The CABI Trial: An Unblinded Parallel Group Randomised Controlled Feasibility Trial of Long Course Antibiotic Therapy (28 Days) Compared to Short Course (≤10 Days) in the Prevention of Complicated Intra-ABdominal Infection Relapses in Adults Treated for Complicated Intra-ABdominal Infection
Phase: PHASE2
Conditions: Complicated Intraabdominal Infections
Sponsor: University of Leeds

. 
1 
 
FULL/LONG TITLE OF THE TRIAL 
 
The CABI trial: An unblinded parallel group randomised controlled 
feasibility trial of long course antibiotic therapy (28 days) compared to 
short course (≤10 days) in the prevention of Complicated intra-
ABdominal Infection relapses in adults treated for Complicated intra-
ABdominal Infection. 
 
SHORT STUDY TITLE / ACRONYM 
 
CABI: Antibiotic duration for Complicated intra-ABdominal Infection. 
 
This protocol has regard for the HRA guidance and order of content. 
 
RESEARCH REFERENCE NUMBERS 
 
Leeds Teaching Hospitals Trust R&I number:  
The University of Leeds reference number: 
IRAS 
 
TRIAL REGISTRY NUMBER AND DATE 
Clinical trials.gov: NCT 
 
PROTOCOL VERSION NUMBER AND DATE 
Version 0.92 18.11.2016 
 
SPONSOR 
 
 
 
 
 
 
 
 
 
The University of Leeds  
 
FUNDER 
 
 
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
2 
 
SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the 
principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), 
amended regulations (SI 2006/1928) and any subsequent amendments of the clinical trial regulations, 
GCP guidelines, the Sponsor’s SOPs, and other regulatory requirements as amended. 
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 clinical investigation without the prior written 
consent of the Sponsor 
I also confirm that I will make the findings of the study publically 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. 
 
For and on behalf of the Study Sponsor: 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): 
...................................................................................................... 
 
 
Position: 
...................................................................................................... 
 
 
 
Chief Investigator: 
Signature: 
...................................................................................................... 
 
Date: 
....../....../...... 
Name: (please print): 
...................................................................................................... 
 
 
Statistician: 
 
 
Signature: 
...................................................................................................... 
 
 
Name: (please print): 
...................................................................................................... 
 
 
 
Position: 
...................................................................................................... 
 
 
 
 
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
3 
 
KEY TRIAL CONTACTS 
 
Chief Investigator 
Andrew Kirby 
0113 3923929 
a.kirby@leeds.ac.uk 
Trial Co-ordinator 
Andrew Kirby 
0113 3923929 
a.kirby@leeds.ac.uk 
Sponsor 
University of Leeds 
0113 3434897 
Clare Skinner 
Funder(s) and support in kind 
 
The University of Leeds 
0113 34 37587 
governance-ethics@leeds.ac.uk 
 
Leeds Teaching Hospitals NHS Trust 
0113 39 20152 
leedsth-tr.lthtresearch@nhs.net 
 
 
Department of Surgery, Leeds Teaching Hospitals NHS Trust 
0113 2066877 
dermotburke@nhs.net 
Clinical Trials Unit 
None 
Key Protocol Contributors 
Dermot Burke 
0113 2066877 
dermotburke@nhs.net 
 
Andrew Kirby 
0113 3923929 
a.kirby@leeds.ac.uk 
 
Dr Shafaque Shaikh 
S.Shaikh@leeds.ac.uk 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
4 
 
 
Dr Anne Melhuish 
annemelhuish@nhs.net 
 
Dr Shadia Ahmed 
shadiaahmed@nhs.net 
Statistician 
None 
Trials pharmacist 
Caroline Bedford 
Research Nurse Lead 
Catherine Moriarty 
Health economics 
Armando Vargas-Palacios 
Committees 
Trial Steering Committee (TSC) 
Committee contact 
Dr Andrew Kirby 
0113 3923929 
a.kirby@leeds.ac.uk 
 
 
 
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
5 
 
TRIAL SUMMARY 
Trial Title 
The CABI trial: An unblinded parallel group randomised 
controlled feasibility trial of long course antibiotic therapy (28 
days) compared to short course (≤10 days) in the prevention 
of Complicated intra-ABdominal Infection relapses in adults 
treated for Complicated intra-ABdominal Infection. 
Short title 
CABI: Antibiotic duration for Complicated intra-ABdominal 
Infection. 
Clinical Phase  
Phase II/Feasibility 
Trial Design 
A randomised controlled unblinded parallel group trial 
Trial Participants 
Adults hospitalised with complicated intra-abdominal infection 
Planned Sample Size 
60 
Treatment duration 
Up to 10 days or 28 days. 
Follow up duration 
90 days from start of antibiotic treatment for CABI 
Planned Trial Period 
February 2017-February 2019 
 
Objectives 
Outcome Measures 
Primary 
 
To determine 
 
The willingness of 
participants to be 
randomised 
 
The willingness of 
clinicians to allow 
patients to be 
recruited 
 
The number of eligible 
patients 
 
Follow up rates 
 
 
 
 
Screening logs, recruitment 
rates and follow up rates will 
be recorded 
 
A full study which may follow this feasibility study would have clinical objectives as primary and 
secondary objectives. In order to determine the feasibility of collecting data relevant to these clinical 
objectives, e.g. rate of relapse, we have included these objectives within the secondary objectives. We 
do not include them as true objectives in the sense that we anticipate obtaining evidence relevant to 
the objective e.g. we do not expect to demonstrate that different treatment strategies are associated 
with different rates of relapse.   
Secondary  
 
To reduce the rate of relapse 
after treatment of 
complicated intra-abdominal 
infection. 
 
To reduce the rate of all 
infections after treatment of 
Relapse of complicated intra-
abdominal infection. 
 
 
All infections within 90 days 
of CABI diagnosis. 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
6 
 
complicated intra-abdominal 
infection. 
 
To reduce the rate of 
antibiotic consumption 
 
 
To reduce length of hospital 
stay after diagnosis of 
complicated intra-abdominal 
infection 
 
To reduce mortality after 
treatment of complicated 
intra-abdominal infection. 
 
To reduce rates of 
complications from antibiotic 
therapy including Clostridium 
difficile infection (CDI) 
diarrhoea and catheter 
related blood stream infection 
(CRBSI) 
 
To reduce the number of 
source control procedures 
required for the management 
of CABI 
 
To improve quality of life after 
treatment of complicated 
intra-abdominal infection. 
 
 
To improve the health-
economics of managing 
complicated intra-abdominal 
infection. 
 
 
Days of antibiotic therapy 
within 90 days of antibiotic 
therapy. 
 
 
Length of hospital stay after 
diagnosis of a CABI & total 
days of hospitalisation within 
90 days of diagnosis. 
 
Mortality 90 days after 
diagnosis of CABI.  
 
 
CDI and CRBSI rates within 
90 days of diagnosis. 
 
 
 
 
Number of source control 
procedures within 90 days 
after diagnosis of CABI. 
 
 
Quality of life scores (EQ-5D) 
at time of diagnosis of CABI, 
30 and 90 days post 
diagnosis of a CABI, as well 
at the times of relapses. 
 
Costs of healthcare treatment 
within 90 days after diagnosis 
of CABI. 
 
Medicinal Product(s)  
Antibiotics for the treatment of CABI.  
The choice of antibiotic will be that of the treating physicians.  

