Study characteristics

Methods

Design: a prospective randomised trial with open allocation
A 2:1 randomisation to the treatment arm was performed
Trial duration: 60 days
Treatment duration: 60 days

Participants

Setting: outpatient single tertiary centre trial
Country: USA
Age range (years): 44 to 60
Total numbers randomised (group A/group B): 25 (17/8)
Sex (M/F): not stated
Language: English
Stage/severity of hepatic encephalopathy: Child‐Pugh score A/B/C: 22/3/0.

Cause of hepatic encephalopathy: non‐alcoholic aetiology of cirrhosis.

Inclusions: non‐alcoholic participants with cirrhosis with minimal hepatic encephalopathy. Defined by no alcohol intake within 3 months of the trial and a non‐alcoholic aetiology of cirrhosis.

Exclusions:

• Alcohol use within 3 months.                                

• Alcoholic aetiology of cirrhosis.                              

• Current psychoactive medication use.                 

• On current therapy for prevention or treatment of overt hepatic encephalopathy.

• Lack of English fluency.

• History of overt hepatic encephalopathy.

• Antibiotic use within 6 weeks of the trial.

• Diabetes mellitus.

Interventions

Treatment group (A) probiotic yogurt:

1. Streptococcus thermophilus (log 9 CFU/g on Day 0) for 60 days.

2. Lactobacillus bulgaricus (log 8.7 CFU/g on Day 0) for 60 days.

3. Lactobacillus acidophilus and Lactobacillus casei (log 5.9 CFU/g on Day 0) for 60 days.

4. Bifidobacteria (log 5.2 CFU/g on Day 0) for 60 days.

Participants received 12 ounces of yogurt a day.
The specific probiotic used in this yogurt was Yo‐Fast 88 manufactured by Chr‐Hansen Inc in Denmark.
Yogurt is manufactured by CC Jersey Crème, Spring Valley, Wisconsin.

Control group (B): no treatment.

Outcomes

1. Minimal hepatic encephalopathy reversal.

2. Overt hepatic encephalopathy development.

3. Adherence.

4. Child‐Pugh score.

5. MELD score.

6. SF‐36 score.

7. Venous ammonia.

8. IL‐6 and TNF‐alpha levels.

Notes

Contacted Professor JS Bajaj on 14 October 2010, who provided additional information.

Funding source: "The General Clinical Research Center at the Medical College of Wisconsin sponsored by the NIH supported this study". This study declared the funding source and was deemed to be independently funded.

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Low risk

Adequate sequence generation. A 2:1 randomisation was performed using a random numbers table.

Allocation concealment

High risk

The treatment allocation was not concealed from the principal investigator.

Blinding
Participants

High risk

Participants knew whether they were in the treatment group or the control group.

Blinding
Personnel

High risk

The investigator knew whether a participant was included in the treatment group or the control group.

Blinding
Outcome assessors

Low risk

The outcome scorer was blinded.

Incomplete outcome data
All outcomes

Low risk

3 out of 17 participants in the treatment group dropped out: 1 died from sepsis unrelated to the trial on day 67 but did not come to his first visit, and 2 did not like the taste and dropped out on days 13 and 17, respectively.

2 out of 8 participants in the control group dropped out; they developed OHE on days 22 and 35.

Primary analysis used an intention‐to‐treat approach.

Selective outcome reporting

Low risk

All outcomes mentioned in the methods (minimal hepatic encephalopathy reversal, overt hepatic encephalopathy development, and adherence) were described in the results at baseline, after 30 days, and after 60 days. Personal communication with the author revealed no other outcomes were assessed.

Funding source

Low risk

The General Clinical Research Center at the Medical College of Wisconsin sponsored by the NIH supported this study.

Study characteristics

Methods

Design: a parallel randomised trial

Trial duration: 8 weeks

Treatment duration: 8 weeks

Participants

Setting: outpatient clinic setting

Country: USA

Age range (years): inclusion criteria 18 to 65 years; mean age (SD) in treatment group 56.3 +/‐ 9.0, placebo group 58.4 +/‐ 4.3; range not specified

Total numbers randomised (treatment group/placebo group): 37 (18/19)

Sex (M/F): 25/12

Language: English

Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy, MELD score (mean +/‐ SD of intervention, control group: 8.6 +/‐ 2.2, 8.3 +/‐ 2.0)

Cause of hepatic encephalopathy: cirrhosis due to HCV, HCV + alcohol, alcohol, NASH, and other causes

Inclusions: "Patients with cirrhosis defined as having histological evidence or evidence with radiology and endoscopy of cirrhosis whose disease had been stable for 6 months without specific treatment changes, and were between the age range 18–65 were included."

Exclusions: "We excluded patients with an unclear diagnosis of cirrhosis, those who had consumed alcohol within 6 months, those with an upper gastrointestinal bleeding episode or need to be on systemic antibiotics within 6 weeks, those on current or past specific treatment for HE, with hepatocellular cancer, with yogurt/probiotic consumption within 2 weeks, those with inflammatory bowel disease, history of pancreatitis, psychoactive medication use (apart from chronic anti‐depressants), with a recent absolute neutrophil count <500/mm³ and those with liver transplant."

Interventions

Lactobacillus GG AT strain 53103, 3 batches of LGG and placebo were used. Each LGG batch had > 50 billion CFU/g (51, 61, and 53, respectively), without any other organisms. No live organisms were detected in the placebo batches.

Outcomes

1. Detection of LGG in stool.

2. Serum and urine metabolomics.

3. Cognition and QoL.

4. Adverse events and serious adverse event.

Notes

This study was carried out under the IND mechanism of Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA) (IND number BB13870).

Contacted Professor JS Bajaj on 14 March 2015, who provided additional information.

Funding source: "JSB received funding from NCCAM, NIH grant U01AT004428 for this trial. No other personal or funding interests exist. Writing and preparation of this paper was performed by the authors". This study declared the funding source and was deemed to be independently funded.

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Low risk

"Subjects were then randomised into placebo or LGG for 4 weeks using blocks of 4 created by the VCU Investigational Pharmacy using a random sequence generator."

Allocation concealment

Low risk

Treatment allocation only available to investigational pharmacy staff.

Blinding
Participants

Low risk

Participants were blinded.

Blinding
Personnel

Low risk

Personnel were blinded.

Blinding
Outcome assessors

Low risk

Outcome assessors were blinded.

