Decompensated CirrhosisPhase 2NCT01701297
VSL#3 and Spontaneous Bacterial Peritonitis
A Phase 2 study testing cotrimoxazole and VSL#3 active in people with Decompensated Cirrhosis and Ascites, run by Nottingham University Hospitals NHS Trust at 1 site in United Kingdom.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Decompensated Cirrhosis, Ascites
- What is being tested?
- cotrimoxazole and VSL#3 active
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 10 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Feb 2012to Oct 2014
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 9Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
NUH NHS Trust
Nottingham, Nottinghamshire, NG7 2UH
About this study
Official title: The Effect of Probiotics on the Incidence of Spontaneous Bacterial Peritonitis in Patients With Cirrhosis and Ascites
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.
Read the 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
- Being tested
- cotrimoxazole, VSL#3 active, VSL#3 placebo
- Keywords
- Cirrhosis, ascites, infection
- Medical subject headings
- Ascites, Fibrosis, Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
cotrimoxazoleDrug
Also called Cotrimoxazole (septrin)
Cotrimoxazole 960mg orally each day (two 480mg tablets)
VSL#3 activeDrug
The prescribed dose was 2 sachets (containing 900 billion bacteria) orally each day for 48 weeks
VSL#3 placeboDrug
This was two placebo sachets identical to VSL#3 active sachet. The prescribed dose was 2 sachets orally each day for 48 weeks
| Study group | Role | What they receive |
|---|---|---|
| Co-trimoxazole | Active comparator | Co-trimoxazole 960mg daily po Receives: Drug: cotrimoxazole |
| VSL#3 active | Experimental | VSL#3 active 2 sachets/daily Receives: Drug: VSL#3 active |
| VSL#3 placebo | Placebo comparator | VSL#3 placebo 2 sachets/daily Receives: Drug: VSL#3 placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Liver-related mortality and liver related morbidity
Measured: 12 months
Secondary outcomes (1)
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.
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Oct 2012 (estimated)
- Study startFeb 2012
- Primary completionOct 2014
- Study completionOct 2014
Why it stopped: Unable to obtain QP release certification from the manufacturer (VSL3) for shipment of IMP
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Decompensated CirrhosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Nottingham University Hospitals NHS Trust
- Sponsor type
- University, hospital or other
- Collaborators
- VSL Pharmaceuticals
- Responsible party
- Sponsor
- Investigators
- Martin W James, BM BS FRCP PhD, Principal investigator, NUH NHS Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01701297
- Sponsor's protocol ID
- 10GA021
- Other IDs
- 2010-022886-92, 10/H0405/81
- Status last verified
- Oct 2016
- First submitted
- 8 Aug 2012
- Last updated
- 28 Oct 2016
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 28 Oct 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Probiotics on the Incidence of Spontaneous Bacterial Peritonitis in Patients With Cirrhosis and Ascites
- ClinicalTrials.gov ID
- NCT01701297
- Acronym / sponsor ID
- 10GA021
- Conditions
- Decompensated Cirrhosis, Ascites
- Keywords
- Cirrhosis, ascites, infection
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Unable to obtain QP release certification from the manufacturer (VSL3) for shipment of IMP
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Nottingham University Hospitals NHS TrustUniversity, hospital or other
- Collaborators
- VSL Pharmaceuticals
- Study start
- Feb 2012
- Primary completion
- Oct 2014 (actual)
- Study completion
- Oct 2014 (actual)
- First posted
- 5 Oct 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Co-trimoxazole | Active comparator | Drug: cotrimoxazoleCo-trimoxazole 960mg daily po |
| VSL#3 active | Experimental | Drug: VSL#3 activeVSL#3 active 2 sachets/daily |
| VSL#3 placebo | Placebo comparator | Drug: VSL#3 placeboVSL#3 placebo 2 sachets/daily |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| cotrimoxazoleAlso: Cotrimoxazole (septrin)Cotrimoxazole 960mg orally each day (two 480mg tablets) | Drug | Co-trimoxazole |
| VSL#3 activeThe prescribed dose was 2 sachets (containing 900 billion bacteria) orally each day for 48 weeks | Drug | VSL#3 active |
| VSL#3 placeboThis was two placebo sachets identical to VSL#3 active sachet. The prescribed dose was 2 sachets orally each day for 48 weeks | Drug | VSL#3 placebo |
Primary outcome
Liver-related mortality and liver related morbidity
Time frame: 12 months
1 secondary outcome
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.
Time frame: 12 months
Results and safety
The study was stopped early (reason given: Unable to obtain QP release certification from the manufacturer (VSL3) for shipment of IMP). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Oct 2016.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Martin W James, BM BS FRCP PhD principal investigator
NUH NHS Trust
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing cotrimoxazole and VSL#3 active in people with Decompensated Cirrhosis and Ascites, run by Nottingham University Hospitals NHS Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 28 Oct 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Unable to obtain QP release certification from the manufacturer (VSL3) for shipment of IMP). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Liver-related mortality and liver related morbidity (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Oct 2016.