the COVID-19 pandemic, that this appointment will need to be virtual, using NHS-
approved video conferencing software. If this is the case and a participant is using a paper-based 
symptom diary then a stamped addressed envelope will be sent to them so that it can be returned. 
 
Electronic health records will also be used to assess for any antibiotic use for cellulitis within 
secondary and primary care, for the latter this will involve accessing the participant’s Summary Care 
Record (SCR). The SCR is accessible to the hospital-based research team through NHS smartcards, 
so participants’ GPs will not need to be contacted for this information. In the rare situation where a 
patient cannot recall if they have received a new prescription of antibiotics for cellulitis and is opted out 
of the SCR, the general practice will be contacted. An email will be sent from an NHS email account to 
the Practice Manager with the participant’s ICF attached asking for details on acute antibiotic 
prescriptions for cellulitis. 
 
At the 28-day follow-up, participants will also be asked whether the cellulitis has exacerbated their 
other medical conditions, whether they experienced any antibiotic adverse events, and their daily 
patient-reported symptoms of pain and swelling will be reviewed. 
 
Day 90 follow-up 
The primary outcome of sustained recovery, defined as no initiation of new antibiotic treatment for 
cellulitis at the same site through to 90 days, will be assessed during the follow-up and through 
electronic health records. Electronic health records will also be accessed to assess cellulitis 
readmissions and mortality within 90 days. Participants will also be asked about their return to normal 
activities and answer the SF-12 (quality of life questionnaire) during a telephone follow-up at day 90 
(+/- 5 days). 
 
Day 180 follow-up 
Participants recruited within the first year of the study will be telephoned at 180 days (+/- 5 days) and 
be asked about any recurrence in their symptoms, their return to normal activities and answer the SF-

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12 (quality of life) questionnaire. The trust’s Patient Administration System will be checked prior to 
calling the patient to check that they are still alive. 
 
An attempt will be made to book follow-up appointment dates during the initial study visits. If this is not 
possible, participants will be contacted a maximum of six times by phone from a non-withheld number 
to arrange each follow-up appointment. On enrolment into the study, participants will be asked which 
phone number they prefer to be contacted on and whether voice messages are acceptable. If they do 
not respond to any of these contact attempts, they will be identified as lost to follow-up. Data that can 
be collected from electronic health records will be used. These follow-up appointments would not 
usually be undertaken as routine standard of care. 
 
5.5 
Withdrawal of participants  
 
Participants are free to withdraw their consent for the study at any time. No further data will be 
collected from the time of withdrawal. However, de-identified data that have already been collected will 
continue to be used (and any person-identifiable data will be destroyed). 
 
In addition, the Chief Investigator may discontinue a participant from the study at any time if they 
consider it necessary for ineligibility (either arising during the study or retrospectively having been 
overlooked at screening). The reason for withdrawal will be recorded. 
 
5.6 
Definition of End of Study 
 
The study will end at the completion of all primary and secondary, endpoints and their corresponding 
analyses. 
6 
STATISTICS & DATA ANALYSIS 
 
6.1 
Sample size calculation 
 
Cellulitis recurrence rates range from 11-18% within 6-12 months,9,42,43 with the most recent trial reporting 
an overall 90-day recurrence rate of 14%.21 We do not know the prevalence of the different factors that 
we will investigate. We, therefore, consider factors present in the final sample size at prevalence 10%, 
20%, 30%... 90%. We assume that the overall event rate is 14%, and differences in this event rate 
between those with and without the factor of interest is 15%. We can use this 15% difference and the 
prevalence of the factor to work out the event rates in those with and without the factor that would give us 
14% overall. We then conduct a standard two group binomial proportion sample size assuming 80% 
power and 2-sided alpha to detect this difference between two groups of the relevant size. We repeat this 
for a 20% difference in event rate between those with and without the factor of interest. See Stata 
program in Appendix 2. 
 

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With a 10% loss to follow-up, 220 patients provide 80% power to detect differences in recurrence rates of 
15% associated with high-risk exposures prevalent at >30% and of 20% associated with high-risk 
exposures prevalent at 15-30%. During 2018, 741 patients were discharged from Brighton and Sussex 
University Hospitals NHS Trust with a primary diagnosis code of lower limb cellulitis, so over 18-months, 
this would require recruiting ~20% of cases. 
 