Incomplete outcome data
All outcomes

Low risk

"Thirty‐seven patients were randomised. Two patients withdrew consent within the first month due to logistic reasons without any adverse events (both LGG group). One additional patient had to be scheduled for a splenic arterial embolisation for which he would need antibiotics and narcotics (LGG group) and was withdrawn before receiving medication. Four patients withdrew due to infections or other contraindications to continuation of the study [one broke her wrist and needed antibiotics (placebo), one had an asymptomatic urinary tract infection based on urine collected before randomisation with methicillin‐sensitive Staphylococcus aureus (placebo), two were found to have dental issues within a week of randomisation that needed antibiotics (one placebo and one LGG)]"

Selective outcome reporting

Unclear risk

"Blood was collected for MELD score, ammonia, serum albumin and pre‐albumin, and the dietician met with them to confirm continued adherence on the prescribed diet. If there were no adverse events requiring discontinuation, the subjects were re‐prescribed their medication for another 4 weeks. The end‐of‐drug visit was carried out 4 weeks later (8 weeks after drug initiation) where all procedures including physical examination, cognitive testing, HRQOL evaluation, dietary assessment, sample (blood, urine, stool) collection and evaluation of adherence and adverse events were performed."

Only information at the end of 8 weeks was reported.

Funding source

Low risk

"JSB received funding from NCCAM, NIH grant U01AT004428 for this trial. No other personal or funding interests exist. Writing and preparation of this paper was performed by the authors."

Study characteristics

Methods

Design: randomised parallel trial/double‐blind, randomised, placebo‐controlled study

Trial duration: 16 weeks

Treatment duration: 16 weeks

Participants

Setting: unspecified

Country: India

Age range (years): 45.5 to 52.5

Total numbers randomised: 80

Sex (M/F): 71/9

Language: unspecified

Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy

Cause of hepatic encephalopathy: unspecified

Inclusions: cirrhotics with MHE

Exclusions: unspecified

Interventions

40 participants received probiotic (1 sachet of VSL#3 (CD Pharma India Pvt. Ltd, New Delhi), at a dose of 900 billion bacteria daily, and 40 participants received placebo.

Outcomes

1. Reversal of MHE.

2. Figure connection test‐A.

3. Digit symbol test.

4. Plasma IL‐6.

5. Plasma oxindole.

6. Plasma ammonia.

7. MCS of SF‐36 HRQOL.

8. Adverse events/serious adverse event.

Notes

Clinical Trials Registry ‐ India /2008/091/000268

Contacted Professor RK Dhiman on 22 December 2014. Awaiting additional information from author.

Funding source: abstract only, unable to assess funding source

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Unclear risk

Abstract only, unable to assess

Allocation concealment

Unclear risk

Abstract only, unable to assess

Blinding
Participants

Unclear risk

Abstract only, unable to assess

Blinding
Personnel

Unclear risk

Abstract only, unable to assess

Blinding
Outcome assessors

Unclear risk

Abstract only, unable to assess

Incomplete outcome data
All outcomes

Unclear risk

Abstract only, unable to assess

Selective outcome reporting

Unclear risk

Abstract only, unable to assess

Funding source

Unclear risk

Abstract only, unable to assess

Study characteristics

Methods

Design: a parallel‐group randomised trial
Study duration: unknown
Treatment duration: 30 days

Participants

Setting: outpatient
Country: China
Age range (years): 43 to 69
Total numbers randomised (group A/group B/group C): 55 (20/20/15)
Group C was not relevant to our analysis.
Sex (M/F): 53/2
Language: English
Stage/severity of hepatic encephalopathy: Child‐Pugh score A/B+C: 8/47
Cause of hepatic encephalopathy: people with cirrhosis and hepatic encephalopathy without known precipitants of hepatic encephalopathy such as renal impairment, alcohol‐related hepatic encephalopathy, complicating hepatocellular carcinoma, etc.

Inclusions:

• Cirrhotic patients with minimal hepatic encephalopathy, without over hepatic encephalopathy.

• People who had been abstinent from alcohol for at least 2 months, as corroborated by family members or caregivers or both.

Exclusions:

• Histological features of alcoholic hepatitis.

• A history within the previous 6 weeks of factors including infection, treatment with antibiotics, lactulose or immunomodulatory drugs, and gastrointestinal haemorrhage.

• Other causes of reversible hepatic functional decompensation such as drug‐related hepatotoxicity and choledocholithiasis.

• Other known precipitants of hepatic encephalopathy, including renal impairment, electrolyte imbalance, and complicating hepatocellular carcinoma.

Interventions

Treatment group (A)
Oral supplementation with a synbiotic preparation containing Pediacoccus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei, and Lactobacillus plantarum (each probiotic at 10¹⁰ CFUs/day, total dose of probiotics in a day: 4 x 10¹⁰ CFUs) plus 10 g of bioactive fermentable fibre (2.5 g beta glucan, 2.5 g inulin, 2.5 g pectin, 2.5 g resistant starch) for 30 days.

Treatment group (B)
10 g of bioactive fermentable fibre (2.5 g beta glucan, 2.5 g inulin, 2.5 g pectin, 2.5 g resistant starch) for 30 days.

Control group (C)
Placebo (non‐fermentable fibre) for 30 days.

Outcomes

1. Faecal pH.

2. Venous ammonia levels.

3. Serum endotoxin levels.

4. Minimal hepatic encephalopathy status.

5. Child‐Pugh score.

6. Adverse events.

7. Overt hepatic encephalopathy development.

Notes

Contacted Dr Q Liu on 15 October 2010, received no response.

Funding source: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

High risk

1 sachet was randomly drawn from a pool for each participant, which is equivalent to drawing lots. We feel that this does not represent best practise for randomisation, and so have judged this category as high risk of bias according to our predefined criteria.

Allocation concealment

Low risk

Sachets were coded and contents unknown to investigators when drawn.

Blinding
Participants

Unclear risk

Not stated for participants

Blinding
Personnel

Unclear risk

Which sachets (A, B, or C) contained the synbiotic, fermentable fibre or non‐fermentable fibre preparations was unknown to the investigators until after the study had been completed and results had been analysed.

Blinding
Outcome assessors

Unclear risk

Not stated for outcome assessors

Incomplete outcome data
All outcomes

Unclear risk

Unclear from the study

Selective outcome reporting

Unclear risk

Unclear from the study

Funding source

Unclear risk

Not stated

Study characteristics

Methods

Design: a parallel‐group randomised trial
Study duration: 23 days
Treatment duration: 10 days

Participants

Setting: outpatient
Country: Italy
Age range (years): 25 to 68
Total numbers randomised (group A/group B): 40 (20/20)
Sex (M/F): 26/14
Language: English
Stage/severity of hepatic encephalopathy: grade I or II
Cause of hepatic encephalopathy: alcohol, hepatitis, cirrhosis

Inclusions: cirrhotic patients with non‐advanced hepatic encephalopathy (grade I or II).