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
7 
 
A list of recommended antibiotics will be provided as not all 
antibiotics are likely to be effective for complicated intra-
abdominal infection. This list will be comprehensive but not 
exhaustive. Treating physicians will not be restricted to the list 
of recommended antibiotics.  
Antibiotics must be used within their licenced indications. All 
will be antibiotics routinely used in the NHS (within the British 
National formulary (BNF)). Recommended regimens will 
provide antibacterial activity against Gram positive, Gram 
negative and anaerobic bacteria. Where antibiotic 
susceptibilities of bacteria believed to be causing CABI are 
available, these should be considered in the choice of 
antibiotic.  
The recommended antibiotic list is: 
1- Amoxicillin (or glycopeptide/linezolid), ciprofloxacin 
and metronidazole 
2- Amoxicillin (or glycopeptide/linezolid), aztreonam and 
metronidazole 
3- Amoxicillin (or glycopeptide/linezolid), gentamicin and 
metronidazole 
4- Amoxicillin-clavulanic acid (+/-glycopeptide/linezolid) 
5- Piperacillin—tazobactam 
6- Cefuroxime and metronidazole 
7- Ertapenem (+/- glycopeptide/linezolid) 
8- Meropenem (+/- glycopeptide/linezolid) 
9- Tigecycline (+/-ciprofloxacin) 
Formulation, Dose, Route of 
Administration 
British National Formulary recommended doses are required 
in this study. The standard doses of the recommended 
antibiotics are: 
Amoxicillin 1g IV or PO 8 hourly 
Ciprofloxacin 400mg IV 12 hourly or 500mg PO 12 hourly 
Amoxicillin-clavulanic acid 1.2g IV 8 hourly (not 
recommended orally) 
Cefuroxime 1.5 grams IV 8 hourly 
Metronidazole 400mg PO 8 hourly or 500mg IV 8 hourly 
Aztreonam 1g IV 8 hourly 
Tigecycline 100mg loading dose followed by 50mg 12 hourly 
IV. 
Ertapenem 1g IV 24 hourly 
Meropenem 1g IV 8 hourly 
Piperacillin-tazobactam 4.5g IV 8 hourly 
Linezolid 600mg IV or PO 12 hourly 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
8 
 
Glycopeptides/Aminoglycosides: Dosed according to renal 
function and therapeutic drug monitoring results. 
 
FUNDING AND SUPPORT IN KIND 
FUNDER(S) 
FINANCIAL/NON FINANCIALSUPPORT GIVEN 
The University of Leeds 
 
Employment of Mr Dermot Burke 
Employment of Dr Andrew Kirby 
Employment of Dr Shafaque Shaikh 
Leeds Teaching Hospitals NHS Trust 
 
Employment of Anne Melhuish 
Employment of Caroline Bedford 
Employment of Catherine Moriarty 
Department of Surgery, Leeds Teaching 
Hospitals NHS Trust 
Facilities for recruitment and intervention 
Resources available 
Dr Andrew Kirby has 5 programmed activities per 
week available to support research. Research support 
is also provided by Catherine Moriarty and the 
colorectal research staff. 
 
ROLE OF STUDY SPONSOR  
The University of Leeds is the Sponsor of the trial and employer of the Chief Investigator. This is an 
investigator-led single-site trial. The study is managed and conducted by the Chief Investigator, with 
the UoL / LTHT Sponsor overseeing the activity to ensure appropriate regulatory and governance 
procedures are in place.  
 
ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITEES/GROUPS & 
INDIVIDUALS 
The trial steering committee (TSC) 
The TSC will provide overall supervision of the trial concentrating on the trial’s progress, including 
adherence to the approved protocol, subject safety, and consideration for new information. This group 
will monitor the on-going relevance and need for the trial in view of published literature and be 
responsible for the on-going compliance to ethical and regulatory standards. The CI is responsible for 
maintaining the TSC documentation during the course of the trial to ensure compliance with the Trial 
Master File. 
Committee members include:  

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
9 
 
Chair: Dr Andrew Kirby 
Research doctor: Mr Dermot Burke 
Research doctor: Dr Shafaque Shaikh 
Research doctor: Dr Shadia Ahmed 
Research Nurse: Catherine Moriarty 
Trials pharmacist: Caroline Bedford 
Sponsors representative (invited to meetings) 
Frequency of meetings: Pre-initiation meeting, End of study meeting. 
Meeting documentation: A formal meeting report will be written and disseminated to TSC members, 
the sponsor and the lead research nurse 
 
Data Management Committee (DMC) 
A DMC will not be required for the following reasons: The low risk nature of the trial, the open design, 
the small size of the trial (single site feasibility study) and the established safety profiles of the IMPs. 
 
Protocol contributors 
Mr Dermot Burke 
Dr Andrew Kirby 
Dr Shafaque Shaikh 
Dr Anne Melhuish 
Dr Shadia Ahmed 
Caroline Bedford 
Catherine Moriarty 
The sponsor was not directly involved in the design of the trial outside of the grant application review 
process. A funder will have no input into conduct, data analysis and interpretation, manuscript writing, 
or dissemination of results. A funder will not control the final decision regarding any of these aspects 
of the trial. 
The protocol has been reviewed by service users through a Leeds Patient and Public Involvement in 
Research Group. 
 
KEY WORDS: 
 
Antibiotic; Complicated intra-abdominal infection; 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
10 
 
Duration, Pharmacodynamics, Relapse, Resistance. 
LIST of CONTENTS 
GENERAL INFORMATION 
Page No. 
TITLE PAGE  
 
RESEARCH REFERENCE NUMBERS 
 
 
SIGNATURE PAGE 
 
TRIAL SUMMARY 
 
 
FUNDING 
 
 
KEY TRIAL CONTACTS 
 
 
ROLE OF SPONSOR AND FUNDER 
 
ROLES & RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES, GROUPS AND 
INDIVIDUALS  
 
 
LIST of CONTENTS  
 
LIST OF ABBREVIATIONS 
 
TRIAL FLOW CHART 
 
SECTION  
1. BACKGROUND 
 
 
2. RATIONALE 
 
 
3. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS  
 
4. TRIAL DESIGN 
 
5. STUDY SETTING 
 
6. ELIGIBILITY CRITERIA 
 
7. TRIAL PROCEDURES 
 
8. TRIAL MEDICATION 
 
9. PHARMACOVIGILANCE 
 
10. STATISTICS AND DATA ANALYSIS 
 
11. DATA HANDLING 
 
12. MONITORING, AUDIT & INSPECTION 
 
13. ETHICAL AND TRIAL ADMINISTRATION 
 
14. DISSEMINATION POLICY 
 
15. REFERENCES 
 
16. APPENDICIES 
 
 
 
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
11 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AR 
Adverse Reaction 
BNF 
British National Formulary 
CA 
Competent Authority 
CDI 
Clostridium difficile infection 
CI 
Chief Investigator 
CABI 
Complicated intra-abdominal infection 
CRBSI 
Catheter related blood stream infection 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product  
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EC 
European Commission 
EMEA 
European Medicines Agency 
EU 
European Union 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE 
European database for Pharmacovigilance 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical 
requirements for registration of pharmaceuticals for human 
use. 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised Controlled Trials 
 
Number 
IV 
Intravenous 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
12 
 
MA 
Marketing Authorisation 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MS 
Member State 
NHS R&D 
National Health Service Research & Development   
NIMP 
Non-Investigational Medicinal Product 
PI 
Principal Investigator 
PIC 
Participant Identification Centre 
PIS 
Participant Information Sheet 
PO 
Per Os (By mouth (oral)) 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person  
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure  
SmPC 
Summary of Product Characteristics  
SSI 
Site Specific Information 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
TMF 
Trial Master File 
 
 
 
 
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
13 
 
TRIAL FLOW CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Short course treatment: ≤ 10 days 
antibiotic treatment 
Patient diagnosed with a complicated 
intra-abdominal infection 
Long course treatment: ≥ 28 days 
antibiotic treatment 
Patient invitation to research study 
Patient provides, after 24 hours, 
consent for research study 
Patient randomised 
Quality of life questionnaire 
completed (EQ-5D) 
Research team identify eligible 
patient 
Questionnaires on day 30, day 90 and at the time of relapses (day 0 = date of diagnosis e.g. 
Quality of life questionnaire (EQ-5D) and resource utilisation. 
Where clinical appointments are not required postal/phone completion of questionnaires will be 
carried out.
Weekly in-patient assessment of 
patient notes  
Attendance at routine day 30 and 90 post diagnosis clinic appointment where clinically relevant 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
14 
 
STUDY PROTOCOL 
 
The CABI trial: An unblinded parallel group randomised controlled feasibility trial of long course 
antibiotic therapy (28 days) compared to short course (≤10 days) in the prevention of Complicated 
intra-ABdominal Infection relapses in adults treated for Complicated intra-ABdominal Infection. 
 