The loss to follow-up rate for the most recent randomised controlled trial for antibiotic treatment duration 
in cellulitis was <5%. Therefore, the loss to follow-up for this study has been conservatively estimated as 
potentially being higher than this (10%). The project supervisors agree with this figure based on their 
research experience of conducting observational studies within the NHS. 
Patients who die before experiencing a recurrence or before reaching the 90-day primary endpoint will be 
unable to contribute to the study data, due to competing risks between death and recurrence. As of July 
2022, 5% (5/100) of study patients died (unrelated to the study) before they developed a recurrence or 
reached the 90-day primary endpoint, therefore a larger sample size target of up to 240 patients will be 
used. 
 
6.2 
Statistical analysis plan 
 
6.2.1 Cohort primary and secondary outcome analysis 
 
Descriptive summaries of the data, including antibiotic treatment, will be performed. Continuous 
variables will be reported as means with standard deviations or medians with interquartile range and 
categorical variables as proportions. 
 
The primary analysis method for the primary outcome will be standard logistic multivariable 
regression. Backwards elimination will be used to identify the most important predictors. As there will 
be a large number of factors to investigate, newer variable selection techniques including elastic 
net/lasso will be used. Time-to-event methods will be used to assess the prognostic value of time-
updated measures of response to treatment. Similar predictive models will be fitted for secondary 
outcomes, as suitable for the nature of the endpoint (binary, categorical, continuous, time-to-event). 
 
The performance of a previously developed predictive model for recurrence or death in cellulitis will be 
assessed using receiver-operating characteristic analysis on this dataset. The net reclassification 
index will be used to assess whether the current model improves outcome prediction. Changes in 
patient-reported symptoms over time will be calculated and their temporal association with the 
duration of antibiotics assessed. 
 
6.2.2 Technology comparison analysis 
 
Repeatability of the measurements will be assessed on at least the first 50 patients recruited to 
estimate the within-person standard deviation to within 20% of the population value. Sample size 
justification: 
sw = within-subject standard deviation 

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n = number of subjects 
m = number of observations per subject 
1.96 x sw / √(2𝑛(𝑚−1) 
After the first 50 patients, based on the estimates of the standard deviation obtained, either repeated 
measurements will be continued to improve study power to identify effects or halted. Time taken for 
repeated measurements will also be taken into consideration. One-way analysis of variance (ANOVA) 
models will be fitted to the data to estimate the between-person SD, which can be used to estimate 
the repeatability coefficient. The repeatability of the measurement difference between the affected and 
unaffected limbs will also be quantified. 
 
A methods comparison will be undertaken, using device A as the more established method as it is the 
only device previously used to measure clinical response in cellulitis.29 The difference in each patient’s 
measurements from devices A and B will be plotted against the mean of their measurements to create 
a Bland-Altman plot.44 The variability of the differences will be visually inspected to indicate how well 
device B agrees with device A. The agreement between the methods will be quantified by estimating 
the limits of agreement (the range within which 95% of future differences in measurements between 
the two methods are expected to lie). This will be repeated comparing devices A and C. 
 
The mean time taken to measure and record skin surface temperature will be compared using one-
way ANOVA. Failure rates in obtaining a measurement of skin surface temperature will be compared 
using the Chi-squared test. Changes over time in the three temperature measurement technologies 
will also be summarised to investigate whether they improve the predictive ability of the model using 
the same methods as 6.2.1. 
 
7 
DATA MANAGEMENT  
 
The plans for the data management of the study are outlined below. There is not a separate Data 
Management document in use for the study.  
 
7.1 
Source data  
 
Source documents are where data are first recorded, and from which participants’ data are obtained. 
For this study, these include but are not limited to, medical records (demographics, comorbidities), 
medication charts (antibiotic use), vital signs charts, laboratory records, electronic health records 
(cellulitis readmissions and mortality), and symptom diaries. Electronic Case Report Form (eCRF) 
entries will be considered source data if the eCRF is the site of the original recording (e.g. there is no 
other written or electronic record of data). On all study-specific documents, other than the signed 
consent, the participant will be referred to by their study number, not by name. 
 

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7.2 
Case Report Forms 
 
All data will be transferred into an eCRF which will be labelled using a pseudo-anonymised study 
number. All study data in the eCRF will be extracted from and be consistent with the relevant source 
documents. Data from the online symptom diary will be imported into the eCRF. If a paper-based diary 
is used, then a member of the research team will manually enter data into the eCRF. The eCRFs will 
be completed by a member of the research team in a timely manner. 
 