Exclusions:

• HE degree > 2.

• Alcohol use at the moment of the study.

• Mental disorders or benzodiazepine use or both.

• Non‐compliance.

Interventions

Treatment group (A)
Enterococcus lactic acid bacteria strain SF68 (2 capsules, each containing 75 x 10⁶ CFUs, 3 times daily, for 10 days). Bioflorin is a trade name of Giuliani and is distributed by Gipharmex SpA, Italy.

Control group (B)
30 mL lactulose 4 times daily, for 10 days.

Outcomes

1. Mental state.

2. Bowel function.

3. Presence/absence abdominal pain.

4. Blood ammonia level.

5. Presence/absence meteorism.

6. Reitan's test (Number Connection Test).

7. Adverse events.

Notes

Additional information on 'Risk of bias' criteria provided by the author. Contacted Professor C Loguercio on 15 October 2010.

Funding source: "Gipharmex (Milan, Italy) supported this study". This study declared the funding source and was deemed to be industry funded.

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Unclear risk

Participants were randomly assigned to a treatment group. No further information about randomisation

Allocation concealment

Unclear risk

Information not provided

Blinding
Participants

Low risk

Participants were blinded.

Blinding
Personnel

Low risk

Personnel were blinded.

Blinding
Outcome assessors

Low risk

The outcome scorer was blinded.

Incomplete outcome data
All outcomes

High risk

All participants completed the treatment period. 5 participants given lactulose and 4 given Enterococcus SF68 did not arrive for post‐treatment follow‐up. On day 15, 2 participants given lactulose were withdrawn from the study because of marked hyperammonaemia and a worsening of hepatic encephalopathy.

Selective outcome reporting

Unclear risk

Unclear from study

Funding source

High risk

Gipharmex (Milan, Italy) supported this study.

Study characteristics

Methods

Design: randomised parallel trial

Trial duration: 18 weeks

Treatment duration: 3 periods of 4 weeks

Participants

Setting: outpatient setting

Country: Italy

Age range (years): 41 to 76

Total numbers randomised: 40

Sex (M/F): 26/14

Language: unspecified

Stage/severity of hepatic encephalopathy: grade 1 to 2 hepatic encephalopathy

Cause of hepatic encephalopathy: alcoholic/other: 21/19

Inclusions: "Forty patients with cirrhosis, with low grade 1‐2 hepatic encephalopathy of the chronic recurrent type and ammonia plasma levels above 59 uM (normal values: < 44 uM) were considered suitable for the study."

Exclusions: "Exclusion criteria in the selection of patients included the presence of one of these pathologies: grade 3‐4 hepatic encephalopathy, ascites that needed treatment with furosemide, alcohol abuse or recent abstinence (<6 months), liver tumour, and hepatorenal syndrome. We also excluded patients with severe sight disorders, colour blindness, alterations of the eye fundus and disorders of the anterior segment."

Interventions

Participants entered a 15‐day run‐in period. 1 group of participants took, after main meals, 2 capsules containing a total of 150 million Enterococcus faecium strain SF68 3 times a day for 4 weeks; the participants in the lactulose treatment branch ingested, after main meals, 30 mL (20 g) oral lactulose 3 times a day for the same time span. The treatment was repeated for three 4‐week periods, each separated by a 2‐week wash‐out interval. During the 2‐week wash‐out period participants were treated as during the run‐in period.

Outcomes

1. Arterial ammonia concentration.

2. NCT score.

3. Mental state.

4. Encephalopathy Global Score.

5. Flash evoked visual potentials.

Notes

Contacted Professor C Loguercio on 7 June 2015, received no response.

Funding source: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Low risk

"After the basal evaluation, the patients enrolled in the study were assigned to one of two treatments according the Broc Plan computerised randomisation scheme (kindly provided by the Biometrics Division of Bracco SPA)."

Allocation concealment

Low risk

Computer randomisation was provided by external providers.

Blinding
Participants

Unclear risk

Unclear from the study

Blinding
Personnel

Unclear risk

Unclear from the study

Blinding
Outcome assessors

Unclear risk

Unclear from the study

Incomplete outcome data
All outcomes

High risk

21 participants were initially randomised to SF68 and 19 to lactulose group.

"Seven patients in the lactulose group interrupted the treatment: one because of diarrhoea and fever during the second period, two because of drug intolerance with diarrhoea (one during the second period and one during the third period), and four because of deterioration of the neurological state (one during the first period, two during the first wash‐out period, and one during the second period). Therefore, only 14 patients treated with SF68 and 11 treated with lactulose completed the study."

Selective outcome reporting

Unclear risk

Unclear from the study

Funding source

Unclear risk

Unclear from the study

Study characteristics

Methods

Design: parallel randomised trial

Trial duration: mean follow‐up of group 1 participants was 38.6 ± 8.80 weeks and group 2 participants was 34.3 ± 9.8 weeks

Treatment duration: 3 months

Participants

Setting: unspecified

Country: India

Age range (years): range unspecified, mean (SD): 46.6 (13.1)

Total numbers randomised: 81

Sex (M/F): 47/28

Language: unspecified

Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy

Cause of hepatic encephalopathy: unspecified in abstract

Inclusions: unspecified in abstract

Exclusions: unspecified in abstract

Interventions

Cirrhotic patients with MHE were divided into: group 1 (probiotics, n = 42, VSL#3) and group 2 (control, n = 39).

Outcomes

All participants underwent psychometric tests, critical flicker frequency, glucose hydrogen breath test for SIBO and lactulose hydrogen breath test for OCTT.
Primary endpoint was reversal of MHE.
Mortality.
Arterial ammonia.
Small intestinal bowel overgrowth.
Orocaecal transit time.

Notes

Contacted Dr Manish Lunia on 22 December 2014. Awaiting additional information from author.

Funding source: abstract only, unable to assess funding source

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Unclear risk

Abstract only, unable to assess

Allocation concealment

Unclear risk

Abstract only, unable to assess

Blinding
Participants

Unclear risk

Abstract only, unable to assess

Blinding
Personnel

Unclear risk

Abstract only, unable to assess

Blinding
Outcome assessors

Unclear risk

Abstract only, unable to assess

Incomplete outcome data
All outcomes

Unclear risk

Abstract only, unable to assess

Selective outcome reporting

Unclear risk

Abstract only, unable to assess

Funding source

Unclear risk

Abstract only, unable to assess

Study characteristics

Methods

Design: a double‐blind, parallel‐group randomised trial
Study duration: 2004 to 2007
Treatment duration: 60 days

Participants

Setting: inpatient
Country: Italy
Age range (years): not stated
Total numbers randomised (group A/group B): 125 (63/62)
Sex (M/F): 62/63
Language: English
Stage/severity of hepatic encephalopathy: Child‐Pugh score A/B/C: 46/59/20
Cause of hepatic encephalopathy: chronic hepatitis and cryptogenic cirrhosis with spontaneous hepatic encephalopathy

Inclusions:

• Chronic hepatitis with spontaneous manifest hepatic encephalopathy (mental state grade I or II according to the West Haven criteria) and a Number Collection Test‐A performance time > 30 seconds.