1 
BACKGROUND 
 
Complicated intra-abdominal infection (CABI) extends beyond the hollow viscus of origin into the 
peritoneal space and is associated with either abscess formation or peritonitis [Solomkin 2010]. CABIs 
are heterogeneous in aetiology and include spontaneous infections arising from a perforated viscus, 
including the stomach, biliary tree, colon, appendix and reproductive organs. In addition there are 
post-operative complications such as peritonitis, abscess, and failure of surgical anastomoses. CABIs 
are also heterogeneous in their characteristics.  A recent review of organ space Surgical Site 
Infections (SSI-Os) after colorectal surgery demonstrated that infections were varied with regard their 
location, as well as size and number and nature of collections, and presence of an ongoing source 
e.g. anastomotic breakdown (Rothwell 2016).   Despite the varied origin of these infections, there are 
similar management strategies which centre on the source control, e.g. drainage of intra-abdominal 
fluid collections, and administration of antibiotic therapy. CABIs are a common in-hospital clinical 
challenge, in part due to the varied pathology they are caused by, and are associated with significant 
morbidity and mortality (DeFrances 2005, Brun-Buisson 1995). Despite this burden of disease, there is 
little clinical evidence with which to base treatment on, even before taking account of their 
heterogeneous nature. One study of CABI following source control procedures evaluated a short 
course of antibiotics (4 days) compared to a course of up to 2 weeks after clinical and biochemical 
improvement (up to 10 days). Whilst there was little difference in outcomes, both groups had a high 
relapse rate of approximately 15%. In addition, it is common for source control procedures not to be 
completed in routine clinical practice, being completed in only 17% of Leeds patients with post-
operative CABI (Rothwell 2016). In this Leeds data of post-operative CABIs, where source control 
rates are low relapse rates were 40% (Rothwell 2016). For CABI infections, standard UK management 
is variable and involves between 4 and 42 days’ antibiotics.   This indicates an unacceptably high 
relapse rate in patients treated for CABI where source control is and is not undertaken. We therefore 
propose to investigate if long course antibiotic therapy (28 days) is clinically more effective than short 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
15 
 
course antibiotics (4 days) in preventing relapses of CABI. This study will include patients who have 
and have not undergone source control procedures which will be completed as per standard practice. 
 
2 
RATIONALE  
 
Complicated intra-abdominal infections require source control when possible, e.g. a surgical 
procedure to remove an infection, and antibiotic therapy to obtain cure.  Source control is not always 
possible.  CABIs are associated with mortality and prolongation of hospitalisation. After apparently 
effective treatment, potentially including source control procedures and antibiotics, infections can 
relapse.  There are a number of reasons for relapse; one is that antibiotic treatment may not have 
been given for long enough to eradicate the bacteria from, what should be, a sterile intra-abdominal 
cavity.  Antibiotics are given until a patient is better, but not until all bacteria are eradicated, allowing 
them to regrow and re-start an infection. Standard antibiotic duration is variable: some doctors provide 
long courses and others short.   We therefore want to compare durations, to see if longer courses of 
antibiotics are able to help prevent these relapses, or if shorter courses are as effective but have fewer 
side effects. We have not identified closely related strategies which may optimise the management of 
CABIs.  
The research hypothesis is therefore: In patients with CABI, regardless of source control intervention, 
there will be a lower relapse rate when treated with 28 days of antibiotics compared to ≤10 days of 
antibiotics. 
 
2.1 
Assessment and management of risk 
 
Risks: Standard practice with regarding the duration of antibiotic therapy is variable. Therefore there 
are not specific risks above normal clinical practice for this research study. The choice of antibiotic 
used in this study is within antibiotics those routinely used in NHS practice. The decision as to the use 
of a source control procedure is not altered by being involved in this study.  
This trial has been categorised by the MHRA as: Not a CTIMP 
 
 
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
16 
 
3 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
 
3.1 
Primary objectives 
To determine 
 
The willingness of participants to be randomised 
 
The willingness of clinicians to allow patients to be recruited 
 
The number of eligible patients 
 
Follow up rates 
3.2 
Secondary objectives 
A full study which may follow this feasibility study would have clinical objectives as primary and 
secondary objectives. In order to determine the feasibility of collecting data relevant to these clinical 
objectives, e.g. rate of relapse, we have included these objectives within the secondary objectives. We 
do not include them as true objectives in the sense that we anticipate obtaining evidence relevant to 
the objective e.g. we do not expect to demonstrate that different treatment strategies are associated 
with different rates of relapse.   
To reduce the rate of relapse after treatment of complicated intra-abdominal infection. 
To reduce the rate of all infections after treatment of complicated intra-abdominal infection; 
To reduce the rate of antibiotic consumption; 
To reduce length of hospital stay after diagnosis of complicated intra-abdominal infection; 
To reduce mortality after treatment of complicated intra-abdominal infection 
To reduce rates of complications from antibiotic therapy including Clostridium difficile infection (CDI) 
diarrhoea and catheter-related blood stream infection (CRBSI); 
To reduce the number of source control procedures required for the management of CABI; 
To improve quality of life after treatment of complicated intra-abdominal infection; 
To reduce the cost of healthcare treatment associated with treatment of complicated intra-abdominal 
infection. 
 
3.3 
Outcome measures 
 
3.31 
Primary outcomes 
Screening logs, recruitment rates and follow up rates will be recorded to determine the feasibility of 
performing a larger study. 
 
3.32 
Secondary endpoints/outcomes 
Relapse (definite or probable CABI relapse) of complicated intra-abdominal infection within 90 days of 
diagnosis of primary CABI.  
 
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
17 
 
Primary CABI: The diagnosis of a definite CABI will be assigned with: 
 
A combination of radiological AND clinical features consistent with CABI including a fluid 
collection or perforated viscus, a temperature of ≥38 degrees and a neutrophilia (neutrophil 
count > 7.5 x 10*9/L), or 
 
Intra-operative confirmation of an abscess 
 
Day 0: The first day of infection will be defined as the first day effective antibiotic therapy was 
initiated for the treatment of CABI. This date may precede the day the CABI was confirmed 
radiologically. Effective therapy will be considered not to be on going if microbiological results 
suggest antibiotic resistance and there is at the same time clinical failure to antibiotic therapy.  
Relapse CABI:  
 
A relapse can only occur after surgical and antibiotic therapy to manage the primary CABI has 
been considered successful. This will normally be demonstrated by antibiotics being stopped 
and no further source control procedures planned.  
 
The diagnosis of a definite CABI relapse will be assigned with: 
o A combination of radiological AND clinical features consistent with CABI including a 
fluid collection, a temperature of ≥38 degrees and a neutrophilia (neutrophil count > 7.5 
x 10*9/L) 
o Intra-operative confirmation of an abscess, or 
 
The diagnosis of a probable CABI relapse will be assigned when: 
o In the absence of radiological imaging, but where no other source of infection was 
identified, and the patient was managed for a relapsed CABI. 
 
