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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 31, 2020
Sponsor:
Collaborators:
Erasmus Medical Center
Leiden University Medical Center
Maastricht University Medical Center
Radboud University
University Medical Center Groningen
Universitaire Ziekenhuizen Leuven
Norgine
Information provided by (Responsible Party):
Dr. Bart Takkenberg, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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.

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

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.

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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
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 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




Primary Outcome Measures :
  1. post-TIPS Hepatic Encephalopathy [ Time Frame: First 3 months after TIPS placement ]
    post-TIPS Hepatic Encephalopathy


Secondary Outcome Measures :
  1. Mortality [ Time Frame: 90 days ]
    Mortality

  2. Transplant free survival [ Time Frame: One year ]
    Transplant free survival

  3. time to development of post-TIPS HE episode(s) [ Time Frame: One year ]
    time to development of post-TIPS HE episode(s)

  4. development of a second episode of post-TIPS HE [ Time Frame: 3 months ]
    development of a second episode of post-TIPS HE

  5. 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

  6. 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

  7. change in one-minute animal naming test compared to baseline [ Time Frame: One year ]
    change in one-minute animal naming test compared to baseline

  8. 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

  9. 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;


Other Outcome Measures:
  1. 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

  2. Disease rrelated Quality of life [ Time Frame: One year ]
    Health related Quality of life, Liver Disease Symptom Index (LDSI) 2.0 questionnaire.

  3. 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)



Information from the National Library of Medicine

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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
Criteria

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
  7. History of OHE not induced by Spontaneous bacterial peritonitis (SBP) or gastrointestinal bleed
  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

Information from the National Library of Medicine

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


Contacts
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Contact: Koos de Wit, MD 0031-20-5668468 leverresearch@amc.uva.nl

Locations
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Belgium
Universitaire Ziekenhuizen Leuven Recruiting
Leuven, Belgium
Contact: Frederik Nevens, prof. dr.         
Netherlands
Academic Medical Centre Recruiting
Amsterdam, Netherlands
Contact: Bart Takkenberg, dr.         
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Erasmus Medical Center
Leiden University Medical Center
Maastricht University Medical Center
Radboud University
University Medical Center Groningen
Universitaire Ziekenhuizen Leuven
Norgine
Investigators
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Principal Investigator: Bart Takkenberg, MD, PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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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 31, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dr. Bart Takkenberg, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
Rifaximin
Lactulose
post-TIPS HE
Prevention
Additional relevant MeSH terms:
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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