VSL#3 and Spontaneous Bacterial Peritonitis

NCT ID: NCT01701297

Last Updated: 2016-10-28

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-02-29
• Study Completion Date: 2014-10-31

Brief Summary

Research question: Do oral probiotics in patients with cirrhosis and ascites reduce intestinal bacterial concentrations, ascitic bacterial DNA, SBP and bacteraemia compared to antibiotics or placebo?

This study is designed to investigate the effects of an oral probiotic (VSL#3; a mixture of "healthy" bacteria for the intestines) compared to an antibiotic or placebo in preventing infection developing in the abdominal fluid ("ascites") that collects in patients with advanced liver disease ("cirrhosis"). Patients already having had infection will be excluded from the study. Clear inclusion and exclusion criteria will be met and patients will be monitored throughout the study to examine whether they have required more hospitalisations, their rate infection in abdominal fluid or elsewhere and the level of liver function.

Detailed Description

The prevalence of cirrhosis is increasing in the UK. Decompensation heralds a poor outcome, with mortality in those developing ascites approximately 50% over the following 1-2 years. Spontaneous bacterial peritonitis (SBP) in ascitic fluid further reduces survival and occurs due to a combination of increased intestinal epithelial dysfunction, bacterial translocation to mesenteric lymph nodes and ascitic fluid, and reduced opsonisation and neutrophil function. Even with antibiotic treatment, 3-month mortality from SBP is approximately 40% and results in expensive in-patient care. Several studies have confirmed the benefit of secondary prophylaxis with long-term oral antibiotics in patients with advanced liver disease (e.g. norfloxacin, co-trimoxazole) and others suggest that in patients at high risk of developing SBP, primary antibiotic prophylaxis improves rates of sepsis and survival. Problems with these strategies include emergence of bacterial resistance, and development of antibiotic-associated diarrhoea (including C. difficile infection, which has a high case-fatality rate in those with cirrhosis). Local bacterial resistance profiles and association with C. difficile infection favour the choice of co-trimoxazole in our study population. Patients with advanced cirrhosis taking co-trimoxazole have previously demonstrated reduced liver-related outcomes such as infection and death3. Probiotic preparations alter intestinal bacterial flora and improve intestinal barrier and neutrophil function. Faecal bacterial counts of E. coli and Streptococcus (organisms commonly responsible for SBP) showed a 2-log fall with probiotics, although whether they could reduce the incidence of SBP remains unexamined.

Conditions

Decompensated Cirrhosis; Ascites

Keywords

Cirrhosis, ascites, infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Co-trimoxazole

Co-trimoxazole 960mg daily po

Group Type: ACTIVE_COMPARATOR

cotrimoxazole

Intervention Type: DRUG

Cotrimoxazole 960mg orally each day (two 480mg tablets)

VSL#3 active

VSL#3 active 2 sachets/daily

Group Type: EXPERIMENTAL

VSL#3 active

Intervention Type: DRUG

The prescribed dose was 2 sachets (containing 900 billion bacteria) orally each day for 48 weeks

VSL#3 placebo

VSL#3 placebo 2 sachets/daily

Group Type: PLACEBO_COMPARATOR

VSL#3 placebo

Intervention Type: DRUG

This was two placebo sachets identical to VSL#3 active sachet. The prescribed dose was 2 sachets orally each day for 48 weeks

Interventions

cotrimoxazole

Cotrimoxazole 960mg orally each day (two 480mg tablets)

Intervention Type: DRUG

VSL#3 active

The prescribed dose was 2 sachets (containing 900 billion bacteria) orally each day for 48 weeks

Intervention Type: DRUG

VSL#3 placebo

This was two placebo sachets identical to VSL#3 active sachet. The prescribed dose was 2 sachets orally each day for 48 weeks

Intervention Type: DRUG

Other Intervention Names

Cotrimoxazole (septrin)

Eligibility Criteria

Inclusion Criteria

• Participant is willing and able to give informed consent for participation in the study.
• Male or Female, aged 18 years or above.
• Diagnosed with required disease/severity/symptoms as outlined in 6.3.1.
• Stable dose of current regular medication (e.g. diuretics, beta-blockers, vitamin supplementation) for at least 4 weeks prior to study entry.
• Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during the study and for 3 months thereafter
• Participants have clinically acceptable laboratory tests and ECG within 14 days of enrolment.
• Able (in the Investigators opinion) and willing to comply with all study requirements.

Willing to allow their General Practitioner and consultant

Exclusion Criteria

• Female participants who is pregnant, lactating or planning pregnancy during the course of the study.
• Presence of hepatocellular carcinoma
• Scheduled elective surgery or other procedures requiring general anaesthesia during the study.
• Participant who is terminally ill
• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study.
• Use of antibiotics or probiotics in the last 2 weeks
• Known hypersensitivity to trimethoprim, sulphonamides or any other ingredients in co-trimoxazole tablet.
• History of acute porphyria or serious haematological disorder.
• Participants who have participated in another research study involving an investigational product in the past 12 weeks

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

VSL Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Nottingham University Hospitals NHS Trust

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Martin W James, BM BS FRCP PhD

Role: PRINCIPAL_INVESTIGATOR

NUH NHS Trust

Locations

NUH NHS Trust

Nottingham, Nottinghamshire, United Kingdom

Countries

United Kingdom

Other Identifiers

2010-022886-92

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

10/H0405/81

Identifier Type: OTHER

Identifier Source: secondary_id

10GA021

Identifier Type: -

Identifier Source: org_study_id