All infections within 90 days of CABI diagnosis. 
Days of antibiotic therapy within 90 days of antibiotic therapy. 
Length of hospital stay within 90 days of diagnosis of a CABI. 
Total days of hospitalisation within 90 days of diagnosis. 
90 day mortality after diagnosis of CABI.  
Adverse events of CDI and CRBSI within 90 days of CABI diagnosis. 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
18 
 
Number of source control procedures required for the management of CABI within 90 days of CABI 
diagnosis. 
Quality of life scores (EQ-5D) at time of diagnosis of CABI, 30 and 90 days post diagnosis of a CABI, 
as well at the times of relapses. 
Costs of healthcare treatment within 90 days after diagnosis of CABI. 
 
4 
TRIAL DESIGN 
 
An unblinded parallel group randomised controlled feasibility trial of long course antibiotic therapy (28 
days) compared to short course (≤10 days) in the prevention of Complicated intra-ABdominal Infection 
relapses in adults treated for Complicated intra-ABdominal Infection. The choice of antibiotic will be 
decided by the clinical team caring for the patient; hence the trial compares strategies of antibiotic 
prescribing (i.e. short course vs long course) rather than individual drugs or specified combinations of 
drugs. The antibiotic prescribed will be chosen according to the available clinical and microbiological 
data, in conjunction with local antibiotic guidelines, and will be altered according to good clinical care 
as new results and clinical information become available. During the study period, a clinician with 
specialist training in infection will provide consultation as needed to select antibiotics and advise on 
management.  
 
5 
STUDY SETTING 
Leeds Teaching Hospitals NHS Trust 
Interventions will be carried out by the following staff 
o Recruitment and allocation: Research nurse and research doctor.  
o Informed consent and eligibility will be requested and carried out by a medically 
qualified doctor. Research nurses will not be permitted to request consent. 
o Intervention: Antibiotic duration will be dictated by randomisation.  
o Outcome data collection: Research nurse or research doctor. 
 
 
6 
ELIGIBILITY CRITERIA 
This study is pragmatic as it is intended that the intervention would be applied to all patients with CABI 
without there being restrictive eligibility criteria.  
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
19 
 
 
6.1 
Inclusion criteria 
 
Age: Adults  >18 years 
 
Capable of giving informed consent 
 
No practical or clinical barriers to consuming 28 days of antibiotic therapy, which may include 
consumption of antibiotics at home. 
6.2 
Exclusion criteria 
Patients will be excluded if they have: 
 
a CABI diagnosed within the previous year 
 
their CABI was diagnosed >6 days prior to screening 
 
primary appendicitis 
 
intra-abdominal infection associated with pancreatitis, pelvic inflammatory disease, primary 
(spontaneous) bacterial peritonitis (SBP), continuous ambulatory peritoneal dialysis peritonitis 
(CAPD peritonitis) and Clostridium difficile infection.  
 
Concurrent infection requiring more than ten days of therapy. 
These criteria intend to ensureː  
 
we are studying primary episodes of CABI 
 
that the cases included are not biased towards more complicated cases 
 
we exclude primary appendicitis for which good data already exists  
 
In the case of necrotising pancreatitis, SPB and CAPD peritonitis these pathologies are 
excluded as they consist of a discrete disease process.  
 
Infection with a highly resistant bacterium such that antibiotic treatment is considered to be a 
significantly sub-optimal by the treating microbiologist e.g. multi-resistant carbapenemase 
producing Entrobacteriacea. 
Clarifications of which infections are to be included and excluded from CABI are provided 
below. 
 
 
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
Removal from the study 
Clinicians will be free to prescribe antibiotics after the planned treatment duration has elapsed if their 
clinical assessment supports such a prescription. For example, the patient may develop a new 
infection. They will also be able to stop antibiotics if there is a clinical indication, for example, a patient 
may have an allergy or other adverse event to an antibiotic. These patients may therefore have their 
assigned intervention modified. This will not result in these patients being removed from the study, 
they will instead be assessed on an intention-to-treat basis.  
Haematological or biochemical abnormalities at the end of assigned treatment duration will not be 
sufficient basis to withdraw a patient from an assigned duration of therapy. 
 
7 
TRIAL PROCEDURES  
Schedule of procedures: Appendix 2. 
 
 
7.1 
Recruitment 
Included conditions 
Excluded conditions 
Post-operative surgery CABI including colorectal (including 
appendiceal), biliary, small bowel and gastric surgery (including 
iatrogenic perforations) e.g.  peri-anastomotic abscess. 
Uncomplicated cholecystitis/cholangitis/gall bladder 
empyema (no perforation or extra-biliary abscess) 
Gastrointestinal fistula communicating with the peritoneal space 
Skin and soft tissue infection/abscess not communicating 
with the peritoneal space 
Oesophageal rupture into the peritoneal space & perforated 
duodenal/gastric ulcer 
Spontaneous bacterial peritonitis &  continuous 
ambulatory peritoneal dialysis 
Ischaemic bowel and volvulus with perforation 
Primary complicated or uncomplicated appendicitis 
managed surgically. 
Perforations associated with malignancies 
Intraabdominal infection associated with pancreatitis 
Complicated diverticulitis & perforated Meckel’s diverticulum 
Pelvic inflammatory disease  
CABI secondary to inflammatory bowel disease pathology 
Adnexal abscess without communication to the peritoneal 
cavity 
Primary complicated appendicitis managed conservatively 
Clostridium difficile colitis with perforation (long course 
antibiotics unlikely to be acceptable for this group 
Renal/Adrenal/Liver/Spleen abscess communicating with the 
peritoneal cavity. 
 
Adnexal abscess communicating with the peritoneal cavity 
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
21 
 
Participants who are screened for trial entry and are not randomised will have data collected for 
Consolidated Standards of Reporting Trials (CONSORT) reasons to allow reporting of the 
generalisability of the results. Anonymised information on participants who are not randomised for will 
include: Age, Gender, Charlson’s co-morbidity index, site of origin of CABI, underlying pathology, 
admitted to HDU/ITU, perforated viscus at onset of CABI, whether the patient is registered or not 
registered, the reason not eligible for trial participation, or if they are eligible but declined and the 
reason for declining.  
 
7.1.1 Patient identification 
Participant eligibility screening process. 
Patients will be identified for trial entry by a number of methods including: 
- 
Notification by a member of the patient’s clinical team, to the research team, a patient has 
been diagnosed with a CABI. This is only expected to happen after the patient has been seen 
whilst an in-patient.  
- 
Identification by a member of the patient’s clinical team that a patient has a CABI by reviewing 
clinical notes or radiological reports. 
Initial approach: The member of staff making the initial approach will be involved in the care of the 
patient. Eligibility will be confirmed by a medical practitioner. 
 
7.1.2 Screening 
No non-routine (non-clinically indicated) tests will be required for study entry. 
CT scans completed as part of routine care will contribute to the diagnosis of CABI.  
7.1.3 Stratification 
Patients with each intervention arm will be stratified into two groups on a 1:1 basis 
 
Post-operative CABIs (CABI within 90 days of surgery) 
 
Non post-operative CABIs 
Each intervention arm will therefore contain 15 post-operative CABIs and 15 non-post operative 
CABIs. 
No ordering of patient recruitment to these groups is required 
 
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
22 
 
7.2 Consent  
The Principal Investigator (PI) retains overall responsibility for the informed consent of participants at 
their site and will ensure that any person delegated responsibility to participate in the informed consent 
process is duly authorised, trained and competent to participate according to the ethically approved 
protocol, principles of Good Clinical Practice (GCP) and Declaration of Helsinki.  
Delegation of consent: 
Informed consent will be obtained prior to the participant undergoing procedures specifically for the 
purposes of the trial.  
The right of a participant to refuse participation without giving reasons will be respected.   
The participant will remain free to withdraw at any time from the trial without giving reasons and 
without prejudicing his/her further treatment. They will be provided with a contact point where he/she 
may obtain further information about the trial.  
The PI takes responsibility for ensuring that all vulnerable subjects are protected and participate 
voluntarily in an environment free from coercion or undue influence. 
The consenting protocol: 
 
There will be discussion between the potential participant and an individual knowledgeable 
about the research - its nature and objectives and the possible risks associated with their 
participation. 
 
