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

Prevention of Hepatic Encephalopathy by Administration of Rifaximin and Lactulose in Patients With Liver Cirrhosis Undergoing TIPS Placement: a Multi-centre Randomized, Double Blind, Placebo Controlled Trial.

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.

Study Overview

• Status: Recruiting
• Conditions: Liver Diseases; Hepatic Encephalopathy; Portal Hypertension; Cirrhosis, Liver; Pathological Processes
• Intervention / Treatment: Drug: Rifaximin 550 milligram Oral Tablet [XIFAXAN]; Drug: Lactulose 667 milligram/milliliter Oral Solution; Drug: Placebo oral tablet

Detailed Description

Objective: To assess the incidence of post-TIPS OHE within the first three months after prophylactic administration of lactulose and rifaximin versus placebo in patients who undergo Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement.

Study design: A multicentre, randomized, placebo-controlled, double blind study.

Study population: Adult consecutive patients undergoing elective TIPS placement (for refractory ascites or secondary prophylaxis in variceal bleeding) in all Dutch academic centres where TIPS procedures are performed: Amsterdam UMC, location Academic Medical Centre (AMC), Erasmus MC, Leiden University Medical Centre (LUMC), Maastricht University Medical Centre+ (MUMC+), Radboud University Medical Centre (Radboudumc), University Medical Centre Groningen (UMCG), and University Hospitals Leuven (UZ Leuven) in Belgium.

Intervention: Rifaximin 550 milligram (mg) b.i.d. will be prescribed, in combination with a starting dose of 25 milliliter (mL) lactulose b.i.d. and further dependent on the amount of daily bowel movements, with the objective not to exceed more than two soft stools per day. Intervention will start 72 hours before TIPS placement, and will last till three months after TIPS placement. The control group will receive placebo in combination with lactulose (as described above).

Main study parameters/endpoints: Primary endpoint is the development of OHE within three months after TIPS placement determined by the West Haven criteria. Secondary endpoints are 90 day mortality; development of a second episode of OHE within the first three months; development of OHE in the period between three and twelve months after TIPS placement; development of MHE between TIPS placement and twelve months after placement; the increase of the psychometric hepatic encephalopathy score (PHES) and simplified one minute animal naming test (S-ANT1) compared to baseline. Differences in molecular composition of peripheral / portal blood samples at TIPS placement. Furthermore, quality of life will be assessed.

• Study Type: Interventional
• Enrollment (Estimated): 238
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Koos de Wit, MD; Phone Number: 0031-20-5668468; Email: leverresearch@amc.uva.nl

Study Locations

• Belgium
  • Leuven, Belgium
    • Recruiting
    • Universitaire Ziekenhuizen Leuven
    • Contact: Frederik Nevens, prof. dr.
• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • Academic Medical Centre
    • Contact: Bart Takkenberg, dr.
  • Groningen, Netherlands
    • Recruiting
    • University Medical Center Groningen
    • Contact: F.J.C. Cuperus, Dr.
  • Leiden, Netherlands
    • Recruiting
    • Leiden University Medical Center
    • Contact: M. Coenraad, Dr.
  • Nijmegen, Netherlands
    • Recruiting
    • Radboud University
    • Contact: E.T.T.L. Tjwa, Dr.
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus Medical Center
    • Contact: S. Coenen, Drs.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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

2. Age ≥18 years
3. Confirmed liver cirrhosis as documented by liver biopsy, elastography (e.g. Fibroscan) or combination of usual radiological and biochemical criteria.
4. Signed informed consent

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rifaximin and lactulose; Rifaximin 550 milligram b.i.d. combined with lactulose	Drug: Rifaximin 550 milligram Oral Tablet [XIFAXAN]; Rifaximin 550 milligram b.i.d. 72 hours before TIPS placement till 3 months post-TIPS; Other Names: TARGAXAN; Drug: Lactulose 667 milligram/milliliter Oral Solution; Lactulose based on soft stool frequency, 72 hours before TIPS placement till 3 months post-TIPS; Other Names: Lactulose syrup
Placebo Comparator: Placebo and lactulose; Placebo b.i.d. combined with lactulose	Drug: Lactulose 667 milligram/milliliter Oral Solution; Lactulose based on soft stool frequency, 72 hours before TIPS placement till 3 months post-TIPS; Other Names: Lactulose syrup; Drug: Placebo oral tablet; Placebo b.i.d. 72 hours before TIPS placement till 3 months post-TIPS; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
post-TIPS Hepatic Encephalopathy	post-TIPS Hepatic Encephalopathy	First 3 months after TIPS placement

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality	90 days
Transplant free survival	Transplant free survival	One year
time to development of post-TIPS HE episode(s)	time to development of post-TIPS HE episode(s)	One year
development of a second episode of post-TIPS HE	development of a second episode of post-TIPS HE	3 months
development of post-TIPS HE between 3-12 months after TIPS placement	development of post-TIPS HE between 3-12 months after TIPS placement	3-12 months
change in Psychometric Hepatic Encephalopathy Score (PHES) compared to baseline	change in total PHES score compared to baseline (range -15 - +5) a lower score is a worse outcome	One year
change in one-minute animal naming test compared to baseline	change in one-minute animal naming test compared to baseline	One year
differences in molecular composition of peripheral / portal blood samples	differences in molecular composition of peripheral / portal blood samples at TIPS placement	One year
differences in molecular composition of peripheral blood samples	differences in molecular composition of peripheral blood samples at baseline, compared to day 10 post-TIPS, week 4, week 12, and week 52;	One year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health related Quality of life	Health related Quality of life, measured by EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) questionnaire	One year
Disease rrelated Quality of life	Health related Quality of life, Liver Disease Symptom Index (LDSI) 2.0 questionnaire.	One year
Cost-effectiveness	Cost-effectiveness, measured by a combined questionnaire, based on institute for Medical Technology Assessment (iMTA) Productivity Cost Questionnaire (iPCQ)/Medical Consumption Questionnaire (iMCQ)	One year

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Radboud University Medical Center; Universitaire Ziekenhuizen KU Leuven; University Medical Center Groningen; Maastricht University Medical Center; Erasmus Medical Center; Leiden University Medical Center; Norgine
• Investigators: Principal Investigator: Bart Takkenberg, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2020
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: August 27, 2019
• First Submitted That Met QC Criteria: August 27, 2019
• First Posted (Actual): August 29, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 27, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Prevention; Rifaximin; Lactulose; post-TIPS HE
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Digestive System Diseases; Brain Diseases, Metabolic; Liver Failure; Hepatic Insufficiency; Fibrosis; Liver Diseases; Pathologic Processes; Liver Cirrhosis; Hypertension, Portal; Brain Diseases; Hepatic Encephalopathy; Anti-Bacterial Agents; Anti-Infective Agents; Gastrointestinal Agents; Rifaximin; Lactulose
• Other Study ID Numbers: PEARL trial; 2018-004323-37 (EudraCT Number); 848017009 (Other Grant/Funding Number: ZonMw)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No