Prevention of Post-TIPS Hepatic Encephalopathy by Administration of Rifaximin and Lactulose

NCT04073290 | Recruiting Phase 4

• 3 other identifiers: PEARL trial2018-004323-37848017009
• Study Type: interventional
• Target: 238
• Locations: 2 countries
• Sites: 6

Brief Summary

Rationale: Hepatic encephalopathy (HE) is a major and common complication in patients with liver cirrhosis. HE can be classified in the extensive range of neurocognitive deterioration as minimal HE (MHE), covert HE (grade I), or overt HE (OHE, grade II-IV). Liver cirrhosis is the most common cause of portal hypertension (PH). Patients who develop complications of PH, like variceal bleeding or refractory ascites, can benefit from a Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement. Unfortunately, post-TIPS HE is a common and often severe complication. Incidence of new onset or worsening of HE after TIPS is approximately 20-45%. Currently there is no strategy to prevent post-TIPS HE.

Conditions

Hepatic Encephalopathy; Cirrhosis, Liver; Portal Hypertension; Liver Diseases; Pathological Processes

Keywords

Rifaximin; Lactulose; post-TIPS HE; Prevention

Outcome Measures

Primary Outcomes (1)

• post-TIPS Hepatic Encephalopathy

  post-TIPS Hepatic Encephalopathy

  First 3 months after TIPS placement

Secondary Outcomes (9)

• Mortality

  90 days

• Transplant free survival

  One year

• time to development of post-TIPS HE episode(s)

  One year

• development of a second episode of post-TIPS HE

  3 months

• development of post-TIPS HE between 3-12 months after TIPS placement

  3-12 months

Other Outcomes (3)

• Health related Quality of life

  One year

• Disease rrelated Quality of life

  One year

• Cost-effectiveness

  One year

Study Arms (2)

Rifaximin and lactulose

ACTIVE COMPARATOR

Rifaximin 550 milligram b.i.d. combined with lactulose

Drug: Rifaximin 550 milligram Oral Tablet [XIFAXAN]; Drug: Lactulose 667 milligram/milliliter Oral Solution

Placebo and lactulose

PLACEBO COMPARATOR

Placebo b.i.d. combined with lactulose

Drug: Placebo oral tablet; Drug: Lactulose 667 milligram/milliliter Oral Solution

Interventions

Rifaximin 550 milligram Oral Tablet [XIFAXAN] DRUG

Rifaximin 550 milligram b.i.d. 72 hours before TIPS placement till 3 months post-TIPS

Also known as: TARGAXAN

Rifaximin and lactulose

Placebo oral tablet DRUG

Placebo b.i.d. 72 hours before TIPS placement till 3 months post-TIPS

Also known as: Placebo

Placebo and lactulose

Lactulose 667 milligram/milliliter Oral Solution DRUG

Lactulose based on soft stool frequency, 72 hours before TIPS placement till 3 months post-TIPS

Also known as: Lactulose syrup

Placebo and lactulose; Rifaximin and lactulose

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Elective TIPS placement for refractory ascites or recurrent variceal bleeding:
• Recurrent tense ascites and one or more of the following criteria:
• i. Not responding to the maximal dose of diuretics (400 milligram spironolactone and 160 milligram furosemide).
• ii. Kidney insufficiency (Creatinine \> 135 umol/L) induced by diuretics. iii. Electrolyte disturbances (Sodium \< 125 mmol/L, Potassium \> 5.5 mmol/L) induced by diuretics.
• iv. Not tolerating higher dose of diuretics (e.g. because of subjective side effects like muscle cramps).
• Recurrent variceal bleeding, not responsive to treatment with endoscopic band ligation and beta-blockers, with a high risk of failure of endoscopic treatment:
• i. Patients with a variceal bleeding and Child-Pugh C (10-13 points) cirrhosis or ii. Patients with a variceal bleeding, Child-Pugh B and an active bleeding during endoscopy
• Age ≥18 years
• Confirmed liver cirrhosis as documented by liver biopsy, elastography (e.g. Fibroscan) or combination of usual radiological and biochemical criteria.
• Signed informed consent

You may not qualify if:

• Any absolute contraindications for TIPS placement
• Use of ciclosporin
• Life-threatening variceal bleeding with emergency TIPS placement which can not be delayed 72 hours
• Age \> 80 years
• Non-cirrhotic portal hypertension
• Portal vein thrombosis (main trunk)
• HIV
• Current or recent (\<3 months) use of rifaximin
• Overt neurologic diseases such as Alzheimer's disease, Parkinson's disease
• Pregnant or breastfeeding women
• Patients refusing or unable to sign informed consent

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• Erasmus Medical Center: collaborator
• Leiden University Medical Center: collaborator
• Maastricht University Medical Center: collaborator
• Radboud University Medical Center: collaborator
• University Medical Center Groningen: collaborator
• Universitaire Ziekenhuizen KU Leuven: collaborator
• Norgine: collaborator

Study Sites (6)

Universitaire Ziekenhuizen Leuven

Leuven, Belgium

RECRUITING

Academic Medical Centre

Amsterdam, Netherlands

RECRUITING

University Medical Center Groningen

Groningen, Netherlands

RECRUITING

Leiden University Medical Center

Leiden, Netherlands

RECRUITING

Radboud University

Nijmegen, Netherlands

RECRUITING

Erasmus Medical Center

Rotterdam, Netherlands

RECRUITING

Related Publications (2)

• Zacharias HD, Kamel F, Tan J, Kimer N, Gluud LL, Morgan MY. Rifaximin for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. 2023 Jul 19;7(7):CD011585. doi: 10.1002/14651858.CD011585.pub2.

  PMID: 37467180 DERIVED

• de Wit K, Schaapman JJ, Nevens F, Verbeek J, Coenen S, Cuperus FJC, Kramer M, Tjwa ETTL, Mostafavi N, Dijkgraaf MGW, van Delden OM, Beuers UHW, Coenraad MJ, Takkenberg RB. Prevention of hepatic encephalopathy by administration of rifaximin and lactulose in patients with liver cirrhosis undergoing placement of a transjugular intrahepatic portosystemic shunt (TIPS): a multicentre randomised, double blind, placebo controlled trial (PEARL trial). BMJ Open Gastroenterol. 2020 Dec;7(1):e000531. doi: 10.1136/bmjgast-2020-000531.

  PMID: 33372103 DERIVED

MeSH Terms

Conditions

Hepatic Encephalopathy; Liver Cirrhosis; Hypertension, Portal; Liver Diseases; Pathologic Processes

Interventions

Rifaximin

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Digestive System Diseases; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Fibrosis; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Bart Takkenberg, MD, PhD

  Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Koos de Wit, MD

CONTACT

0031-20-5668468; leverresearch@amc.uva.nl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Study Chair

Study Record Dates

• First Submitted: August 27, 2019
• First Posted: August 29, 2019
• Study Start: January 21, 2020
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: January 28, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

NL (5); BE (1)