The presentation of written material (invitation letter, patient information leaflet and consent 
form [approved by the REC and in compliance with GCP], local regulatory requirements and 
legal requirements) will be given to potential participants. 
 
There will be an opportunity for potential participants to ask questions. 
 
There will be an assessment of capacity. Participants must be capable of giving consent for 
themselves. A capable person will:  
o understand the purpose and nature of the research  
o understand what the research involves, its benefits (or lack of benefits), risks and 
burdens  
o understand the alternatives to taking part  
o be able to retain the information long enough to make an effective decision 
o be able to make a free choice  

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
23 
 
o be capable of making this particular decision at the time it needs to be made (though 
their capacity may fluctuate, and they may be capable of making some decisions but 
not others depending on their complexity) 
o where participants are capable of consenting for themselves but are particularly 
susceptible to coercion, it is important to explain how their interests will be protected 
Where a participant is able to consent but later becomes incapacitated the participant would be 
withdrawn from the study. Identifiable data or tissue already collected with consent would be retained 
and used in the study. No further data or tissue would be collected, or any other research procedures 
carried out on or in relation to the participant. 
The full consent process will be documented in the patient’s medical record along with a copy of the 
signed consent form and Patient Information Sheet. A further copy of the consent form will also be 
provided to the patient. The original consent form will be maintained in the TMF. 
 
7.3 
The randomisation scheme 
Simple randomisation with a 1:1 allocation ratio will be used to allocate patients.  
 
7.3.1 Method of implementing the allocation sequence 
The allocation sequence will involve: 
- 
Generation of an unpredictable allocation sequence  
- 
Concealment of that sequence until assignment irreversibly occurs 
A web-based randomisation/treatment allocation system will be used. 
 The allocation system will provide sealed envelopes to be accessed upon a decision to allocate a 
participant to a treatment arm.   
 Sixty patients will be randomised equally to the control or intervention arm by generating four lists 
of random numbers using an online sequence generator (https://www.random.org/sequences/) 
(list 1/2: post-operative patients-control and intervention, list 3/4, non post-operative patients, 
control and intervention). A person not associated with the study will generate these lists. Sealed 
envelopes containing labels with ‘control’ or ‘intervention’ will be designated with numbers 
generated by the above sequence generator.  
 Patients will be randomised after providing their consent to participate in the study. 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
24 
 
 A copy of allocation information will be documented in the patients’ notes. 
 
7.4 
Baseline data 
 
Data required prior to being eligible for study entry include:  
 
Full blood count demonstrating the patient has elevated neutrophils. 
 
CT scan with radiology reports being consistent with a CABI.  
 
Both the CT scan and full blood count will be undertaken as part of routine clinical practice and 
are not therefore trial specific procedures.  
 
7.5 
Trial assessments 
Baseline assessment-Visit 1-In patient within 2 days of recruitment 
- 
Medical/surgical history 
- 
Antibiotic history 
- 
QofL assessment 
Weekly assessments-Visit 2a, 2b, etc. In-patient only (7days +/-3 days) 
- 
Medical/surgical history 
- 
Antibiotic history 
Questionnaires-“Visit” 3 
- 
QofL assessmentː day 30, day 90 and at time of relapse where possible 
- 
By post or in-person.** 
Final assessment-Visit 4-In-patients or surgical clinic/home (day 90 +/- 10 days) 
- 
Medical/surgical history 
- 
Antibiotic history 
- 
Resource utilisation questionnaire 
 
 
**= Day 30/90 assessments will occur at the time of routine clinic appointments where possible, or via 
post/phone as required.  
 
 
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
25 
 
Schedule of procedures 
Procedures 
Screening 
 
Baseline 
Within 2 days 
of 
recruitment 
Treatment 
Phase 
Weekly (+/- 3 
days) 
assessments 
whilst an in-
patient 
Questionnaires 
Day 30, 90 and 
at relapse where 
possible 
Final visit 
Day 90 (+/- 10 
days) 
Informed consent 
x 
Visit 1 
Visit 2a,2b etc. 
Visit 3 
Visit 4 
Demographics 
 
x 
 
 
 
Medical history 
x 
x 
x 
 
x 
Physical examination 
 
 
 
 
 
Vital signs 
 
 
 
 
 
CT scan 
x 
 
 
 
 
Concomitant medications 
 
x 
x 
 
x 
Eligibility assessment 
x 
 
 
 
 
Randomisation 
x 
 
 
 
 
Dispensing of trial drugs 
 
 
x 
 
 
Adverse event assessments  
 
 
x 
 
x 
Compliance with intervention 
 
 
x 
 
x 
Questionnaires 
 
x 
 
x 
 
 
 
7.6 
Long term follow-up assessments 
None 
 
7.7 
Withdrawal criteria  
It is always within the remit of the physician responsible for a patient to amend a patient’s treatment 
based on clinical need.  
Subjects will be not be withdrawn from the study if their treatment is amended but followed up and 
analysed on an intention to treat basis.  
 
7.8 
Safety assessment and stopping treatment 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
26 
 
Standard NHS processes will be undertaken to monitor the safety of patients.  
Treatment will be stopped according to the research protocol for participants, but clinicians will not be 
restricted from initiating antibiotics, according to their assessment of clinical need, at any time for a 
participant not receiving antibiotics.  
7.9 
End of trial 
The date of the last visit of the last patient undergoing the trial is the trial end definition. 
The PI will notify the REC at the end of the trial within 90 days of its completion or within 15 days in 
the event of early termination. 
 
8 
TRIAL MEDICATION 
8.1 
Name and description of medicinal product(s)  
 
Antibiotics for the treatment of CABI.  
The choice of antibiotic will be that of the treating physicians.  
A list of recommended antibiotics will be provided as not all antibiotics are likely to be effective for 
complicated intra-abdominal infection. This list will be comprehensive but not exhaustive. Treating 
physicians will not be restricted to the list of recommended antibiotics.  
Antibiotics must be used within their licenced indications. All will be antibiotics routinely used in the 
NHS (within the British National formulary (BNF)). Recommended regimens will provide antibacterial 
activity against Gram positive, Gram negative and anaerobic bacteria. Where antibiotic susceptibilities 
of bacteria believed to be causing CABI are available, these should be considered in the choice of 
antibiotic.  
The recommended antibiotic list is: 
1- Amoxicillin (or glycopeptide/linezolid), ciprofloxacin and metronidazole 
2- Amoxicillin (or glycopeptide/linezolid), aztreonam and metronidazole 
3- Amoxicillin (or glycopeptide/linezolid), gentamicin and metronidazole 
4- Amoxicillin-clavulanic acid (+/-glycopeptide/linezolid) 
5- Piperacillin—tazobactam 
6- Cefuroxime and metronidazole 
7- Ertapenem (+/- glycopeptide/linezolid) 
8- Meropenem (+/- glycopeptide/linezolid) 
9- Tigecycline (+/-ciprofloxacin) 
British National Formulary recommended doses are required in this study. The standard doses of the 
recommended antibiotics are: 
Amoxicillin 1g IV or PO 8 hourly 
Ciprofloxacin 400mg IV 12 hourly or 500mg PO 12 hourly 
Amoxicillin-clavulanic acid 1.2g IV 8 hourly (not recommended orally) 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
27 
 
Cefuroxime 1.5 grams IV 8 hourly 
Metronidazole 400mg PO 8 hourly or 500mg IV 8 hourly 
Aztreonam 1g IV 8 hourly 
Tigecycline 100mg loading dose followed by 50mg 12 hourly IV. 
Ertapenem 1g IV 24 hourly 
Meropenem 1g IV 8 hourly 
Piperacillin-tazobactam 4.5g IV 8 hourly 
Linezolid 600mg IV or PO 12 hourly 
Glycopeptides/Aminoglycosides: Dosed according to renal function and therapeutic drug monitoring 
results. 
 
