A trial of using antibiotics to prevent infection in patients with advanced liver disease
| ISRCTN | ISRCTN33225996 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN33225996 |
| EudraCT/CTIS number | 2019-000581-38 |
| IRAS number | 262176 |
| ClinicalTrials.gov number | NCT04395365 |
| Secondary identifying numbers | CTU/2017/308, IRAS 262176, HTA 176701 |
- Submission date
- 29/04/2020
- Registration date
- 29/04/2020
- Last edited
- 14/02/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Digestive System
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 18 months prevents development of SBP and improves overall survival. 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 432 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 18 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 3 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 May 2025
Who is funding the study?
National Institute for Health and Care Research (UK)
Who is the main contact?
Prof. Alastair O’Brien (scientific), a.o’brien@ucl.ac.uk
Contact information
Scientific
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
 ORCID ID |
0000-0002-9168-7009 |
|---|---|
| a.o'brien@ucl.ac.uk |
Study information
| Study design | Multicentre placebo-controlled randomized double-blind trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Prevention |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | Primary Antibiotic prophylaxis using co-trimoxazole to prevent SpontanEous bacterial PeritoniTIs in Cirrhosis |
| Study acronym | ASEPTIC |
| Study hypothesis | Current study hypothesis as of 13/05/2021: 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 an 18-month trial period. Previous 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(s) | 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 |
| Condition | Spontaneous Bacterial Peritonitis (SBP) in adults with liver cirrhosis and ascites |
| Intervention | Current interventions as of 13/05/2021: 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. Co-trimoxazole OR Placebo, 960mg capsules orally consumed daily for 18 months. Patients randomised using Sealed Envelope online database. Previous interventions: 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Co-trimoxazole |
| Primary outcome measure | Current primary outcome measure as of 13/05/2021: Overall survival measured using patient records at 18 months Previous primary outcome measure: Time to first incidence of spontaneous bacterial peritonitis up to 24 months following randomisation measured using patient records |
| Secondary outcome measures | Current secondary outcome measures as of 13/05/2021: The following will be measured for a minimum period of 18 months from randomisation: 1. Time to first incidence of spontaneous bacterial peritonitis (SBP) (SBP is defined as per the standard guidelines: ascitic fluid polymorphonuclear (PMN) cell count >250/mm³ with either positive or negative ascitic fluid culture without an evident intra-abdominal surgically treatable source of infection. A white cell count >500 cell/mm2 or positive microbial culture may be considered as evidence of previous SBP if the site PI considers this was in the context of a likely clinical diagnosis of SBP) 2. Hospital admission rates 3. Incidence of C. difficile-associated diarrhoea 4. Incidence of infections other than SBP that require hospital admission 5. Incidence of other cirrhosis related events (e.g. variceal haemorrhage) 6. Incidence of renal dysfunction with creatinine >133 µmol/L (1.5mg/dL) at any point during hospital admission 7. Incidence of anti-microbial resistance 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 serious 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 16. Incidence of Transjugular intrahepatic portosystemic shunt (TIPS) insertion Previous 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 study start date | 01/01/2019 |
| Overall study end date | 31/05/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 548 |
| Total final enrolment | 442 |
| Participant inclusion criteria | Current participant inclusion criteria as of 13/05/2021: 1. Liver cirrhosis and ascites persisting for >3 months despite standard treatment 2. Aged ≥18 years 3. Documented informed consent to participate Previous 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 exclusion criteria | Current participant exclusion criteria as of 13/05/2021: 1. Current or previous Spontaneous Bacterial Peritonitis (defined as ascitic polymorphonuclear cell count >250/mm³ with either positive or negative ascitic fluid culture without an evident intra-abdominal surgically treatable source of infection. A white cell count >500 cell/mm² or positive microbial culture may be considered as evidence of previous SBP if the site PI considers this was in the context of a likely clinical diagnosis of SBP) 2. Receiving palliative care with a 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. Serum potassium (>5.5 mmol/l) related to pre-existing kidney disease which cannot be reduced 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. Patients with pathological blood count changes: 10.1. Haemoglobin (Hb) <70 g/l 10.2. Granulocytopenia defined as absolute neutrophil counts of less than 500 cells per microliter 10.3. Severe thrombocytopenia with a platelet count <30 x10⁹/l 11. Severe renal impairment, with eGFR <15 ml/min 12. Skin conditions: exudative erythema multiform, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug eruption with eosinophilia and systemic symptoms 13. Congenital conditions: congenital glucose-6-Phosphate dehydrogenase deficiency of the erythrocytes, haemoglobin anomalies such as Hb Köln and Hb Zürich 14. Acute porphyria 15. Any clinical condition which the investigator considers would make the patient unsuitable for the trial As some investigations may change in patients with cirrhosis and long-term ascitic drains may be removed, patients can be re-screened for eligibility if this occurs. Previous 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 | 31/08/2023 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Hampstead
London
NW3 2QG
United Kingdom
Sponsor information
University/education
Gower Street
London
WC1E 6BT
England
United Kingdom
| Phone | +44 (0)2076705748 |
|---|---|
| ctu.aseptic@ucl.ac.uk | |
| Website | https://www.ucl.ac.uk/comprehensive-clinical-trials-unit/ |
"ROR" |
https://ror.org/02jx3x895 |
Funders
Funder type
Not defined
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/12/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| 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 plan | The current data sharing plans for this study are unknown and will be available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version v3.0 | 13/08/2019 | 29/04/2020 | No | No |
| Protocol file | version 4.0 | 25/08/2020 | 13/05/2021 | No | No |
| HRA research summary | 28/06/2023 | No | No |
Additional files
- ISRCTN33225996_PROTOCOL_v3.0_13Aug2019.pdf
- uploaded 29/04/2020
- ISRCTN33225996_PROTOCOL_v4.0_25Aug2020.pdf
- Uploaded 13/05/2021
Editorial Notes
14/02/2025: A contact was removed.
12/02/2025: The overall study end date was changed from 28/02/2025 to 31/05/2025.
20/01/2025: The following changes were made to the study record:
1. The overall study end date was changed from 31/08/2025 to 28/02/2025.
2. The intention to publish date was changed from 31/01/2025 to 01/12/2025.
11/04/2024: The ClinicalTrials.gov number was added.
17/11/2023: The total final enrolment was changed from 432 to 442.
04/04/2023: The following changes were made to the trial record:
1. The recruitment end date has been changed from 30/04/2023 to 31/08/2023.
2. The overall trial end date has been changed from 31/10/2024 to 31/08/2025.
3. The intention to publish date has been changed from 31/12/2024 to 31/01/2025.
13/05/2021: The following changes have been made:
1. The recruitment end date has been changed from 31/07/2021 to 30/04/2023.
2. The overall trial end date has been changed from 31/12/2023 to 31/10/2024.
3. The total final enrolment number has been added.
4. The study hypothesis has been updated.
5. The interventions have been updated.
6. The primary outcome measure has been updated.
7. The secondary outcome measures have been updated.
8. The participant exclusion criteria have been updated.
9. The plain English summary has been updated to reflect the changes above.
10. Uploaded protocol version 4.0, 25 August 2020 (not peer reviewed).
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.
