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Recruiting NCT04073290

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

Phase IV Interventional Hepatic Encephalopathy Cirrhosis, Liver Portal Hypertension Liver Diseases

For patients and families

In plain language

An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.

What is being studied
The protocol lists: Rifaximin 550 milligram Oral Tablet [XIFAXAN], Placebo oral tablet, Lactulose 667 milligram/milliliter Oral Solution.
Who it may be relevant to
Registry conditions: Hepatic Encephalopathy, Cirrhosis, Liver, Portal Hypertension, Liver Diseases. Basic parameters: 18 years — 80 years · All.
What needs checking
Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
Where it takes place
Belgium, Netherlands
Next step
Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →

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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.

Overview

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.

Interventions

  • Drug Rifaximin 550 milligram Oral Tablet [XIFAXAN]
    Rifaximin 550 milligram b.i.d. 72 hours before TIPS placement till 3 months post-TIPS
  • Drug Placebo oral tablet
    Placebo b.i.d. 72 hours before TIPS placement till 3 months post-TIPS
  • Drug Lactulose 667 milligram/milliliter Oral Solution
    Lactulose based on soft stool frequency, 72 hours before TIPS placement till 3 months post-TIPS

Primary outcome measures

  • post-TIPS Hepatic Encephalopathy [Time frame: First 3 months after TIPS placement]
Secondary outcome measures (9)
  • 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]

Eligibility criteria

Inclusion criteria

  • 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation
Randomized
Model
Parallel assignment
Masking
Triple blind
Primary purpose
Prevention

Study locations

Netherlands · 5 centers
  • Academic Medical Centre — Amsterdam
  • University Medical Center Groningen — Groningen
  • Leiden University Medical Center — Leiden
  • Radboud University — Nijmegen
  • Erasmus Medical Center — Rotterdam
Belgium · 1 center
  • Universitaire Ziekenhuizen Leuven — Leuven

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. PMID 37467180
  • 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 PMID 33372103

Identifiers

NCT: NCT04073290 · PEARL trial · 2018-004323-37 · 848017009

Primary sources (government registries)

View this study on ClinicalTrials.gov ↗