Condition category
Digestive System
Date applied
29/04/2020
Date assigned
29/04/2020
Last edited
30/04/2020
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Liver disease is a common cause of death and the three major causes are excessive alcohol drinking, obesity or infection with viral hepatitis. It develops over 15-30 years and causes irreversible liver scarring, cirrhosis. Some patients develop features of advanced liver disease - yellow skin, vomiting of blood or fluid in their abdomen and this affects 6000 people a year in Britain. They are very vulnerable to infection with bacteria because of their weak immune systems. These infections almost always require hospital admission and worsen their liver disease. A strategy of prevention of infection may be better than cure. The researchers will look at whether giving these people antibiotics when they do not have an infection for 24 months prevents development of SBP. This is called prophylaxis and has been shown to work but only in small numbers of people and for short time frames. The researchers do not know if this would work across a wider population in the long term. Also antibiotic prophylaxis may cause harm. During antibiotic treatment bugs can find ways to stop antibiotics from killing them, antimicrobial resistance. These resistant bugs are even more dangerous as the researchers have fewer antibiotics that work against them. The researchers therefore need to test our approach in a clinical trial.

Aims:
Patients who have advanced liver disease are at high risk of suffering infection, hospital admission and death and it is preferable to prevent infection in the first place. The researchers are targeting a specific infection that affects fluid that builds up in the abdomen (known as ascites) of advanced liver disease patients, called Spontaneous Bacterial Peritonitis (SBP). Preventing SBP could help people with liver disease live longer, healthier lives.

Who can participate?
Adults over 18 years, with liver cirrhosis and ascites.

What does the study involve?
The researchers will recruit 548 people with cirrhosis and ascites but no SBP from 30 hospitals. Each will be given a pill once a day. These pills will look identical but half of patients will take an antibiotic whilst the other half will take an inactive tablet, a placebo. The antibiotic is co-trimoxazole, commonly used for urine infections. Neither patients nor doctors will know which is which, a double-blind trial. Patients and investigators know which pill they are taking otherwise this can affect results even with an inactive drug, the placebo effect. Participants will take the medication for 24 months and meet research nurses every 3 months to determine if they have developed SBP or required admission to hospital. Information on liver function and quality of life will be collected and participants tested for antimicrobial resistance.

What are the possible benefits and risks of participating?
Co-trimoxazole causes significant side effects in 1 of every 100 patients, usually skin rashes. Very rarely (1-7 cases per million people per year) a severe dangerous skin rash develops, Stevens-Johnson, which people will be taught to look out for. High blood potassium levels can also occur and will be monitored by 2 monthly blood testing. Information will be stored securely so that participants cannot be identified and analysed by statisticians to inform us if co-trimoxazole prophylaxis prevents SBP effectively and safely.

Patient and public involvement
An infection in cirrhosis patient group has been set up to inform about concerns e.g. safety or adverse effects. The researchers will meet before the trial to design the protocol, consent forms, patient information sheets and a lay FAQ sheet for patients.

Where is the study run from?
Royal Free Hospital (UK)

When is the study starting and how long is it expected to run for?
September 2019 to December 2023

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
David Gear (public), david.gear.16@ucl.ac.uk
Prof. Alastair O’Brien (scientific), a.o’brien@ucl.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Mr David Gear

ORCID ID

Contact details

90 High Holborn
Holborn
WC1V 6LJ
United Kingdom
+44 (0)2076705748
david.gear.16@ucl.ac.uk

Type

Scientific

Additional contact

Prof Alastair O'Brien

ORCID ID

http://orcid.org/0000-0002-9168-7009

Contact details

University College London
University College Hospital & UCL Institute for Liver and Digestive Health
Upper 3rd Floor
Division of Medicine
Royal Free Campus
Rowland Hill Street
London
NW3 2PF
United Kingdom
-
a.o'brien@ucl.ac.uk

Additional identifiers

EudraCT number

2019-000581-38

ClinicalTrials.gov number

Nil known

Protocol/serial number

CTU/2017/308, IRAS 262176, HTA 176701

Study information

Scientific title

Primary Antibiotic prophylaxis using co-trimoxazole to prevent SpontanEous bacterial PeritoniTIs in Cirrhosis

Acronym

ASEPTIC

Study hypothesis

The primary objective of ASEPTIC is to determine whether primary antibiotic prophylaxis with co-trimoxazole reduces the incidence of spontaneous bacterial peritonitis compared to placebo in adults with cirrhosis and ascites over a 2-year trial period.