8.2 
Legal status of the drugs  
Licensed in the UK 
 
8.3 
Summary of Product Characteristics (SmPC) 
As a non CTIMP study using standard treatments SmPCs are not provided.  
 
8.4 
Drug storage and supply  
As per standard NHS storage and supply procedures. 
 
 
8.5  
Preparation and labelling of Medicinal Product 
As per standard NHS preparation and labelling.  
Trial-specific labelling is not required where the MP: 
• has a marketing authorisation in the UK, and 
• is being used within the terms of its marketing authorisation, and 
• is dispensed to a trial participant in accordance with a prescription given by an authorised healthcare 
professional and is labelled in accordance with the requirements of Schedule 5 to the Medicines for 
Human Use (SI 1994/3194) (Marketing Authorisations Etc) Regulations 1994 that apply in relation to 
dispensed relevant medicinal products. 
 
 
8.6 
Dosage schedules 
Dosing regimens will be devised by treating clinicians with the exception of the duration of therapy. 
 
8.7 
Dosage modifications  
Modifications as per standard NHS practice. 
 
8.8 
Known drug reactions and interaction with other therapies 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
28 
 
Treating clinicians will be responsible for assessing treatment reactions and interactions.  
 
8.9 
Concomitant medication 
Not applicable. 
 
8.10 
Trial restrictions  
No trial restrictions have been set.  
 
8.11 
Assessment of compliance 
A compliance check will be carried out and documented at each in-patient visit by assessing patient’s 
drug charts. No routine outpatient assessments are planned before the end of study visit. An end of 
study out-patient visit will include a compliance check on antibiotic consumption through discussion 
with the participant to quantitatively estimate antibiotic consumption. Compliance (or non-compliance) 
checks will be documented on case report forms.  
 
9 
PHARMACOVIGILANCE 
Pharmacovigilance procedures for this trial are based on this study being classified as a CTIMP. These 
procedures will be modified if the study is not classified as a CTIMP. 
9.1 
Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a 
medicinal product has been administered, including occurrences 
which are not necessarily caused by or related to that product. 
Adverse Reaction 
(AR) 
 
An untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose 
administered to that participant. 
The phrase "response to an investigational medicinal product" means 
that a causal relationship between a trial medication and an AE is at 
least a reasonable possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically-qualified 
professional or the Sponsor as having a reasonable suspected causal 
relationship to the trial medication qualify as adverse reactions. 
Serious Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
 results in death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
 results in persistent or significant disability/incapacity 
 consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
29 
 
they jeopardise the participant or require an intervention to prevent 
one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the 
reporting Investigator, believed with reasonable probability to be due 
to one of the trial treatments, based on the information provided. 
Suspected 
Unexpected Serious 
Adverse Reaction 
(SUSAR) 
A serious adverse reaction, the nature and severity of which is not 
consistent with the information about the medicinal product in 
question set out: 
 in the case of a product with a marketing authorisation, in the summary 
of product characteristics (SmPC) for that product 
 in the case of any other medicinal product, in the investigator’s 
brochure (IB) relating to the trial in question 
 
NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and 
“severe”, the following note of clarification is provided: “Severe” is often used to describe intensity of a 
specific event, which may be of relatively minor medical significance. “Seriousness” is the regulatory 
definition supplied above. 
 
9.2 
Operational definitions  
 
(S)AEs, (S)ARs and SUSARs will be defined according to standard definitions, section 9.1.  
 
9.3 Recording and reporting of (S)AEs,  (S)ARs AND SUSARs  
SAEs, S(AR)s and SUSARS will be recorded on case report forms. 
AEs will not be reported to the sponsor. AEs will not be recorded on case report forms. 
SAEs will be reported to the sponsor, except for specific exemption, via e-mail (governance-
ethics@leeds.ac.uk) using a form provided by the sponsor with 24 hours of the research team becoming 
aware of the event.   SAEs which are exempt form reporting to the sponsor are those which occur 
commonly in this patient population. The reason for this is that it is not possible to determine if an event 
which is common is related to a study intervention. SAE exemptions are: 
 
Infections including surgical wound infections, respiratory, urinary and skin infections (including 
fungal infections). 
 
Failure of a surgical procedure-specifically anastomotic breakdown or development of a fistula. 
 
Deterioration of the existing condition specifically progression of a cancer. 
 
Treatment which was elective or pre-planned, for a pre-existing condition not associated with any 
deterioration in condition, e.g. pre-planned hip replacement operation which does not lead to 
further complications. 
 
Any admission to hospital or other institution for general care where there was no deterioration in 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
30 
 
condition. 
 
ARs will not be reported to the sponsor. ARs will not be recorded on case report forms. 
SARs will be reported to the sponsor, except for specific exemptions, via e-mail (governance-
ethics@leeds.ac.uk) using a form provided by the sponsor with 24 hours of the research team 
becoming aware of the event. The exemptions to SAR reporting are because this is a trial using 
antibiotics within their licensed indications at standard doses with well documented adverse reaction 
profiles. SARs will not be reported to the sponsor if reporting will not improve the knowledge regarding 
the safety profile of the drug, i.e. if the event or reaction is listed as known event within the drug’s 
Summary of Product Characteristics. 
 
SUSARs will be reported to the sponsor, except for specific exemptions, via e-mail (governance-
ethics@leeds.ac.uk) using a form provided by the sponsor with 24 hours. All SAEs assigned by the PI or 
delegate (or following central review) as both suspected to be related to MP-treatment and unexpected 
will be classified as SUSARs and will be reported to the Medicines and Healthcare Products Regulatory 
Agency (MHRA) via the yellow card scheme.  
 
The period of time over which ARs, SAEs, SARs and SUSARs may be recorded starts at the date of 
consent and finishes at 90 days post initiation of CABI treatment.  
The period of time over which SAEs, SARs and SUSARs may be reported starts at the date of 
consent and finishes at 90 days post initiation of CABI treatment. 
 
All SAEs* / SUSARs occurring from the time of randomisation until 90 days post diagnosis of 
CABI must be recorded on the appropriate sponsors SAE reporting form. Where they are to be 
reported to the sponsor, they will be e-mailed to the sponsor within 24 hours of the research 
staff becoming aware of the event. Once all resulting queries have been resolved, the sponsor 
will request the original form should also be posted to the Sponsor and a copy to be retained on 
site. 
For each SAE / SAR/ SUSAR the following information will be collected: 
 
full details in medical terms and case description 
 
event duration (start and end dates, if applicable) 
 
action taken 
 
outcome 
 
seriousness criteria 
 
causality (i.e. relatedness to trial drug / investigation), in the opinion of the investigator 
 
whether the event would be considered expected or unexpected. 
Any change of condition or other follow-up information should be faxed to the Sponsor as soon 
as it is available, or at least within one working day of the information becoming available. 
Events will be followed up until resolved or a final outcome reached.   
 
9.4 
Responsibilities 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
31 
 
Principal Investigator (PI):  
Checking for AEs and ARs when participants attend for treatment / follow-up. 
1. Using medical judgement in assigning seriousness, causality and expectedness using 
the Reference Safety Information approved for the trial. The reference information sheet 
for the trial is each drugs SmPC. 
2. Ensuring that all SAEs and SARs (including SUSARs) are recorded and reported to the 
sponsor within 24 hours of becoming aware of the event and provide further follow-up 
information as soon as available. Ensuring that SAEs and SARs (including SUSARs) are 
chased with Sponsor if a record of receipt is not received within 3 working days of initial 
reporting.  
3. Ensuring that ARs are recorded and reported to the Sponsor in line with the 
requirements of the protocol.  
 