7.3 
Data handling and record-keeping 
 
Participants will be identified only by a pseudo-anonymised study number only in study data. The only 
person-identifiable data will be held on consent forms (name) and in a log linking hospital number to 
pseudo-anonymised study number (necessary to link to electronic healthcare records). These will be 
stored in a locked room on the research site and a password-protected file on a secure NHS server, 
respectively. De-identified study data will be stored within secure University servers and retained for 
10 years after the end of the study. 
 
7.4 
Access to Data 
 
All documents will only be accessible by authorised members of the research team. Access will be 
granted to authorised representatives from the sponsor, host institution and regulatory authorities, for 
monitoring and/or audit of the study to ensure compliance with regulations. 
 
8 
MONITORING, AUDIT & INSPECTION 
 
The research team will meet monthly throughout the study to discuss the conduct of the research and 
ensure that it is progressing as expected. Agenda items will include a review of progress against the 
research timetable, an update on the recruitment and follow-up of patients, and a review of the 
monthly expenditure reports. The Sponsor will audit and monitor the research in accordance with the 
risk assessment and Sponsor Standard Operating Procedures. The Trust will also monitor the 
research as part of their routine research monitoring of active research studies. Periodic reports will 
also be submitted to the National Institute for Health Research. 
 
9  
ETHICAL & REGULATORY CONSIDERATIONS 
 
9.1  
Declaration of Helsinki 
 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki.  
 

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9.2  
Guidelines for Good Clinical Practice 
 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and 
with Good Clinical Practice (GCP). 
 
9.3  
Research Ethics Committee (REC) approvals 
 
Following Sponsor approval, the protocol, PIS, ICF and other relevant material (e.g. questionnaires) 
will be submitted to an appropriate Research Ethics Committee (REC), Health Research Authority 
(HRA) and host institution for written approval. The Chief Investigator will submit and, where 
necessary, obtain approval from the above parties for all substantial amendments to the original 
approved documents. All correspondence with the REC will be retained in the Investigator Site File. 
 
9.4  
Reporting 
 
The Chief Investigator shall submit once a year throughout the study, or on request, an Annual 
Progress report to the REC, Sponsor, host organisation and NIHR. Recruitment data with be uploaded 
as part of the NIHR Clinical Research Network (CRN) Portfolio of studies. An End of Study notification 
and a final report will be submitted to the same parties. 
 
9.5  
Data protection and patient confidentiality  
 
The study will comply with the General Data Protection Regulation (GDPR) and Data Protection Act 
2018, which require data to be de-identified as soon as it is practical to do so. The processing of the 
personal data of participants will be minimised by using a pseudo-anonymised study number only in 
study data. The only person-identifiable data will be held on consent forms (name) and in a log linking 
hospital number to pseudo-anonymised study number (necessary to link to electronic healthcare 
records). These will be stored in a locked room on the research site and a password-protected file on 
a secure NHS server, respectively. All documents will only be accessible by authorised members of 
the research team. Access will be granted to authorised members of the sponsor, host institution and 
regulatory authorities if required. 
 
9.6  
Public and Patient Involvement 
 
This study has involved patients and the public in the design of the research through the James Lind 
Alliance Cellulitis Priority Setting Partnership and the NIHR Community Healthcare MIC ‘appropriate 
antibiotic prescribing’ patient and public involvement group. Another public involvement group 
consisting of people with prior cellulitis have worked through the proposed outcome measures, 
identified additional outcomes to measure and improved upon the data collection methods for some of 
the outcomes. The members of this group will continue to work throughout the study on: 
• 
Foreseeing and managing barriers to recruitment. 

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• 
Checking that patient information materials are understandable and contain relevant 
information. 
• 
Understanding the results of the research from a patients’ perspective. 
• 
Ensuring that the presentation of results is clear and highlights findings that are more relevant 
to the public. 
• 
Planning dissemination activities to communicate findings with the wider public. 
 
The INVOLVE resources have been used to calculate reimbursement of their travel costs, refreshments 
and time (£20 per hour). 
 
9.7 
Payments 
 
All participants will be reimbursed for travel to and from the 28-day follow-up appointment. A £20 
voucher will also be provided for the inconvenience of attending as a token of recognition of giving their 
time and contribution to the study. 
 
9.8  
Financial and other competing interests  
 
There are no financial or competing interests to disclose. 
 
9.9  
Indemnity 
 
The insurance to meet the potential legal liability of the sponsor(s) for harm to participants arising from 
the management of the research will be covered by University of Sussex insurance policies. The 
insurance to meet the potential legal liability of the sponsor(s) or employer(s) for harm to participants 
arising from the design of the research will be covered by University of Sussex insurance policies. 
 
