VSL#3 and Spontaneous Bacterial Peritonitis

Sponsor

Nottingham University Hospitals NHS Trust (Other)

Overall Status

Terminated

CT.gov ID

NCT01701297

Collaborator

VSL Pharmaceuticals (Industry)

Enrollment

Location

Arms

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Decompensated Cirrhosis Ascites	Drug: cotrimoxazole Drug: VSL#3 active Drug: VSL#3 placebo	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

10 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

The Effect of Probiotics on the Incidence of Spontaneous Bacterial Peritonitis in Patients With Cirrhosis and Ascites

Study Start Date :

Feb 1, 2012

Actual Primary Completion Date :

Oct 1, 2014

Actual Study Completion Date :

Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Co-trimoxazole Co-trimoxazole 960mg daily po	Drug: cotrimoxazole Cotrimoxazole 960mg orally each day (two 480mg tablets) Other Names: Cotrimoxazole (septrin)
Experimental: VSL#3 active VSL#3 active 2 sachets/daily	Drug: VSL#3 active The prescribed dose was 2 sachets (containing 900 billion bacteria) orally each day for 48 weeks
Placebo Comparator: VSL#3 placebo VSL#3 placebo 2 sachets/daily	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

Arm

Intervention/Treatment

Active Comparator: Co-trimoxazole

Co-trimoxazole 960mg daily po

Drug: cotrimoxazole

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

Other Names:

Cotrimoxazole (septrin)

Experimental: VSL#3 active

VSL#3 active 2 sachets/daily

Drug: VSL#3 active

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

Placebo Comparator: VSL#3 placebo

VSL#3 placebo 2 sachets/daily

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

Outcome Measures

Primary Outcome Measures

Liver-related mortality and liver related morbidity [12 months]

Secondary Outcome Measures

Incidence of SBP, variceal bleeding, any non-SBP sepsis (e.g. pneumonia, urinary tract infection), clinical episodes of encephalopathy and the incidence of C. difficile infection. [12 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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