Ethics approval

Approved 25/06/2019, South Central - Oxford B Research Ethics Committee (Level 3, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT, UK; +44 (0)2071048046; oxfordb.rec@hra.nhs.uk), ref: 19/SC/0311

Study design

Multicentre placebo-controlled randomized double-blind trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Prevention

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Spontaneous Bacterial Peritonitis (SBP) in adults with liver cirrhosis and ascites

Intervention

This multicentre placebo-controlled randomised double-blind trial assesses efficacy, cost-effectiveness and safety of the use of co-trimoxazole for two years to prevent SBP in patients with cirrhosis and a low ascitic fluid protein count (<2.0 g/dL).

Co-trimoxazole OR Placebo, 960mg capsules orally consumed daily for 24 months.
Patients randomised using Sealed Envelope online database.

Intervention type

Drug

Phase

Phase III

Drug names

Co-trimoxazole

Primary outcome measure

Time to first incidence of spontaneous bacterial peritonitis up to 24 months following randomisation measured using patient records

Secondary outcome measures

The following will be measured up to 24 months from randomisation using patient records unless otherwise stated:
1. All-cause mortality
2. Incidence of spontaneous bacterial peritonitis infection
3. Hospital admission rates
4. Incidence of C. difficile-associated diarrhoea
5. Incidence of infections other than spontaneous bacterial peritonitis with hospital admission.
6. Incidence of other cirrhosis related events (e.g. variceal haemorrhage)
7. Incidence of renal dysfunction with creatinine >133 μmol/L (1.5mg/dL) at any point during hospital admission
8. Incidence of liver transplantation
9. Progression of liver disease assessed by increase in MELD score between baseline and end of trial follow up.
10. Safety and treatment-related adverse events
11. Treatment adherence (assessed by MARS questionnaire)
12. Health-related quality of life assessed using EQ-5D-5L questionnaire
13. Health and social care resource use assessed using Hospital Episode Statistics (HES) database
14. Mean incremental cost per quality-adjusted life year gained (QALY)
15. Incidence of resolution of ascites with diuretic treatment not required for 6 months

Overall trial start date

01/01/2019

Overall trial end date

31/12/2023

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Liver cirrhosis and ascites with ascitic fluid protein count <2.0 g/dL (from sample taken within <12 weeks prior to randomisation)
2. Ascitic polymorphonuclear count <250 cells/mm3 and negative microbial culture at 5 days (on the last sample sent within <12 weeks prior to randomisation)
3. At least 18 years of age
4. Documented informed consent to participate

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

548

Participant exclusion criteria

1. Previous Spontaneous Bacterial Peritonitis (SBP)
2. Receiving palliative care with an expected life expectancy of <8 weeks
3. Allergic to co-trimoxazole, trimethoprim or sulphonamides
4. Pregnant or lactating mothers
5. Enrolled in a clinical trial of investigational medicinal products (IMPs) that would impact on their participation in the study
6. Persistent hyperkalaemia (>6.5 mmol/L) related to pre-existing kidney disease with reduction not possible
7. Receiving antibiotic prophylaxis (except for rifaximin)
8. Long-term ascites drains
9. Women of child bearing potential and males with a partner of child bearing potential without effective contraception for the duration of trial treatment
10. Pathological blood count changes (granulocytopenia, megaloblastic anaemia)
11. Severe thrombocytopenia with a platelet count <30 x109 /L
12. Severe renal impairment, with eGFR <15 ml/min
13. Skin conditions: exudative erythema multiform, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug eruption with eosinophilia and systemic symptoms
14. Congenital conditions: congenital glucose-6-Phosphate dehydrogenase deficiency of the erythrocytes, haemoglobin anomalies such as Hb Köln and Hb Zürich
15. Acute porphyria
16. Any clinical condition which the investigator considers would make the patient unsuitable for the trial

Recruitment start date

28/09/2019

Recruitment end date

31/07/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Royal Free hospital
Pond St Hampstead
London
NW3 2QG
United Kingdom

Sponsor information

Organisation

University College London

Sponsor details

Gower Street
London
WC1E 6BT
United Kingdom
+44 (0)2076705748
ctu.aseptic@ucl.ac.uk

Sponsor type

University/education

Website

https://www.ucl.ac.uk/comprehensive-clinical-trials-unit/

Funders

Funder type

Not defined

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The results will be spread to patients, the public and health care workers via medical publications, meetings, British Liver Trust, social and conventional media.

IPD sharing statement:
The current data sharing plans for this study are unknown and will be available at a later date

Intention to publish date

31/12/2024

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

30/04/2020: Internal review. 29/04/2020: Uploaded protocol (not peer reviewed) as an additional file. 29/04/2020: Trial’s existence confirmed by National Institute for Health Research HTA.