NHS indemnity will apply to meet the potential legal liability of investigators/collaborators arising from 
harm to participants in the conduct of the research. 
 
10  
DISSEMINATION & PUBLICATION POLICY 
10.1  Dissemination policy 
 
The findings of the study will be shared with all of the study participants and public involvement group 
via a letter. The study findings will also be presented in-person to the public involvement group. They 
will help to ensure that the presentation of results is clear. They will also work with the research team 
on planning dissemination activities to communicate findings with the wider public. This will include 
publishing results through the Modernising Medical Microbiology newsletter, the Lymphoedema 
Support Network charity’s newsletter and website, social media and other public engagement events. 
 

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The research findings will also be disseminated at the local Trusts and universities; regionally, at the 
CRN Kent, Surrey & Sussex Regional Infection Specialty Days; and nationally/internationally, at key 
infection, acute/general medicine, dermatology and diagnostic conferences. The write-ups of the 
research will also be submitted to peer-reviewed journals. 
 
The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: 
guidelines will be used for reporting the cohort study. The National Institute for Health Research will be 
acknowledged as the funding source in any publications. 
 
10.2  Publication policy 
 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and 
any other publications arising from the study. The authors will acknowledge study funding by the 
National Institute for Health Research. Authorship will be determined in accordance with the 
International Committee of Medical Journal Editors (ICMJE) guidelines and other contributors will be 
acknowledged. 
 
 

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11 
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Onakpoya IJ, Walker AS, Tan PS, et al. Overview of systematic reviews assessing the 
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Cranendonk DR, Opmeer BC, van Agtmael MA, et al. Antibiotic treatment for 6 days versus 12 
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Bader MS, Twells L, Hawboldt J. Risk factors of cellulitis treatment failure with once-daily 
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Garau J, Blasi F, Medina J, et al. Early response to antibiotic treatment in European patients 
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Montalto M, Davies F, Marijanovic N, et al. Skin surface temperature: a possible new outcome 
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Corey GR, Stryjewski ME. New Rules for Clinical Trials of Patients With Acute Bacterial Skin 
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Ko LN, Raff AB, Garza-Mayers AC, et al. Skin Surface Temperatures Measured by Thermal 
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Li DG, Dewan AK, Xia FD, et al. The ALT-70 predictive model outperforms thermal imaging for 
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Raff AB. 504 Dual parameter predictive model utilizing skin temperature and diffuse 
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34. 
James Lind Alliance Priority Setting Partnerships. Cellulitis Top 10. May 2017. 
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Smith E, Patel M, Thomas KS. Which outcomes are reported in cellulitis trials? Results of a 
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Brindle R, Williams OM, Davies P, et al. Adjunctive clindamycin for cellulitis: a clinical trial 
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38. 
Wang K, Gill P, Wolstenholme J, et al. Horizon Scan Report 0025. Diagnostic Technology: 
Non-contact infrared thermometers. Oxford: Primary Care Diagnostic Horizon Scanning Centre 
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FLIR. FLIR ONE Gen 3 Thermal Camera for Smart Phones. 2020. 
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40. 
Van den Bruel A, Verbakel J, Wang K, et al. Non-contact infrared thermometers compared with 
current approaches in primary care for children aged 5 years and under: a method comparison study. 
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41. 
Wang K, Gill P, Wolstenholme J, et al. Non-contact infrared thermometers for measuring 
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42. 
Lazzarini L, Conti E, Tositti G, et al. Erysipelas and cellulitis: Clinical and microbiological 
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43. 
Lee CY, Tsai HC, Kunin CM, et al. Clinical and microbiological characteristics of purulent and 
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Clinical Measurement. The Lancet 1986; 327(8476): 307-10. 
12.  
APPENDICES 
 
12.1 Appendix 1 – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
1 
1.1 
03 JUN 2021 Elizabeth 
Cross 
Minor change to inclusion and 
exclusion criteria so that days 0, 1, 2, 3 
are defined by calendar days (as 
opposed to 24 hours periods) 
 
Performing 2 instead of 1 repeat 
temperature measurements for device 
A 
2 
1.2 
25 JUN 2021 Elizabeth 
Cross 
Minor changes to inclusion criteria and 
exclusion criteria to better define the 
study population 
 
Replacement of quality of life 
questionnaire (SF-36) with the shorter 
version (SF-12) 
 