• Hyperammonaemia (venous ammonia concentration > 50 mmol/L).

• Co‐operative, hospitalised, adult patients with liver cirrhosis diagnosed by clinical, histological, and ultrasonographic findings (reduced dimensions of the liver as well as splenomegaly) and oesophageal varices (stages II or III) observed by endoscopy.

Exclusions:

• Major complications of portal hypertension, such as gastrointestinal blood loss, hepatorenal syndrome, or bacterial peritonitis.

• Acute superimposed liver injury.

• Other neurological disease and metabolic disorders such as alcoholism, diabetes mellitus, unbalanced heart failure and/or respiratory failure or end‐stage renal disease.

• Severe hepatic encephalopathy (mental state grade III to IV).

• Administration of anti‐hepatic encephalopathy medications such as neomycin, branched‐chain amino acids.

• Any additional precipitating factors such as high protein intake (additional high‐protein meals), constipation, or intake of psychostimulants, sedatives, antidepressants, benzodiazepines or benzodiazepines antagonists (flumazenil).

• Fever, sepsis, or shock were also excluded to avoid variations caused by body temperature.

Interventions

Treatment group (A)
Bifidobacterium (subtype not stated) + (FOS) fructo‐oligosaccharides for 60 days (dose not stated).

Control group (B)
Lactulose for 60 days (dose not stated).

Note: FOS and lactulose were considered comparable because they are both complex carbohydrates, which are indigestible to humans but digestible to bacteria. We were unable to locate any efficacy data comparing FOS to lactulose in people with hepatic encephalopathy.

Outcomes

1. Trail Making Test.

2. Cognitive functions.

3. Grade of hepatic encephalopathy.

4. Child‐Pugh score.

Notes

Contacted Dr M Malaguarnera on 15 October 2010, received no response.

Funding source: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Low risk

Randomisation was based on a computer‐generated list.

Allocation concealment

Unclear risk

Unclear from study

Blinding
Participants

Unclear risk

Stated it was a double‐blind trial, but not for whom.

Blinding
Personnel

Unclear risk

Stated it was a double‐blind trial, but not for whom.

Blinding
Outcome assessors

Unclear risk

Not stated for outcome assessors

Incomplete outcome data
All outcomes

Unclear risk

Unclear from study

Selective outcome reporting

Unclear risk

Unclear from study

Funding source

Unclear risk

Not stated

Study characteristics

Methods

Design: a parallel randomised trial
Study duration: October 2007 to October 2009
Treatment duration: 3 months

Participants

Setting: outpatient
Country: India
Age range (years): 32 to 54
Total numbers randomised (group A/group B/group C/group D): 160 (40/40/40/40)
We did not use group B and D in our analysis, as these were not useful to compare to probiotics.
Sex (M/F): 123/37
Language: English
Stage/severity of hepatic encephalopathy: not stated
Cause of hepatic encephalopathy: cirrhosis due to alcoholic liver disease, hepatitis B, hepatitis C, or other causes

Inclusions: people with cirrhosis who have minimal hepatic encephalopathy, diagnosed by 2 or more abnormal (+2SD from the mean) psychometric tests.

Exclusions:

• Overt HE based on detailed neurological examination or history of overt HE in past 6 weeks.

• Recent history (< 6 wk) of gastrointestinal bleed.

• Active ongoing infection.

• Renal impairment with serum creatinine > 1.5 mg %.

• Electrolyte impairment (serum sodium < 130 or > 150 meq/dL, serum potassium < 3.0 or > 5.5 meq/dL).

• Recent alcohol use (< 6 wk) as reported by the person, recent use of antibiotic, lactulose, or LOLA (< 6 wk), use of psychotropic drugs in last 6 weeks.

• TIPS, shunt surgery.

• Hepatocellular carcinoma.

• Severe comorbidity such as congestive heart failure, pulmonary disease, neurological and psychiatric problems impairing quality of life, or poor vision precluding neuropsychiatric assessment.

Interventions

Control group (A)
No treatment.

Treatment group (B)
30 mL to 60 mL lactulose twice daily for 3 months.

Treatment group (C)
VSL#3 (containing Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus) 110 billion CFUs twice daily for 3 months.

Treatment group (D)
6 g (LOLA) L‐ornithine L‐aspartate 3 times daily for 3 months.

Outcomes

1. Minimal hepatic encephalopathy recovery.

2. Minimal hepatic encephalopathy improvement.

3. Arterial ammonia level.

4. Development of overt hepatic encephalopathy.

5. Sickness Impact Profile Score (quality of life).

Notes

Author provided additional information on 'Risk of bias' criteria. Contacted Professor BC Sharma on 14 October 2010.
Author provided unpublished data.

Funding source: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Low risk

Participants were randomised to 1 of the treatment groups using computer‐generated random tables.

Allocation concealment

Low risk

"The sequences were concealed until a decision to enrol a patient was taken after assessment for eligibility and after receiving informed consent."

Blinding
Participants

High risk

Different way of administering for every treatment, therefore participants knew which treatment they had received.

Blinding
Personnel

High risk

Compliance was assessed primarily using pill and bottle count, therefore blinding was not possible.

Blinding
Outcome assessors

High risk

Compliance was assessed primarily using pill and bottle count, therefore blinding was not possible.

Incomplete outcome data
All outcomes

Unclear risk

11 participants were lost to follow‐up, 3 from group A, 1 from group B, 3 from group C, and 4 from group D. During treatment, 7 participants had to be admitted to the hospital for causes other than overt hepatic encephalopathy. Of these 7 participants, 2 participants died, 1 each in group A and D.

Primary analysis used an intention‐to‐treat approach, probably with imputation.

