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Clinical Trial Results:
The effect of probiotics on the incidence of spontaneous bacterial peritonitis in patients with cirrhosis and ascites.

Summary
EudraCT number	2010-022886-92
Trial protocol	GB
Global end of trial date	08 Oct 2014

Results information
Results version number	v1(current)
This version publication date	25 Jul 2016
First version publication date	25 Jul 2016
Other versions
Summary report(s)	10GA021 VSL3 End of Study Report Appendix 1 - Protocol Deviations Appendix 5 - Log of Serious Adverse Events Appendix 2 - Participant Consent Form Appendix 3 - Participant Information Sheet Appendix 4 - Log of AEs Appendix 6 - Visit Schedule Appendix 7 - Participant Data

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

10GA021

ISRCTN number

US NCT number

NCT01701297

WHO universal trial number (UTN)

Sponsor organisation name

Nottingham University Hospitals NHS Trust

Sponsor organisation address

QMC, Derby Road, Nottingham, United Kingdom, NG7 2UH

Public contact

Research & Innovation Dept, Nottingham University Hospitals NHS Trust, +44 01159249924, researchsponsor@nuh.nhs.uk

Scientific contact

Research & Innovation Dept, Nottingham University Hospitals NHS Trust, +44 01159249924, researchsponsor@nuh.nhs.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

08 Oct 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

08 Oct 2014

Global end of trial reached?

Yes

Global end of trial date

08 Oct 2014

Was the trial ended prematurely?

Yes

Main objective of the trial

Do oral probiotics (VSL#3 sachets)or oral antibiotics (cotrimoxazole) reduce the incidence and severity of liver-related complications in cirrhotic patients with ascites?

Protection of trial subjects

Eligibility criteria ensured that participants were not recruited to the study if there were likely to be an known contra-indications to the IMPs. Safety reporting was adhered to according to Directive 2001/20/EC and the investigator was able to unblind and withdraw participants if necessary.

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Jan 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 10

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

VSL3 was a single centre study open to recruitment at Nottingham University Hospitals NHS Trust only. The first participant consent was taken on 13th March 2013 and the final participant consent was on 9th December 2013. Recruitment ended on the 8th October 2014 when the study was stopped prematurely.

Screening details

Patients having ascitic samples taken to investigate the cause or to exclude infection (SBP) were considered for the study. 334 patient’s records were reviewed to consider eligibility. 17 consented to be screened for the study and 10 were randomised. 1 of the 10 patients was withdrawn due to active infection found following the ascitic sample.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

Sachets were plain white and indistinguishable from placebo sachets, but labelled with a study/code number, and provided by VSL#3 pharmaceuticals. The study medications were supplied as matched appearance sachets for active and placebo VSL3 and as open label cotrimoxazole tablets. Tablets and sachet counts were confirmed with patients at each study visit to document compliance.

Are arms mutually exclusive

Yes

Active Probiotic VSL#3

Arm description

VSL#3 probiotic preparations. Each packet of VSL#3® contained 450 billion live lactic acid bacteria and bifidobacteria. There are 8 different strains of bacteria contained in VSL#3: Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii subsp. Bulgaricus. Other ingredients included maltose and silicon dioxide. The prescribed dose was 2 sachets (containing 900 billion bacteria) orally each day. Sachets were plain white and indistinguishable from placebo sachets, but labelled with a study/code number, and provided by VSL#3 pharmaceuticals. Probiotics and placebo sachets should have been opened and the contents stirred into cold water or another non-fizzy cold drink (but not with hot drinks or hot food). Study patients were prohibited from taking any other probiotics during the study (such as Yakult®).

Arm type

Experimental

Investigational medicinal product name

VSL#3®

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for oral solution

Routes of administration

Oral use

Dosage and administration details

The prescribed dose was 2 sachets (containing 900 billion bacteria) orally each day for 48 weeks. Probiotics and placebo sachets should have been opened and the contents stirred into cold water or another non-fizzy cold drink (but not with hot drinks or hot food).

VSL#3 Placebo

Arm description

VSL#3 Placebo. This was two placebo sachets identical to VSL#3 active sachet.

Arm type

Placebo

Investigational medicinal product name

VSL#3 Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for oral solution

Routes of administration

Oral use

Dosage and administration details

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. Sachets were plain white and indistinguishable from active sachets, but labelled with a study/code number, and provided by VSL#3 pharmaceuticals. Probiotics and placebo sachets should have been opened and the contents stirred into cold water or another non-fizzy cold drink (but not with hot drinks or hot food).