Time given to read the PIS prior 
reduced from 30 to 10 minutes, as all 
participants enrolled thus far have 
taken less than 5 minutes 
 
Reminders for participants if they have 
not filled in their symptom diary for two 
or more days 
 
To clarify that data on antibiotic-related 
adverse events will be collected from 
the medical notes, laboratory records 
and patient-reported at 28 days 
 
When repeating measurements, 
holding the device approximately '5cm' 
from the skin (as opposed to the '10cm' 
specified) 
 
Repeated skin temperature 
measurements will be continued for at 

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least the first 50 participants (as 
opposed to only the first 50) 
 
The time taken to measure and record 
skin surface temperature using each 
device will be measured to provide 50 
comparisons (as opposed to for all 
participants) 
 
Due to numbers of available devices, 
storage and cost implications, skin 
temperature measurements in these 
settings may be taken with device A 
only in follow-up settings outside of the 
hospital 
3 
1.3 
15 NOV 
2021 
Elizabeth 
Cross 
Minor change to the exclusion criteria to 
exclude those who have been treated 
for a previous episode of cellulitis within 
the past 28 days 
 
An amendment to the PIS to explain 
that if they are no longer thought to 
have cellulitis then they would be 
excluded from the study 
 
A clarification on the inclusion criteria 
that the clinicians' diagnosis of cellulitis 
(or change to an alternate diagnosis) 
applies from days 0-3 (relates to above 
change) 
4 
1.4 
17 FEB 2022 Elizabeth 
Cross 
Reminders for participants if they have 
not filled in their symptom diary, to 
avoid missing patient-reported 
outcomes data. Previous reminders had 
focused on participants filling in the 
online diaries (as the research team are 
able to monitor remotely whether or not 
this has been filled in). To prevent 
missing patient reported data for 
participants filling in a paper diary a 
more regular system of reminders is 
required. 
5 
1.5 
07 APR 
2022 
Elizabeth 
Cross 
Due to delays acquiring device C 
(Kronikare), from the company's end 
due to Brexit and COVID-19, to add the 
Thermofocus® 0800 device to measure 
skin temperature change to the nested 
technology comparison. 
6 
1.6 
25 JUL 2022 
Elizabeth 
Cross 
Patients who die before experiencing a 
recurrence or before reaching the 90-
day primary endpoint will be unable to 
contribute to the study data, due to 

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competing risks between death and 
recurrence. As of July 2022, 5% (5/100) 
of study patients died (unrelated to the 
study) before they developed a 
recurrence or reached the 90-day 
primary endpoint, therefore a larger 
sample size target of up to 240 patients 
will be used. 
 
Outcomes are measured at 90 days (+/- 
180 days on a subset of patients 
recruited in the first year). This will be 
changed to the outcomes being 
measured at 90 days (+/- 180 days on a 
subset of patients in whom there is 
>180 days available before the study 
ends). This will allow for the more 
accurate measurement of longer term 
outcomes on a larger proportion of the 
study population. 
 
12.2 Appendix 2 – Sample size Stata program 
 
* difference in outcome rate of 15% - only works for prevalence of first 
factor 30-70% 
noi di _n _dup(80) "*" _n "15% difference in outcome" _n _dup(80) "*"  
forval i=0.1(0.1)0.9 { 
   * proportion in second group 
   local j=1-`i' 
   * overall event rate is 0.14: find power to detect 0.15 difference 
between groups 
   * so if x is rate in higher risk group with prevalence `i' 
   *       y is rate in lower  risk group with prevalence `j' 
   * x-y=0.15, then  
   local y=0.14-0.15*`i' 
   local x=0.15+`y' 
   local nratio =`j'/`i' 
   noi power twoprop `x' `y', n(200) nratio(`nratio') 
} 
 
* difference in outcome rate of 20% - only works for prevalence of first 
factor 30-70% 
noi di _n _dup(80) "*" _n "20% difference in outcome" _n _dup(80) "*"  
forval i=0.1(0.05)0.3 { 
   * proportion in second group 
   local j=1-`i' 
   * overall event rate is 0.14: find power to detect 0.20 difference 
between groups 
   * so if x is rate in higher risk group with prevalence `i' 
   *       y is rate in lower  risk group with prevalence `j' 
   * x-y=0.20, then  

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   local y=0.14-0.20*`i' 
   local x=0.20+`y' 
   local nratio =`j'/`i' 
   * can't make this work for all values 
   if `y'>0 noi power twoprop `x' `y', n(200) nratio(`nratio') 
}