Hepatic EncephalopathyPhase 4PEARLNCT04073290
Prevention of Post-TIPS Hepatic Encephalopathy by Administration of Rifaximin and Lactulose
A Phase 4 study testing Rifaximin 550 milligram Oral Tablet [XIFAXAN] and Lactulose 667 milligram/milliliter Oral Solution in people with Hepatic Encephalopathy and Cirrhosis, Liver, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 6 sites in 2 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Hepatic Encephalopathy, Cirrhosis, Liver, Portal Hypertension
- What is being tested?
- Rifaximin 550 milligram Oral Tablet [XIFAXAN] and Lactulose 667 milligram/milliliter Oral Solution
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 238 participants
- Where
- 6 sitesin 2 countries
- Study dates
- 21 Jan 2020to 31 Dec 2026
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Elective TIPS placement for refractory ascites or recurrent variceal bleeding:
- Recurrent tense ascites and one or more of the following criteria:
- Not responding to the maximal dose of diuretics (400 milligram spironolactone and 160 milligram furosemide).
- Kidney insufficiency (Creatinine > 135 umol/L) induced by diuretics. iii. Electrolyte disturbances (Sodium < 125 mmol/L, Potassium > 5.5 mmol/L) induced by diuretics.
- 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:
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- 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
Who cannot join
- 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)
Show all 11Show fewer
- 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
Trial locations and contacts
6 sites in 2 countries. Contact the study team or a site near you to ask about taking part.
6 sites in 2 countries
Netherlands5 sites, 5 recruiting
- Recruiting
Academic Medical Centre
Amsterdam
Bart Takkenberg, dr.
- Recruiting
University Medical Center Groningen
Groningen
F.J.C. Cuperus, Dr.
- Recruiting
Leiden University Medical Center
Leiden
M. Coenraad, Dr.
- Recruiting
Radboud University
Nijmegen
E.T.T.L. Tjwa, Dr.
- Recruiting
Erasmus Medical Center
Rotterdam
S. Coenen, Drs.
Belgium1 site, 1 recruiting
- Recruiting
Universitaire Ziekenhuizen Leuven
Leuven
Frederik Nevens, prof. dr.
About this study
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.
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.
Read the 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.
- Conditions
- Hepatic Encephalopathy, Cirrhosis, Liver, Portal Hypertension, Liver Diseases, Pathological Processes
- Being tested
- Rifaximin 550 milligram Oral Tablet [XIFAXAN], Placebo oral tablet, Lactulose 667 milligram/milliliter Oral Solution
- Keywords
- Rifaximin, Lactulose, post-TIPS HE, Prevention
- Medical subject headings
- Hepatic Encephalopathy, Liver Cirrhosis, Hypertension, Portal, Liver Diseases, Pathologic Processes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rifaximin 550 milligram Oral Tablet [XIFAXAN]Drug
Also called TARGAXAN
Rifaximin 550 milligram b.i.d. 72 hours before TIPS placement till 3 months post-TIPS
Placebo oral tabletDrug
Also called Placebo
Placebo b.i.d. 72 hours before TIPS placement till 3 months post-TIPS
Lactulose 667 milligram/milliliter Oral SolutionDrug
Also called Lactulose syrup
Lactulose based on soft stool frequency, 72 hours before TIPS placement till 3 months post-TIPS
| Study group | Role | What they receive |
|---|---|---|
| Rifaximin and lactulose | Active comparator | Rifaximin 550 milligram b.i.d. combined with lactulose Receives: 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 Receives: Drug: Placebo oral tablet; Drug: Lactulose 667 milligram/milliliter Oral Solution |
What is being measured
The primary outcome is the main question the study is designed to answer.
post-TIPS Hepatic Encephalopathy
post-TIPS Hepatic Encephalopathy
Measured: First 3 months after TIPS placement
Secondary outcomes (9)
Mortality
Mortality
Measured: 90 days
Transplant free survival
Transplant free survival
Measured: One year
time to development of post-TIPS HE episode(s)
time to development of post-TIPS HE episode(s)
Measured: One year
development of a second episode of post-TIPS HE
development of a second episode of post-TIPS HE
Measured: 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
Measured: 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
Measured: One year
change in one-minute animal naming test compared to baseline
change in one-minute animal naming test compared to baseline
Measured: One year
differences in molecular composition of peripheral / portal blood samples
differences in molecular composition of peripheral / portal blood samples at TIPS placement
Measured: 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;
Measured: One year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Aug 2019
- Study start21 Jan 2020
- Primary completion30 Sep 2026 (estimated)
- Study completion31 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Hepatic EncephalopathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 238 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Sponsor type
- University, hospital or other
- Collaborators
- Erasmus Medical Center, Leiden University Medical Center, Maastricht University Medical Center, Radboud University Medical Center, University Medical Center Groningen, Universitaire Ziekenhuizen KU Leuven, Norgine
- Responsible party
- Principal investigator, Dr. Bart Takkenberg, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Investigators
- Bart Takkenberg, MD, PhD, Principal investigator, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04073290
- Sponsor's protocol ID
- PEARL trial
- Other IDs
- 2018-004323-37, 848017009, 2018
- Acronym
- PEARL
- Status last verified
- Jan 2025
- First submitted
- 27 Aug 2019
- Last updated
- 28 Jan 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 37467180de 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.