Selective outcome reporting

Unclear risk

Unclear from the trial

Funding source

Unclear risk

Not stated

Study characteristics

Methods

Design: randomised controlled trial

Trial duration: 2 months

Treatment duration: 2 months

Participants

Setting: tertiary care medical centre

Country: India

Age range (years): range unspecified, mean (SD): lactulose group 44.2 (10.4); probiotic group 39.6 (11.4)

Total numbers randomised: 120

Sex (M/F): 110/10

Language: English

Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy; CTP (A/B/C): probiotics group (14/24/22); lactulose group (15/30/15)

Cause of hepatic encephalopathy: alcoholic/viral/other: probiotics group (24/24/12); lactulose group (21/24/15)

Inclusions: The inclusion criterion was the diagnosis of MHE in people with cirrhosis aged between 15 and 80 years.

Exclusions: "The exclusion criteria were: history of overt HE in the past 6 weeks; history of intake of lactulose or probiotics or antibiotics within the past 6 weeks; presence of any other neurological or psychiatric diseases; history of undergoing shunt surgery or transjugular intrahepatic portosystemic shunt for portal hypertension; currently on medications which were likely to interfere with psychometric performance; history of alcohol intake during the past 6 weeks; history of gastrointestinal bleeding or spontaneous bacterial peritonitis in the past 6 weeks; presence of hepatocellular carcinoma, renal failure or portal vein thrombosis; presence of significant co‐morbidities such as diabetes, congestive heart failure, chronic respiratory disease, chronic kidney disease or malignancy; and visual impairment and refusal for consent."

Interventions

Participants were randomised to receive either lactulose (Lark Laboratories; Rajasthan, India) or probiotics (VSL#3; Sun Pharmaceutical, Mumbai, India) for a period of 2 months. Lactulose was given at a dose of 30 to 60 mL/day orally to ensure 2 to 3 soft stools per day. VSL#3 was given at a dose of 4 capsules (2 twice a day) per day, amounting to a total of 450 billion CFU/day; each capsule contained 112.5 billion viable lyophilised bacteria of 4 strains of Lactobacillus (L acidophilus DSM 24735, L plantarum DSM 24730, L paracasei DSM 24733, L delbrueckii subsp. bulgaricus DSM 24734), 3 strains of Bifidobacterium (B longum DSM 24736, B breve DSM 24732, B infantis DSM 24737), and 1 strain of Streptococcus (S thermophilus DSM 24731).

Outcomes

The primary outcome measure was improvement of MHE, which was defined as the normalisation of the prior abnormal neuropsychometric/neurophysiological tests. The secondary outcome measure was change in venous ammonia level with study intervention. The study endpoints were: (i) completion of 2 months of treatment; (ii) development of overt HE; and (iii) death.

Notes

Trial ID: NCT01008293

Contacted Dr VP Mouli on 14 March 2015, received no response.

Funding source: "We thank the Indian Council of Medical Research (ICMR) for providing a research grant and CD Pharmaceuticals India for providing probiotic VSL#3 and lactulose". This study declared the funding source and was deemed to be independently funded.

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Low risk

"Block randomization was used to allocate the patients to lactulose and probiotics groups. The random numbers were generated using Stata software (StataCorp, College Station, TX, USA)."

Allocation concealment

Low risk

"Allocation of the patients to receive the study intervention drugs was done by using the sequentially numbered, opaque, sealed envelope method. The envelopes were prepared by a statistician not associated with the conduct of the study, and were opened sequentially only after the patient’s name, age and sex were written on them by a person not associated with the study."

Blinding
Participants

High risk

The study was limited by being an open‐label trial with a relatively small sample size with a short period of intervention. Blinding was not possible due to the differences in physical state between the drugs.

Blinding
Personnel

High risk

The study was limited by being an open‐label trial with a relatively small sample size with a short period of intervention. Blinding was not possible due to the differences in physical state between the drugs.

Blinding
Outcome assessors

Low risk

The objective nature of the tests for MHE would likely limit the effect of bias on MHE recovery outcomes and venous ammonia.

Incomplete outcome data
All outcomes

Unclear risk

"60 patients each were randomized into the lactulose and probiotics groups. Four patients were dropouts and 19 were lost to follow up, two patients died and 22 developed overt encephalopathy, and hence discontinued with the trial drugs due to different management protocols for overt HE. At the end of intervention (i.e. at 2 months), 40 patients in the lactulose group and 33 patients in the probiotics group were taken for analysis who had completed the study medications."

Selective outcome reporting

Low risk

Outcomes were reported as per protocol found registered at ClinicalTrials.gov identifier NCT01008293.

Funding source

Low risk

"We thank the Indian Council of Medical Research (ICMR) for providing a research grant and CD Pharmaceuticals India for providing probiotic VSL#3 and lactulose".

Study characteristics

Methods

Design: randomised controlled trial

Trial duration: September 2006 to March 2007 (7 months)

Treatment duration: 4 weeks

Participants

Setting: Study was conducted in Department of Neurology, Medical College Calicut, in collaboration with Department of Gastroenterology.

Country: India

Age range (years): range unspecified, mean 49.5 ± 8.05 SD

Total numbers randomised: 40

Sex (M/F): M:F ratio 1:0.05

Language: English

Stage/severity of hepatic encephalopathy: MHE (Child A 14, Child B 26)

Cause of hepatic encephalopathy: alcohol 29, cryptogenic 10, HBV‐related 1

Inclusions:

• Cirrhosis diagnosed by clinical/USG/biopsy.

• Minimal hepatic encephalopathy diagnosed by Number Connection Test‐A and evoked response tests ‐ auditory and visual.

Exclusions:

• Clinically evident hepatic encephalopathy.

• Neurological diseases.

• Alcohol‐free period of less than 2 months.

• Coexistent gastrointestinal haemorrhage.

• Renal impairment and electrolyte disturbances.

• Severe visual or auditory abnormalities.

Interventions

Group A was given probiotic preparation in a dose of 1‐gram sachet containing not less than 1.25 billion cells of Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum, and Saccharomyces boulardii 3 times daily after meals, and group B was given placebo powder in identically looking sachet in a similar dose.

Outcomes

Number Connection Test‐A, arterial ammonia, auditory evoked response tests, visual evoked response tests

Notes

Contacted Dr R Nair on 22 December 2014, full manuscript provided, awaiting additional information from author.

Funding source: "Sachets of drug as well as placebo were supplied by Aristo pharmaceuticals Pvt. Ltd. No financial aid of any form was received from any source for the purpose of conducting this trial". This study declared the funding source and was deemed to be independently funded.

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Low risk

Randomisation was done using random table allocation.

Allocation concealment

Low risk

Treatment allocation was concealed from individual who did the allocation.

Blinding
Participants

Low risk

"The patients, examiners and investigators were blinded as to who is receiving the drug and who receives placebo".

Blinding
Personnel

Low risk

"The patients, examiners and investigators were blinded as to who is receiving the drug and who receives placebo".

