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

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Other)

Overall Status

Recruiting

CT.gov ID

NCT04073290

Collaborator

Erasmus Medical Center (Other), Leiden University Medical Center (Other), Maastricht University Medical Center (Other), Radboud University Medical Center (Other), University Medical Center Groningen (Other), Universitaire Ziekenhuizen Leuven (Other), Norgine (Industry)

238

Enrollment

Locations

Arms

44.3

Anticipated Duration (Months)

39.7

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Anticipated 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 :

Jan 21, 2020

Anticipated Primary Completion Date :

Sep 30, 2022

Anticipated Study Completion Date :

Sep 30, 2023

Arms and Interventions

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 Names: 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 Names: 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 Names: 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 Names: Lactulose syrup

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 Names:

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 Names:

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 Names:

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 Names:

Lactulose syrup

Outcome Measures

Primary Outcome Measures

post-TIPS Hepatic Encephalopathy [First 3 months after TIPS placement]
post-TIPS Hepatic Encephalopathy

Secondary Outcome Measures

Mortality [90 days]
Mortality
Transplant free survival [One year]
Transplant free survival
time to development of post-TIPS HE episode(s) [One year]
time to development of post-TIPS HE episode(s)
development of a second episode of post-TIPS HE [3 months]
development of a second episode of post-TIPS HE
development of post-TIPS HE between 3-12 months after TIPS placement [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 [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 [One year]
change in one-minute animal naming test compared to baseline
differences in molecular composition of peripheral / portal blood samples [One year]
differences in molecular composition of peripheral / portal blood samples at TIPS placement
differences in molecular composition of peripheral blood samples [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

Health related Quality of life [One year]
Health related Quality of life, measured by EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) questionnaire
Disease rrelated Quality of life [One year]
Health related Quality of life, Liver Disease Symptom Index (LDSI) 2.0 questionnaire.
Cost-effectiveness [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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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:

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

Contacts and Locations

Locations

	Site	City	Country
1	Universitaire Ziekenhuizen Leuven	Leuven	Belgium
2	Academic Medical Centre	Amsterdam	Netherlands
3	University Medical Center Groningen	Groningen	Netherlands
4	Leiden University Medical Center	Leiden	Netherlands
5	Radboud University	Nijmegen	Netherlands
6	Erasmus Medical Center	Rotterdam	Netherlands