PubMed 33372103
Study at a glance
From the registry record, last updated by the sponsor on 28 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT04073290
- Acronym / sponsor ID
- PEARL / PEARL trial
- Conditions
- Hepatic Encephalopathy, Cirrhosis, Liver, Portal Hypertension, Liver Diseases, Pathological Processes
- Keywords
- Rifaximin, Lactulose, post-TIPS HE, Prevention
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 238 participants (estimated)
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University, hospital or other
- Collaborators
- Erasmus Medical Center, Leiden University Medical Center, Maastricht University Medical Center, Radboud University Medical Center, University Medical Center Groningen, Universitaire Ziekenhuizen KU Leuven, Norgine
- Study start
- 21 Jan 2020 (actual)
- Primary completion
- 30 Sep 2026 (estimated)
- Study completion
- 31 Dec 2026 (estimated)
- First posted
- 29 Aug 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Rifaximin and lactulose | Active comparator | Drug: Rifaximin 550 milligram Oral Tablet [XIFAXAN], Drug: Lactulose 667 milligram/milliliter Oral SolutionRifaximin 550 milligram b.i.d. combined with lactulose |
| Placebo and lactulose | Placebo comparator | Drug: Placebo oral tablet, Drug: Lactulose 667 milligram/milliliter Oral SolutionPlacebo b.i.d. combined with lactulose |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Elective TIPS placement for refractory ascites or recurrent variceal bleeding:
- Recurrent variceal bleeding, not responsive to treatment with endoscopic band ligation and beta-blockers, with a high risk of failure of endoscopic treatment:
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Rifaximin 550 milligram Oral Tablet [XIFAXAN]Also: TARGAXANRifaximin 550 milligram b.i.d. 72 hours before TIPS placement till 3 months post-TIPS | Drug | Rifaximin and lactulose |
| Placebo oral tabletAlso: PlaceboPlacebo b.i.d. 72 hours before TIPS placement till 3 months post-TIPS | Drug | Placebo and lactulose |
| Lactulose 667 milligram/milliliter Oral SolutionAlso: Lactulose syrupLactulose based on soft stool frequency, 72 hours before TIPS placement till 3 months post-TIPS | Drug | Placebo and lactulose, Rifaximin and lactulose |
Primary outcome
post-TIPS Hepatic Encephalopathy
Time frame: First 3 months after TIPS placement
post-TIPS Hepatic Encephalopathy
9 secondary outcomes
Mortality
Time frame: 90 days
Transplant free survival
Time frame: One year
time to development of post-TIPS HE episode(s)
Time frame: One year
development of a second episode of post-TIPS HE
Time frame: 3 months
development of post-TIPS HE between 3-12 months after TIPS placement
Time frame: 3-12 months
change in Psychometric Hepatic Encephalopathy Score (PHES) compared to baseline
Time frame: One year
change in one-minute animal naming test compared to baseline
Time frame: One year
differences in molecular composition of peripheral / portal blood samples
Time frame: One year
differences in molecular composition of peripheral blood samples
Time frame: One year
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Jan 2025.
- Derived from this study: PubMed 37467180Zacharias 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.
- Derived from this study: PubMed 33372103de 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Bart Takkenberg, MD, PhD principal investigator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
6 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Rifaximin 550 milligram Oral Tablet [XIFAXAN] and Lactulose 667 milligram/milliliter Oral Solution in people with Hepatic Encephalopathy and Cirrhosis, Liver, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 6 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 28 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Netherlands, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Koos de Wit, MD (0031-20-5668468, leverresearch@amc.uva.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
post-TIPS Hepatic Encephalopathy (time frame: First 3 months after TIPS placement). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04073290, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jan 2025; AzTrials last refreshed its copy on 26 Oct 2026.