Blinding
Outcome assessors

Low risk

"The patients, examiners and investigators were blinded as to who is receiving the drug and who receives placebo".

Incomplete outcome data
All outcomes

Low risk

1 dropout in group A and 2 dropouts in group B;

"There were 3 drop outs (Group A ‐ 1, Group B ‐ 2) – one in group A was lost to follow up, so was one in group B. Second patient in Group B decided to withdraw from study due to personal reasons."

Selective outcome reporting

Unclear risk

Unable to assess

Funding source

Low risk

Sachets of drug as well as placebo were supplied by Aristo Pharmaceuticals Pvt. Ltd.

No financial aid of any form was received from any source for the purpose of conducting this trial.

Study characteristics

Methods

Design: a parallel randomised trial
Study duration: unclear
Treatment duration: 6 months

Participants

Setting: outpatient
Country: Israel
Age range (years): 53 to 74
Total numbers randomised (group A/group B): 40 (20/20)
Sex (M/F): unclear
Language: English
Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy
Cause of hepatic encephalopathy: cirrhosis due to alcoholic liver disease, hepatitis B, hepatitis C, or other causes

Inclusions: people with liver cirrhosis and at least 1 major complication of cirrhosis in the past, clinical evidence of portal hypertension, or decreased hepatic synthetic function.

Exclusions:

• Any sign of decompensation from any precipitant including gastrointestinal bleeding, infections, acute renal failure, electrolyte impairment, or hepatocellular carcinoma.

• Those chronically treated with antibiotics or lactulose.

• People with alcoholic cirrhosis, for whom alcohol abstinence for at least 2 months prior to enrolment could not be confirmed.

Interventions

Control group (A)
Wheat‐based non‐fermentable fiber placebo.

Treatment group (B)
Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium bifidum, and Streptococcus thermophilus (Bio Plus, Supherb, Israel), each at a daily dose of 2 x 10¹⁰ CFUs.

Outcomes

1. Plasma ammonia.

2. Adverse events.

Notes

The study was registered in ClinicalTrials.gov (ID: NCT00312910).

Funding source: "Supported by Supherb Ltd, Israel". This study declared the funding source and was deemed to be industry funded.

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Unclear risk

Not stated

Allocation concealment

Unclear risk

Not stated

Blinding
Participants

Unclear risk

Only stated in the title that the trial was double‐blinded ‐ no specific details provided on who was blinded or how blinding was conducted.

Blinding
Personnel

Unclear risk

Only stated in the title that the trial was double‐blinded ‐ no specific details provided on who was blinded or how blinding was conducted.

Blinding
Outcome assessors

Unclear risk

Only stated in the title that the trial was double‐blinded ‐ no specific details provided on who was blinded or how blinding was conducted.

Incomplete outcome data
All outcomes

High risk

Four participants "dropped out", no further details provided.

Selective outcome reporting

Unclear risk

Unclear from the trial

Funding source

High risk

Supported by Supherb Ltd, Israel.

Study characteristics

Methods

Design: randomised controlled trial

Trial duration: There was a follow‐up every 1to 2 weeks until treatment ended in which the incidence of hepatic encephalopathy was recorded.

Treatment duration: Treatment lasted for 24 weeks, and there was a follow‐up every 1 to 2 weeks until treatment ended in which the incidence of hepatic encephalopathy was recorded.

Participants

Setting: Laiyang Central Hospital, Yantai

Country: China

Age range (years): age range from 37 to 70, average age was 53.4

Total numbers randomised: 64

Sex (M/F): of the 64 participants, 51 were male and 13 were female

Language: Mandarin

Stage/severity of hepatic encephalopathy: diagnosed with subclinical hepatic encephalopathy (SHE) and recruited for this study after intelligence testing

Cause of hepatic encephalopathy: 54 cases were cirrhosis from hepatitis B, 6 cases were alcoholic cirrhosis, 1 case was primary biliary cirrhosis, 1 case was Budd‐Chiari syndrome, and 2 cases were of unknown cause.

Inclusions: "Inclusion criteria: between August 2004 and August 2008, of all the patients diagnosed with cirrhosis, 64 of them we diagnosed with SHE and recruited for this study after intelligence testing. Cirrhosis diagnosis was based on history, clinical assessment, laboratory findings, ultrasound, and CT scan investigations."

Exclusions: "Exclusion criteria:

1. Currently or previously diagnosed with hepatic encephalopathy.

2. Patients with psychological or neurological disease.

3. Use of any sedatives or CNS depressants in the past 4 weeks.

4. Any GI bleeding, electrolyte/acid‐base disturbances in the past 2 weeks.

5. Patients with alcoholic cirrhosis and continue to drink alcohol."

Interventions

Control group was given compound vitamin B tablets, 2 tablets each time, 3 times a day. Treatment group was given bifid triple viable, 2 tablets each time, 3 times a day.

Outcomes

Outcome measurements: Blood ammonium, ALT, and NCT were measured 1 day before treatment and again 1 day after treatment. NCT used the NCT‐A version, where the patient orders the numbers 1 to 25 and the time it takes to complete the test is recorded, including time spent correcting any mistakes. NCT was measured in seconds; longer time to complete indicates abnormality.

Notes

We could not find author contact details.

Funding source: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Unclear risk

Unclear from the trial

Allocation concealment

Unclear risk

Unclear from the trial

Blinding
Participants

Unclear risk

Unclear from the trial

Blinding
Personnel

Unclear risk

Unclear from the trial

Blinding
Outcome assessors

Unclear risk

Unclear from the trial

Incomplete outcome data
All outcomes

Unclear risk

Unclear from the trial

Selective outcome reporting

Unclear risk

Unclear from the trial

Funding source

Unclear risk

Unclear from the trial

Study characteristics

Methods

Design: a parallel randomised trial/randomised double‐blind, placebo‐controlled trial

Trial duration: 4 weeks

Treatment duration: 4 weeks

Participants

Setting: unclear

Country: India

Age range (years): range unclear, mean age (SD) treatment group/placebo group: 50.6 (5.81)/52.15 (0.18)

Total numbers randomised: total (probiotic/placebo): 43 (21/22)

Sex (M/F): 37/3 excluding dropouts

Language: unspecified

Stage/severity of hepatic encephalopathy: stable cirrhotics in Child’s grade A and B (diagnosed clinically, by ultrasonography or biopsy) with minimal hepatic encephalopathy diagnosed by NCT and evoked responses

Cause of hepatic encephalopathy: Aetiology of cirrhosis was alcohol in the majority of participants (34/40). Other causes included hepatitis B in 2 participants, hepatitis C in 1 participant, and cryptogenic in 3 participants.

