Prevention of Post-TIPS Hepatic Encephalopathy by Administration of Rifaximin and Lactulose (PEARL)
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ClinicalTrials.gov Identifier: NCT04073290 |
Recruitment Status :
Recruiting
First Posted : August 29, 2019
Last Update Posted : January 15, 2021
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Hepatic Encephalopathy Cirrhosis, Liver Portal Hypertension Liver Diseases Pathological Processes | Drug: Rifaximin 550 milligram Oral Tablet [XIFAXAN] Drug: Placebo oral tablet Drug: Lactulose 667 milligram/milliliter Oral Solution | Phase 4 |
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 (Clinical Trial) |
Estimated Enrollment : | 238 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Triple (Participant, Care Provider, Investigator) |
Primary Purpose: | Prevention |
Official Title: | 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. |
Actual Study Start Date : | January 21, 2020 |
Estimated Primary Completion Date : | September 30, 2022 |
Estimated Study Completion Date : | September 30, 2023 |
Arm | Intervention/treatment |
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Active Comparator: Rifaximin and lactulose
Rifaximin 550 milligram b.i.d. combined with lactulose
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Drug: Rifaximin 550 milligram Oral Tablet [XIFAXAN]
Rifaximin 550 milligram b.i.d. 72 hours before TIPS placement till 3 months post-TIPS
Other Name: 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 Name: Lactulose syrup |
Placebo Comparator: Placebo and lactulose
Placebo b.i.d. combined with lactulose
|
Drug: Placebo oral tablet
Placebo b.i.d. 72 hours before TIPS placement till 3 months post-TIPS
Other Name: Placebo Drug: Lactulose 667 milligram/milliliter Oral Solution Lactulose based on soft stool frequency, 72 hours before TIPS placement till 3 months post-TIPS
Other Name: Lactulose syrup |
- post-TIPS Hepatic Encephalopathy [ Time Frame: First 3 months after TIPS placement ]post-TIPS Hepatic Encephalopathy
- Mortality [ Time Frame: 90 days ]Mortality
- Transplant free survival [ Time Frame: One year ]Transplant free survival
- time to development of post-TIPS HE episode(s) [ Time Frame: One year ]time to development of post-TIPS HE episode(s)
- development of a second episode of post-TIPS HE [ Time Frame: 3 months ]development of a second episode of post-TIPS HE
- development of post-TIPS HE between 3-12 months after TIPS placement [ Time Frame: 3-12 months ]development of post-TIPS HE between 3-12 months after TIPS placement
- change in Psychometric Hepatic Encephalopathy Score (PHES) compared to baseline [ Time Frame: One year ]change in total PHES score compared to baseline (range -15 - +5) a lower score is a worse outcome
- change in one-minute animal naming test compared to baseline [ Time Frame: One year ]change in one-minute animal naming test compared to baseline
- differences in molecular composition of peripheral / portal blood samples [ Time Frame: One year ]differences in molecular composition of peripheral / portal blood samples at TIPS placement
- differences in molecular composition of peripheral blood samples [ Time Frame: One year ]differences in molecular composition of peripheral blood samples at baseline, compared to day 10 post-TIPS, week 4, week 12, and week 52;
- Health related Quality of life [ Time Frame: One year ]Health related Quality of life, measured by EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) questionnaire
- Disease rrelated Quality of life [ Time Frame: One year ]Health related Quality of life, Liver Disease Symptom Index (LDSI) 2.0 questionnaire.
- Cost-effectiveness [ Time Frame: One year ]Cost-effectiveness, measured by a combined questionnaire, based on institute for Medical Technology Assessment (iMTA) Productivity Cost Questionnaire (iPCQ)/Medical Consumption Questionnaire (iMCQ)

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Ages Eligible for Study: | 18 Years to 80 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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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
Exclusion Criteria:
- 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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04073290
Contact: Koos de Wit, MD | 0031-20-5668468 | leverresearch@amc.uva.nl |
Belgium | |
Universitaire Ziekenhuizen Leuven | Recruiting |
Leuven, Belgium | |
Contact: Frederik Nevens, prof. dr. | |
Netherlands | |
Academic Medical Centre | Recruiting |
Amsterdam, Netherlands | |
Contact: Bart Takkenberg, dr. | |
University Medical Center Groningen | Recruiting |
Groningen, Netherlands | |
Contact: F.J.C. Cuperus, Dr. | |
Leiden University Medical Center | Recruiting |
Leiden, Netherlands | |
Contact: M. Coenraad, Dr. | |
Radboud University | Recruiting |
Nijmegen, Netherlands | |
Contact: E.T.T.L. Tjwa, Dr. | |
Erasmus Medical Center | Recruiting |
Rotterdam, Netherlands | |
Contact: S. Coenen, Drs. |
Principal Investigator: | Bart Takkenberg, MD, PhD | Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) |
Responsible Party: | Dr. Bart Takkenberg, Study Chair, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) |
ClinicalTrials.gov Identifier: | NCT04073290 |
Other Study ID Numbers: |
PEARL trial 2018-004323-37 ( EudraCT Number ) 848017009 ( Other Grant/Funding Number: ZonMw ) |
First Posted: | August 29, 2019 Key Record Dates |
Last Update Posted: | January 15, 2021 |
Last Verified: | January 2021 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
Rifaximin Lactulose post-TIPS HE Prevention |
Liver Cirrhosis Liver Diseases Hepatic Encephalopathy Hypertension, Portal Brain Diseases Fibrosis Pathologic Processes Digestive System Diseases Central Nervous System Diseases Nervous System Diseases |
Liver Failure Hepatic Insufficiency Brain Diseases, Metabolic Metabolic Diseases Rifaximin Lactulose Anti-Bacterial Agents Anti-Infective Agents Gastrointestinal Agents |