Chief Investigator (CI) / delegate or independent clinical reviewer: 
1. Clinical oversight of the safety of patients participating in the trial, including an ongoing 
review of the risk / benefit. 
2. Using medical judgement in assigning seriousness, causality and expectedness of SAEs 
where it has not been possible to obtain local medical assessment. 
3. Using medical judgement in assigning expectedness. 
4. Immediate review of all SUSARs.  
 
Trial Steering Committee (TSC):  
In accordance with the Trial Terms of Reference for the TSC. 
 
9.5 
Notification of deaths 
Death is considered as an SAE and will be reported to the sponsor in line with SAE reporting.  
 
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
32 
 
9.6 
Pregnancy reporting  
Where pregnancy is relevant to an antibiotic being recommended as an IMP e.g. caution for use, the 
clinical care team responsible for the patient will be informed and asked to determine a participant’s 
pregnancy status (to determine a participant is not pregnant)  before being administered the IMP.   
Participants will be asked to report to the research team if they become pregnant during treatment.  
 
9.7 
Overdose  
Overdosing will be notified to the sponsor within 24 hours of the research staff becoming aware of the 
event. Overdosing will be documented on the sponsors protocol deviation form. 
Overdosing is an unexpected event in this study. Overdosing would not result in a participant being 
removed from the study for analysis purposes. A patient’s treating clinician would be responsible for 
managing the antibiotic regimen in such a patient.  
 
9.8 
Reporting urgent safety measures  
If any urgent safety measures are taken, the CI/Sponsor shall immediately, and in any event no later 
than 3 working days from the date the measures are taken, inform the relevant REC of the measures 
taken and the circumstances giving rise to those measures. Urgent Safety Measures will be sent to 
the MHRA via the yellow card scheme in addition to the REC 
 
9.9 
The type and duration of the follow-up of subjects after adverse events. 
Follow-up care for subjects after an adverse drug reaction will be one week. 
Adverse events will be identified by review of patient’s medical notes. 
 
9.10 
Development safety update reports 
The CI will not provide DSURs.  
 
10 
STATISTICS AND DATA ANALYSIS 
10.1 
Sample size calculation 
This study is a feasibility study to determine: 
 
the willingness of participants to be randomised 
 
the willingness of clinicians to recruit participants 
 
the number of eligible patients available to be recruited 
 
follow-up rates 
 
practicalities related to the trial.   
Participants who leave the trial will not be replaced.  We are not intending to estimate size of effects 
with any pre-defined accuracy therefore no formal sample size calculation has been performed.  
 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
33 
 
10.2 
 
Planned recruitment rate 
We aim to recruit one to two patients per week over a one to two year period. 
 
10.3 
Statistical analysis plan 
10.3.1 Summary of baseline data and flow of patients 
Baseline data will be summarised in table format. 
Flow of patients will be presented in a flow diagram.  
 
10.3.2 Primary outcome analysis 
Outcomes will be assessed as proportions. 
 
10.3.3 Secondary outcome analysis 
Outcomes will be assessed as proportions or means as appropriate. 
Intention to treat and per protocol analyses will be completed. 
Analysis of outcomes at 60 days post treatment will be compared to outcomes at 90 days post 
initiation of treatment where possible.  
 
10.4 
Subgroup analyses 
Outcomes will be stratified by source control intervention used therapeutically for the management of 
the primary CABI. The definition of source control used for this study will be: any procedure that stops 
the ongoing contamination of the peritoneal cavity and removes the majority of the contaminated 
intraperitoneal contents to the extent that no further acute interventions are felt to be necessary. 
Depending on the site and origin of the infection, multiple techniques could be satisfactory to obtain 
source control. Acceptable procedures might include simple drainage via open, laparoscopic, or 
percutaneous means, repair of a perforated viscus, resection and primary re-anastomosis of a 
perforated viscus, resection of a perforated viscus and proximal diversion, or proximal diversion 
without resection as long as adequate drainage is obtained. The adequacy of source control for any 
given patient will be determined by the local surgeon as adequate or inadequate.  
Outcomes will be stratified by the CABI being assigned as a post-operative CABI and non post 
operative CABI 
 
10.5 
Adjusted analysis 
Not applicable 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
34 
 
10.6 
Interim analysis and criteria for the premature termination of the trial 
An interim analysis will not be performed. 
 
10.7 
Subject population 
Subject populations whose data will be subjected to the study analysis are: Protocol-compliant 
population: Any subject who was randomized and received the protocol required study drug exposure 
and required protocol processing. 
 
10.8 
Health economics evaluation 
A healthcare utility tool, the EQ-5D, will be used to estimate quality adjusted life years (QALYs-area 
under the curve analysis) for individual participants. This will allow the healthcare utility of the two 
interventions, short course and long course antibiotics, to be compared. Baseline patient characterises 
will be obtained to allow for baseline differences in QALYs to be controlled.  The QALY will be the 
primary outcome measure within the economic evaluation. The EQ-5D will be determined at the start 
of the study, at day 30, day 90 and where possible at the time of relapses. Secondary outcome 
measures within the economic evaluation will be healthcare costs including: Length of hospital stay, 
surgical procedures, antibiotic costs, intravenous access costs, nights in critical care and nights on a 
ventilator. The costs of these healthcare activities will be determined using the following resources: 
www. www.  www. The health economics evaluation will be carries out according to the NICE 
guidance on economic evaluation: https://www.nice.org.uk/process/pmg4/chapter/incorporating-
health-economics 
 
Days in hospital, high dependency units, and surgical interventions will be measured to estimate 
economic impact. Formal health economics advice is being requested.  
 
11 
DATA HANDLING 
11.1 
Data collection tools and source document identification 
Data collection will be by paper case report forms (CRFs). 
Records of all participating patients (sufficient information to link records e.g., CRFs, hospital records 
and samples), all original signed informed consent forms and copies of the CRF pages will be kept. 
Records will be stored in a locked room at the Old Medical School, Leeds General Infirmary, Leeds. 
All research forms will be labelled with a patients study number. 
 
11.2 
Data handling and record keeping 
 
Data entry: Data will be added to an excel database stored on Leeds Teaching Hospitals 
NHS Trust. Access to trust computers is password protected.  
 
Data will be stored on a central server that is backed up.  
 
A data quality audit will be completed during and at the end of the study. 

 
CABI: Antibiotic duration for Complicated intra -ABdominal Infection. 
 
                           EudraCT number 
 
 
35 
 
 
Data will be stored on paper. 
 
Data will be pseudonymised. 
 
Data entry will be by a clinical researcher (clinical research nurse or research doctor). 
 
The PI will be responsible for data entry, quality and analysis. 
 
Arrangements to pseudonymise the data: Data (case report forms) will be given a study 
number at the time of collection. A database linking study numbers to patients will be 
created and be separate to the data. Both paper and electronic records will be kept as part 
of a data disaster recovery plan. 
 
Pseudonymised data will be analysed on the University of Leeds computer system, which is 
password protected. Data will be stored centrally.  
11.3 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. 
 
11.4 
Archiving 
 
Archiving will be authorised by the Sponsor following submission of the end of study 
report. 
 
The research group will be responsible for archiving all research data collected. 
 
Paper archiving will be for 5 years from the end of the study and be based in a locked 
room in the Old Medical School, Leeds General Infirmary. 
 
12 
MONITORING, AUDIT & INSPECTION 
 
Any authorised body will be supported by the trial site in monitoring the study. These may 
include providing information for remote monitoring, or putting procedures in place to monitor 
the study internally. 
 