Inclusions: Stable cirrhotics in Child’s grade A and B (diagnosed clinically, by ultrasonography or biopsy) and having minimal hepatic encephalopathy as per the NCT‐A and evoked responses (auditory and visual) were included.

Exclusions: "Those with clinically evident hepatic encephalopathy, neurological disease, alcohol free period of less than 2 months, coexistent gastrointestinal hemorrhage, renal impairment, electrolyte disturbances and those with severe visual or auditory abnormalities were excluded from the study."

Interventions

Group A received probiotic preparation in a dose of 1‐gram sachet containing not less than 1.25 billion spores of Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum, and Saccharomyces boulardii, 3 times daily after meals. Group B received placebo powder in identical‐looking sachet 3 times daily after meals. The duration of treatment was 4 weeks.

Outcomes

At the end of 4 weeks, participants' symptoms were recorded and a thorough examination was done for any features of overt encephalopathy. Investigations were done to reassess the Child’s score. Arterial ammonia, NCT –A, and evoked responses were repeated.

Notes

Both sachets of probiotics and placebo were supplied by Aristo Pharmaceuticals Pvt. Ltd Mumbai.

Contacted Dr S Saji on 14 March 2015, awaiting additional information from author.

Funding source: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Low risk

"Randomization was done using random table allocation."

Allocation concealment

Unclear risk

Unclear from study

Blinding
Participants

Low risk

"Group B received placebo powder in identical looking sachet".

Blinding
Personnel

Unclear risk

"The patients were randomized to two groups and the drugs were administered in a double blind fashion."

Blinding
Outcome assessors

Low risk

Unclear from study, although the objective nature of the tests for MHE would likely limit the effect of bias on MHE recovery outcomes and venous ammonia.

Incomplete outcome data
All outcomes

Low risk

"There were 3 drop‐outs, one in the probiotic group and two in the placebo group."

"The data reported are only for the intent‐to‐treat population."

Selective outcome reporting

Low risk

"At the end of 4 weeks patients symptoms were recorded and a thorough examination was done for any features of overt encephalopathy. Investigations were done to reassess the Child’s score. Arterial ammonia, number connection test–A and evoked responses were repeated."

All of the above outcomes except the Child's score were reported.

Funding source

Unclear risk

"Sachets of probiotics as well as placebo were supplied by Aristo pharmaceuticals Pvt. Ltd Mumbai."

Study characteristics

Methods

Design: open‐label randomised trial
Treatment duration: 1 month
Time period: February 2005 to August 2006

Participants

Setting: India
Age range (years): 30 to 54
Total numbers randomised (group A/group B/group C): 105 (35/35/35)
Sex (M/F): 79/26
Language: English
Stage/severity of hepatic encephalopathy: Child‐Pugh score A/B/C: 36/39/30
Cause of hepatic encephalopathy: cirrhosis due to alcohol consumption, chronic hepatitis, and cryptogenic cirrhosis.

Inclusions: cirrhotic patients with minimal hepatic encephalopathy without overt encephalopathy.

Exclusions:

• The presence of overt hepatic encephalopathy or history of hepatic encephalopathy.

• History of taking lactulose or any antibiotics.

• Alcohol intake.                         

• Gastrointestinal haemorrhage or spontaneous bacterial peritonitis during the past 6 weeks.

• Earlier transjugular intrahepatic portosystemic shunt or shunt surgery.

• Significant comorbid illness such as heart failure, respiratory failure, or renal failure.

• Any neurologic diseases such as Alzheimer’s disease, Parkinson’s disease, and non‐hepatic metabolic encephalopathies.

• Colour blindness and mature cataract, diabetic retinopathy, and people on psychoactive drugs such as antidepressants or sedatives.

Interventions

Control group (A)
30 mL to 60 mL lactulose/day for 1 month.

Treatment group (B)
1 capsule (containing Enterococcus faecalis, Clostridium butyricum, Bacillus mesentericus, Lactic acid Bacillus) 3 times daily for 1 month, dose not stated.

Treatment group (C)
30 mL to 60 mL lactulose plus probiotics daily for 1 month.

Outcomes

1. Venous ammonia level.

2. Child‐Pugh score.

3. Minimal hepatic encephalopathy recovery.

Notes

Additional information provided by the author. Contacted Professor BC Sharma on 14 October 2010.

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Low risk

Participants were randomised according to a computer‐generated randomisation chart.

Allocation concealment

High risk

Trial personnel were able to view the allocation sequence.

Blinding
Participants

High risk

The trial was not blinded.

Blinding
Personnel

High risk

The trial was not blinded.

Blinding
Outcome assessors

High risk

The trial was not blinded.

Incomplete outcome data
All outcomes

High risk

13 participants in the control group and 5 participants in the lactulose plus probiotic group were lost to follow‐up. Reasons are unclear.

Selective outcome reporting

Low risk

All outcomes reported in the methods (psychometric tests outcomes, P300 auditory event‐related potential, venous ammonia level, and Child‐Pugh classification) were measured and discussed on baseline and after 1 month. Personal communication with the author revealed that no other outcomes were assessed.

Funding source

Unclear risk

Not stated

Study characteristics

Methods

Design: a randomised parallel study

Trial duration: 2 months

Treatment duration: Duration of the treatment was 2 months ± 3 days, or unless the participant developed overt encephalopathy, expired, or was lost to follow‑up.

Participants

Setting: Department of Gastroenterology at a teaching hospital

Country: India

Age range (years): range unspecified, mean (SD): 39.1 (12.8)

Total numbers randomised: 124

Sex (M/F): 77/47

Language: unspecified

Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy by psychometric tests (NCT‑A, FCT‑A, and DST) and critical flicker frequency (CFF); CTP A/B/C: 35/52/37

Cause of hepatic encephalopathy: anti‐HCV positive/HBsAg positive/history of ethanol: 17/30/34

Inclusions: A total of 317 cirrhotics were screened; 111 were excluded, and the remaining 206 cirrhotics were screened for MHE using NPTs or CFF test or both.

Exclusions: The exclusion criteria included:

• People with overt HE or a history of overt HE in the past 6 weeks.

• History of alcohol intake during past 6 weeks.

• History of antibiotic or lactulose or probiotics use within the past 3 weeks.

• Gastrointestinal bleed in the past 6 weeks.

• History of recent use of drugs (< 6 weeks) affecting psychometric performance such as antidepressants, antiepileptic, sedatives, psychotropic drugs.

• Spontaneous bacterial peritonitis or other infection in the past 7 days.

• Renal insufficiency with creatinine > 1.5 mg/dL.

• Electrolyte imbalance.

