Secondary Prophylaxis of Hepatic Encephalopathy With a Probiotic Preparation (VSL#3)

Secondary Prophylaxis of Hepatic Encephalopathy: A Double Blind, Randomized, Placebo Controlled Study With Supplementation With a Probiotic Preparation

The aim of the proposed project is to study the effects of a probiotic preparation (VSL#3®) for the prevention of recurrence of HE (Hepatic encephalopathy) in patients after the recovery of an episode of overt HE (secondary prophylaxis)

Study Overview

• Status: Completed
• Conditions: Hepatic Encephalopathy
• Intervention / Treatment: Drug: VSL#3; Other: Placebo

Detailed Description

Hepatic encephalopathy (HE) represents a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain disease. The Working Party at the 11th World Congress of Gastroenterology, Vienna proposed a multi-axial definition of HE that defined both, the type of hepatic abnormality (type A, B or C) and the duration/characteristics of neurological manifestations (episodic, persistent or minimal HE) in chronic liver disease. Overt hepatic encephalopathy occurs in 30%-45% of cirrhotic patients and 10%-50% of patients with transjugular intrahepatic portosystemic shunt. Development of HE is associated with a poor prognosis. Bustamante et al reported the survival probability of 42% at 1 year of follow-up and 23% at 3 years in patients with cirrhosis with a first episode of acute HE. The primary treatment of HE is the identification and treatment of the precipitating factors. The majority of the drugs used in the treatment of HE are primarily directed at the reduction or elimination of the increased neurotoxic ammonia levels. A meta-analysis of 22 randomized trials highlighted the lack of data supporting the efficacy of nonabsorbable disaccharides; however, the investigators concluded that current evidence is insufficient to support or refute the use of nonabsorbable disaccharides for treatment of HE. Recent studies with well defined groups however demonstrated the efficacy of lactulose. Alternative therapies such as benzodiazepine receptor antagonists, branched-chain amino acids, and L-ornithine-L-aspartate also have been shown to have some role. Antibiotics are effective in the treatment of HE, but adverse effects and concerns about long-term safety have limited their widespread use. Probiotics may have multiple beneficial effects in the prevention and/or treatment of HE. All four published studies on the effect of probiotics on hepatic encephalopathy have demonstrated efficacy. Treating patients to prevent development of a first episode is classified as primary prophylaxis of HE and preventing recurrence of HE in patients who had a previous episode of HE as secondary prophylaxis of HE. Sharma et al recently demonstrated that lactulose is effective in secondary prevention of HE. This study will assess the effects of a probiotic preparation for the prevention of recurrence of HE (secondary prophylaxis) in patients after the recovery of an episode of overt HE.

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• India
  • Chandigarh, India, 160012
    • Dept. of Hepatology, PGIMER

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients diagnosed as having cirrhosis of liver at the Inpatient/Outpatient Liver Clinic of Department of Hepatology, PGIMER, Chandigarh, will be candidates for enrollment.
• The diagnosis of cirrhosis of liver will be based on clinical, biochemical, and ultrasonographical or liver histological data.

Exclusion Criteria:

• Alcohol intake during the past 6 weeks
• Hepatocellular carcinoma
• Previous transjugular intrahepatic portosystemic shunt or shunt surgery
• Significant comorbid illness such as heart, respiratory, or renal failure
• Any neurologic diseases such as Alzheimer's disease, Parkinson's disease, and nonhepatic metabolic encephalopathies.
• Patients on psychoactive drugs, such as antidepressants or sedatives
• Those who restart alcohol consumption during follow-up will also be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VSL#3; VSL#3® is made up of 4 strains of Lactobacilli (L. paracasei, L. plantarum, L. acidophilus and L. delbrueckii subsp. bulgaricus), 3 strains of Bifidobacteria (B. longum, B. infantis, B. breve) and 1 strain of Streptococcus thermophilus.	Drug: VSL#3; VSL#3® is made up of 4 strains of Lactobacilli (L. paracasei, L. plantarum, L. acidophilus and L. delbrueckii subsp. bulgaricus), 3 strains of Bifidobacteria (B. longum, B. infantis, B. breve) and 1 strain of Streptococcus thermophilus. Dose would be 1 sachet per day (Each sachet containing 900 Billion CFU). The duration of treatment would be for 24 weeks; Other Names: Probiotic
Placebo Comparator: Placebo; Placebo sachets contain corn starch	Other: Placebo; Placebo sachets contain corn starch. Dose: 1 sachet per day Duration of treatment: 24 weeks; Other Names: Dummy Preparation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary end point will be development of overt HE or completion of a follow-up of 6 months after enrollment	6 months after enrollment

Secondary Outcome Measures

Outcome Measure	Time Frame
Improvement in liver functions (Child and MELD score), psychometry (psychometric hepatic encephalopathy score), blood ammonia, blood cytokines level and survival time after medication	6 months after enrollment

Collaborators and Investigators

• Sponsor: CD Pharma India Pvt. Ltd.
• Collaborators: Postgraduate Institute of Medical Education and Research
• Investigators: Principal Investigator: Radha K Dhiman, MD,DM,MNAMS, Postgraduate Institute of Medical Education & Research (PGIMER)

Publications and helpful links

General Publications

• Dhiman RK, Grover GS, Premkumar M, Roy A, Taneja S, Duseja A, Arora S; MMPHCRF Investigators. Outcomes of Real-World Integrated HCV Microelimination for People Who Inject Drugs: An expansion of the Punjab Model. EClinicalMedicine. 2021 Oct 17;41:101148. doi: 10.1016/j.eclinm.2021.101148. eCollection 2021 Nov.
• Dhiman RK, Grover GS, Premkumar M, Taneja S, Duseja A, Arora S, Rathi S, Satsangi S, Roy A; MMPHCRF Investigators. Decentralized care with generic direct-acting antivirals in the management of chronic hepatitis C in a public health care setting. J Hepatol. 2019 Dec;71(6):1076-1085. doi: 10.1016/j.jhep.2019.07.006. Epub 2019 Jul 17.
• Dhiman RK, Rana B, Agrawal S, Garg A, Chopra M, Thumburu KK, Khattri A, Malhotra S, Duseja A, Chawla YK. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology. 2014 Dec;147(6):1327-37.e3. doi: 10.1053/j.gastro.2014.08.031. Epub 2014 Aug 27.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: April 23, 2010
• First Submitted That Met QC Criteria: April 23, 2010
• First Posted (Estimate): April 26, 2010

Study Record Updates

• Last Update Posted (Estimate): December 30, 2013
• Last Update Submitted That Met QC Criteria: December 26, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: Hepatic Encephalopathy, probiotics
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Failure; Hepatic Insufficiency; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Liver Diseases; Brain Diseases, Metabolic; Hepatic Encephalopathy; Brain Diseases
• Other Study ID Numbers: MHE2-VSL#3-Ver3_30032010