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

Last updated: January 27, 2025
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Overall Status: Active - Recruiting

Phase

4

Condition

Arginase Deficiency

Liver Disorders

Liver Disease

Treatment

Rifaximin 550 milligram Oral Tablet [XIFAXAN]

Lactulose 667 milligram/milliliter Oral Solution

Placebo oral tablet

Clinical Study ID

NCT04073290
PEARL trial
848017009
2018-004323-37
  • Ages 18-80
  • All Genders

Study 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.

Eligibility Criteria

Inclusion

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 bydiuretics. iv. Not tolerating higher dose of diuretics (e.g. because of subjective side effectslike muscle cramps). Recurrent variceal bleeding, not responsive to treatment with endoscopic bandligation 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 orii. Patients with a variceal bleeding, Child-Pugh B and an active bleeding duringendoscopy

  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

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 bedelayed 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 Design

Total Participants: 238
Treatment Group(s): 3
Primary Treatment: Rifaximin 550 milligram Oral Tablet [XIFAXAN]
Phase: 4
Study Start date:
January 21, 2020
Estimated Completion Date:
December 31, 2026

Study 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.

Connect with a study center

  • Universitaire Ziekenhuizen Leuven

    Leuven,
    Belgium

    Active - Recruiting

  • Academic Medical Centre

    Amsterdam,
    Netherlands

    Active - Recruiting

  • University Medical Center Groningen

    Groningen,
    Netherlands

    Active - Recruiting

  • Leiden University Medical Center

    Leiden,
    Netherlands

    Active - Recruiting

  • Radboud University

    Nijmegen,
    Netherlands

    Active - Recruiting

  • Erasmus Medical Center

    Rotterdam,
    Netherlands

    Active - Recruiting

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