Co-trimoxazole

Arm description

Cotrimoxazole 960mg orally each day (two 480mg tablets). Cotrimoxazole is a combination of sulfamethoxazole (800mg) and trimethoprim (160mg). This was supplied by NUH clinical trials pharmacy and is the standard dose for prophylaxis of spontaneous bacterial peritonitis in clinical practice. Cotrimoxazole antibiotics were to be taken with food or any drink

Arm type

Experimental

Investigational medicinal product name

Cotrimoxazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

960mg orally each day (two 480mg tablets) for 48 weeks. Cotrimoxazole antibiotics were to be taken with food or any drink

Number of subjects in period 1	Active Probiotic VSL#3	VSL#3 Placebo	Co-trimoxazole
Started	4	4	2
Completed	2	2	1
Not completed	2	2	1
Ineligible	1	-	-
Consent withdrawn by subject	-	-	1
Study termination (lack of drug supply)	1	2	-

Baseline characteristics

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Reporting group title

Overall trial

Reporting group description

Reporting group values	Overall trial	Total
Number of subjects	10	10
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	7	7
From 65-84 years	3	3
85 years and over	0	0
Gender categorical
Units: Subjects
Female	5	5
Male	5	5

End points

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Reporting group title

Active Probiotic VSL#3

Reporting group description

Reporting group title

VSL#3 Placebo

Reporting group description

VSL#3 Placebo. This was two placebo sachets identical to VSL#3 active sachet.

Reporting group title

Co-trimoxazole

Reporting group description

Primary: Liver related mortality

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End point title

Liver related mortality ^[1]

End point description

End point type

Primary

End point timeframe

Liver-related mortality from enrolment onto the study until the end of the study period (48 weeks of study treatment)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Full analysis not completed due to premature discontinuation

End point values	Active Probiotic VSL#3	VSL#3 Placebo	Co-trimoxazole
Number of subjects analysed	2 ^[2]	2 ^[3]	2 ^[4]
Units: Deaths	1	1	0

Notes
[2] - Full analysis not completed due to premature discontinuation.
[3] - Full analysis not completed due to premature discontinuation
[4] - Full analysis not completed due to premature discontinuation

No statistical analyses for this end point

Primary: Liver related morbidity

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End point title

Liver related morbidity ^[5]

End point description

admission for any liver-related complication and the number of days hospitalisation

End point type

Primary

End point timeframe

From time of enrolment until end of trial (48 weeks of study treatment)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Full analysis not completed due to premature discontinuation

End point values	Active Probiotic VSL#3	VSL#3 Placebo	Co-trimoxazole
Number of subjects analysed	2 ^[6]	2 ^[7]	2 ^[8]
Units: Hospital admissions	1	1	0

Notes
[6] - Full analysis not completed due to premature discontinuation
[7] - Full analysis not completed due to premature discontinuation
[8] - Full analysis not completed due to premature discontinuation

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were recorded from date of consent until the participant's last visit or date of completion/withdrawal.

Adverse event reporting additional description

All AEs occurring during the study observed by the investigator or reported by the participant, whether or not attributed to study medication, will be recorded on the CRF.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

10.0

Reporting group title

Active Probiotic VSL#3

Reporting group description

Reporting group title

VSL#3 Placebo

Reporting group description

VSL#3 Placebo. This was two placebo sachets identical to VSL#3 active sachet.

Reporting group title

Co-trimoxazole

Reporting group description

Serious adverse events	Active Probiotic VSL#3	VSL#3 Placebo	Co-trimoxazole
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 4 (25.00%)	1 / 4 (25.00%)	2 / 2 (100.00%)
number of deaths (all causes)	1	1	0
number of deaths resulting from adverse events	0	1	0
Nervous system disorders
Syncope
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 2 (50.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Gastrointestinal disorders
Haematemesis
subjects affected / exposed	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic encephalopathy
subjects affected / exposed	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
alcoholic liver disease
subjects affected / exposed	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 2 (50.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Active Probiotic VSL#3	VSL#3 Placebo	Co-trimoxazole
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 4 (50.00%)	2 / 4 (50.00%)	0 / 2 (0.00%)
Surgical and medical procedures
Tooth extraction
subjects affected / exposed	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)
occurrences all number	1	0	0
Blood transfusion
subjects affected / exposed	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0
Gastrointestinal disorders
acid reflux
subjects affected / exposed	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0
constipation
subjects affected / exposed	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0
Abdominal discomfort
subjects affected / exposed	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
08 Oct 2014	The IMP was shipped to NUH at the end of 2013, however the IMP remained in quarantine in Pharmacy pending QP release certification to be issued from the manufacturer (VSL3). Numerous attempts were made to acquire the documentation to no avail and given this had been going on for nine months, the decision has come to close the trial. Premature discontinuation of the trial.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Due to premature discontinuation of the trial, a full analysis could not be performed.

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Clinical trials

Clinical Trial Results:
The effect of probiotics on the incidence of spontaneous bacterial peritonitis in patients with cirrhosis and ascites.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Liver related mortality

Primary: Liver related mortality

Primary: Liver related morbidity

Primary: Liver related morbidity

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: The effect of probiotics on the incidence of spontaneous bacterial peritonitis in patients with cirrhosis and ascites.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Liver related mortality

Primary: Liver related mortality

Primary: Liver related morbidity

Primary: Liver related morbidity

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
The effect of probiotics on the incidence of spontaneous bacterial peritonitis in patients with cirrhosis and ascites.