13  
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1  Research Ethics Committee (REC) review& reports 
 
Before the start of the trial, approval will be sought from a REC for the trial protocol, 
informed consent forms and other relevant documents. 
 
Substantial amendments that require review by REC will not be implemented until the REC 
grants a favourable opinion for the study (and/or NHS R&D departments before they can be 
implemented in practice at sites). 
 
All correspondence with the REC will be retained in the Trial Master File/Investigator Site 
File. 
 
An annual progress report (APR) will be submitted to the REC within 30 days of the 
anniversary date on which the favourable opinion was given, and annually until the trial is 
declared ended. 
 
It is the Chief Investigator’s responsibility to produce the annual reports as required. 

 
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 
The Chief Investigator will notify the REC of the end of the study. 
 
If the study is ended prematurely, the Chief Investigator will notify the REC, including the 
reasons for the premature termination. 
 
Within one year after the end of the study, the Chief Investigator will submit a final report 
with the results, including any publications/abstracts, to the REC. 
 
13.2  
Peer review 
Peer review has been completed by Dr Jon Sandoe, Consultant Microbiologist, Leeds Teaching 
Hospitals NHS Trust and Matthew Scarborough, Oxford University Hospitals. 
 
13.3  
Public and Patient Involvement 
PPI assessment has been undertaken in collaboration with Leeds Patient and Public Involvement Group. 
This has resulted in clarifications/amendments to the protocol e.g. criteria for leaving the trial.  
 
13.4  Regulatory Compliance  
 
The protocol and trial conduct will comply with the Medicines for Human Use (Clinical Trials) 
Regulations 2004 and any relevant amendments 
 
Before any site can enrol patients into the trial, the Chief Investigator/Principal Investigator 
or designee will apply for NHS permission from the site’s Research & Development (R&D) 
department 
 
For any amendment that will potentially affect a site’s NHS permission, the Chief 
Investigator/ Principal Investigator or designee will confirm with that site’s R&D department 
that NHS permission is ongoing (note that both substantial amendments, and amendments 
considered to be non-substantial for the purposes of REC may still need to be notified to 
NHS R&D) 
 
13.5  Protocol compliance  
 
Prospective, planned deviations or waivers to the protocol are not allowed under the UK 
regulations on Clinical Trials and must not be used, e.g. it is not acceptable to enrol a subject 
if they do not meet the eligibility criteria or restrictions specified in the trial protocol. 
 
Accidental protocol deviations can happen at any time. They must be adequately 
documented on the relevant forms and reported to the Chief Investigator and Sponsor 
immediately.  
 
13.6  Notification of Serious Breaches to GCP and/or the protocol  
A “serious breach” is a breach which is likely to affect to a significant degree 
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial. 

 
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 
The sponsor will be notified immediately of any case where the above definition applies 
during the trial conduct phase 
 
13.7  Data protection and patient confidentiality  
All investigators and trial site staff will comply with the requirements of the Data Protection Act 1998 
with regards to the collection, storage, processing and disclosure of personal information and will 
uphold the Act’s core principles.  
This includes: 
The creation of coded, depersonalised data where the participant’s identifying information is replaced 
by an unrelated sequence of characters. 
Secure maintenance of the data and the linking code in separate locations using encrypted digital files 
within password protected folders and storage media. 
Limiting access to the minimum number of individuals necessary for quality control, audit, and 
analysis. 
The PI is the data custodian. 
 
13.8  Financial and other competing interests for the chief investigator, PIs at each site and 
committee members for the overall trial management  
None to declare 
 
13.9  Indemnity 
The University of Leeds is providing:  
1. Insurance and/or indemnity to meet the potential legal liability of the sponsor for harm to 
participants arising from the management of the research. 
2. Insurance and/or indemnity to meet the potential legal liability of the sponsor or employer for harm 
to participants arising from the design of the research. 
The NHS is providing: 
3. Insurance and/or indemnity to meet the potential legal liability of investigators/collaborators arising 
from harm to participants in the conduct of the research. 
The sponsor has not made arrangements for payment of compensation in the event of harm to the 
research participants where no legal liability arises. 
 
13.10  Amendments  
All amendments must be sent to the sponsor’s office that will be responsible for classifying the 
amendment as substantial or non-substantial and directing the research team as to which authorities 
the amendment should be submitted.  
An amendment history will be maintained in the trial master file. 
 
13.11  Post trial care 

 
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No post trial care is planned, or relevant to this trial. 
 
13.12  Access to the final trial dataset 
The trial management and data (safety) monitoring group will have access to the final data set.  
  
14  
DISSEMINIATION POLICY 
14.1  
Dissemination policy 
Consort Guidelines will be reviewed prior to generating any publications for the trial to ensure they 
meet the standards required for submission to high quality peer-reviewed journals. 
The data will be owned by The University of Leeds.  
On completion of the trial, the data will be analysed and tabulated and a Final Study Report prepared 
where the full study report can be accessed 
We plan to notify the participants of the outcome of the trial by provision of the publication and via a 
specifically designed newsletter. 
 
14.2  Authorship eligibility guidelines and any intended use of professional writers 
Authorship will include: 
On the final trial report: The Trial Steering Committee 
For individually named authors: According to The International Committee of Medical Journal Editors’ 
definitions for authorship criteria for manuscripts submitted for publication. 
 
15 
REFERENCES 
Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, et al. Diagnosis and 
management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical 
Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(2):133-64.  
 
Rothwell A, Burke D, Burnside G, Kirby A. Characteristics of Organ Space Surgical Site Infection after 
colorectal surgery. In preparation. 
 
DeFrances CJ, Cullen KA, Kozak LJ. National Hospital Discharge Survey:2005 annual summary with 
detailed diagnosis and procedure data. VitalHealth Stat 13 2007; 165:1–209. 
 
Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors, and outcome of severe sepsis and septic 
shock in adults: a multicenter prospective study in intensive care units. French ICU Group for Severe 
Sepsis. JAMA 1995; 274:968–74. 
 
von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the 
Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting 
observational studies. Lancet 2007; 370: 1453–1457. 
 
Sterne JA, White IR, Carlin JB, Spratt M, Royston P, Kenward MG et al. Multiple imputation for missing 
data in epidemiological and clinical research: potential and pitfalls. BMJ 2009; 338: b2393. 

 
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16.  
APPENDICIES 
16.1  Appendix 1-Risk 
Risks associated with trial interventions: LOW ≡ Comparable to the risk of standard medical care 
Justification:  Briefly justify the risk category selected and your conclusions below  (where the table is 
completed in detail the detail need not be repeated, however a summary should be given): 
Both intervention arms are within standard practice. 
What are the key risks related to therapeutic 
interventions you plan to monitor in this trial? How will these risks be minimised? 
IMP/Intervention  
Body system 
Hazard 
Likelihood 
Activity (mitigation) 
Frequency 
Comments 
Antibiotic (all) 
Gastrointestinal tract 
Clostridium difficile 
associated diarrhoea 
Low 
Standard NHS 
monitoring/ 
precautions 
Continuous 
 
Intravenous antibiotic 
Vascular 
Venous catheter 
infection 
Low 
Standard NHS 
monitoring/ 
precautions 
Continuous 
 
Allergy 
All 
Rash-Anaphylaxis 
Low 
Standard NHS 
monitoring/ 
precautions 
Continuous 
 
Antibiotic (all) 
All 
Various drug side 
effects, cautions, 
contra-indications 
and interactions as 
detailed in each 
drugs summary of 
product 
characteristics/ 
British National 
Formulary 
Standard NHS 
monitoring/ 
precautions 
Continuous 
 

 
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Low 
Outline any other processes that have been put in place to mitigate risks to participant safety: 
MHRA assessment of the trial protocol 
Trial oversight committees 
Independent protocol review 
National Research Ethics Committee Review 
 
 
16.3 
Appendix 2 – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made