• Hepatocellular carcinoma.

• Significant comorbid illness, such as heart, respiratory, or renal failure; and any neurological disease that could interfere with intellect or motor performance of the person such as Alzheimer’s or Parkinson’s disease, respectively, or non‐hepatic metabolic encephalopathies.

• Previous transjugular intrahepatic portosystemic shunt or shunt surgery.

• People who restarted alcohol consumption during follow‐up.

• Inability to do psychometric tests due to poor vision, or those having colour blindness.

• People not having a fair knowledge of numbers and not having been to school for at least 2 years.

• Women who were pregnant.

Interventions

After the diagnosis of MHE was made, the participants were randomised into 4 groups: DRUG 1 (l‐ornithine l‐aspartate (LOLA), 2 sachets 3 g each thrice a day) n = 31, DRUG 2 (tab rifaximin 400 mg thrice a day) n = 31, DRUG 3 (cap Velgut (5 billion CFUs of Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus rhamnosus, Streptococcus thermophilus, Saccharomyces boulardii)1 capsule twice a day) n = 32, and DRUG 4 (placebo twice a day) n = 30.

Outcomes

1. Death.

2. Recovery from MHE.

3. Overt HE.

4. CFF.

Notes

Contacted Dr K Sharma on 14 March 2015, received no response.

Funding source: "Source of Support: Nil, Conflict of Interest: None declared". This study declared the funding source and was deemed to be independently funded.

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Low risk

"the block randomization method was utilized for random allocation of drugs."

Allocation concealment

Low risk

"The sequence remained concealed from the investigator and the generator of the random blocks did not participate in screening, enrolment, or drug delivery."

Blinding
Participants

High risk

The study was not blinded.

Blinding
Personnel

High risk

The study was not blinded.

Blinding
Outcome assessors

High risk

The study was not blinded.

Incomplete outcome data
All outcomes

Unclear risk

A total of 20 participants could not be followed up to the end of the study: 10 were lost to follow‐up, 6 went into overt HE, and 4 expired. Of the total 10 participants lost to follow‐up, the most were in the LOLA group (4 cases) followed by the placebo group (3 cases). The largest number of deteriorations in clinical state, i.e. development of overt HE, occurred in the placebo group (3 cases). Of the total 4 deaths, 2 were in the placebo group and 1 each was in the rifaximin and Velgut groups. There were no deaths in the LOLA group.

Selective outcome reporting

Unclear risk

"Maximal number of deteriorations in clinical state, that is, development of overt HE among patients occurred in the placebo (3 cases) group."

Overt HE development was not well reported.

Funding source

Low risk

"Source of Support: Nil, Conflict of Interest: None declared."

Study characteristics

Methods

Design: randomised parallel trial + non‐randomised cohort study

Trial duration: 10 weeks

Treatment duration: 2 weeks

Participants

Setting: The study was conducted on adults with MHE referred consecutively to the gastroenterology clinic of a university hospital in Isfahan city (Iran) between June and October 2012.

Country: Iran

Age range (years): range not given, mean age (SD) 38.4 (9.6) years

Total numbers randomised: total (Gp‐LPr/Gp‐L): 46 (23/23)

Sex (M/F): 48/12

Language: unspecified

Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy; Child‐Pugh score A/B/C: 8/37/14 (data missing for 1 participant)

Cause of hepatic encephalopathy: viral/autoimmune/other: 44/11/5

Inclusions: The study was conducted on adults with MHE referred consecutively to the gastroenterology clinic of a university hospital in Isfahan city (Iran) between June and October 2012. Cirrhosis was diagnosed histologically (unless biopsy was contraindicated) and on clinical and radiological grounds. Diagnosis of MHE was based on the Conn’s modification of the Parsons‐Smith classification (grade 1 and above).

Exclusions: People with overt HE, known brain lesions, active gastrointestinal bleeding, active ongoing infection, renal impairment (serum creatinine > 2 mg/dL), electrolyte abnormalities (serum sodium < 130 or > 150 meq/dL, serum potassium < 3.0 or > 5.5 meq/dL), and those who had received HE treatments such as lactulose and antibiotics or consumed benzodiazepines, narcotics, opioids, or alcohol in the preceding 8 weeks were not included in the trial.

Interventions

Participants were randomised into 2 groups: lactulose + probiotic (Gp‐LPr) and lactulose + placebo (Gp‐L). Another non‐randomised group of participants who received probiotic alone (Gp‐Pr) were included separately for further comparisons; this group received neither placebo nor lactulose.
All participants received routine treatment for cirrhosis, including diuretics, β‐blockers, endoscopic treatment, and a salt‐restricted diet but not protein‐restricted diet in those with ascites. For Gp‐LPr and Gp‐L, lactulose syrup was administered as 30 to 60 mL/day in divided doses for a stool frequency of 2 to 3 soft defecations per day. For Gp‐LPr and Gp‐Pr, a multistrain probiotics compound, Balance (Protexin Co., Somerset, UK), was administered twice daily after meal. Balance capsules contain 7 bacteria species including Lactobacillus strains (L casei, L rhamnosus, L acidophilus, and L bulgaricus), Bifidobacterium strains (B breve and B longum), and Streptococcus thermophilus. Total viable count is 1 × 108 CFU per capsule. Other ingredients are fructo‐oligosaccharides as prebiotic, magnesium stearate, and hydroxypropyl methyl cellulose. These interventions were continued for 14 consecutive days, and compliance was assessed with pill and bottle count.

Outcomes

Primary endpoint was improvement in MHE status, which was assessed by applying the PHES at baseline, 14 days after start of the intervention (14th day), and then at 8 weeks' follow‐up (10th week). The PHES is a set of neuropsychological tests including the Line‐Tracing Test, Digit Symbol Test, Serial Dotting Test, and Number Connection Test. These tests are used in the diagnosis and grading of MHE and examine visual perception, visuospatial orientation, visual construction, motor speed and accuracy, concentration, attention, and memory. Participants could achieve between +6 and −18 points.
Secondary outcomes were development of overt HE, admission to hospital for any other complication of cirrhosis, or death.

Notes

The study was also registered at Iranian Registry of Clinical Trials (IRCT201211012417N9).

Contacted Dr A Shavakhi on 14 March 2015, received no response.

Funding source: "Source of Support: Isfahan University of Medical Sciences, Potential competing interests: None declared". This study declared the funding source and was deemed to be independently funded.

Risk of bias

Bias

Authors' judgement

Support for judgement

Sequence generation

Low risk

"Using a table of random numbers generated by random allocation software, patients were randomized into two groups".

Allocation concealment

Unclear risk

Unclear from study

Blinding
Participants