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

Liver Diseases Clinical Trial

— PEARL  

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04073290
• Other study ID #: PEARL trial
• Secondary ID: 2018-004323-3784
• Status: Recruiting
• Phase: Phase 4
• Start date: January 21, 2020
• Est. completion date: September 30, 2023

Study information

• Verified date: February 2022
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: Koos de Wit, MD
• Phone: 0031-20-5668468
• Email: leverresearch[@]amc.uva.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical 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). 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 238
• Est. completion date: September 30, 2023
• Est. primary completion date: September 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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 (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

Related Conditions & MeSH terms

• Brain Diseases
• Cirrhosis, Liver
• Fibrosis
• Hepatic Encephalopathy
• Hypertension, Portal
• Liver Cirrhosis
• Liver Diseases
• Pathologic Processes
• Pathological Processes
• Portal Hypertension

Intervention

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

Locations

Country	Name	City	State
Belgium	Universitaire Ziekenhuizen Leuven	Leuven
Netherlands	Academic Medical Centre	Amsterdam
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Radboud University	Nijmegen
Netherlands	Erasmus Medical Center	Rotterdam

Sponsors (8)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)	Erasmus Medical Center, Leiden University Medical Center, Maastricht University Medical Center, Norgine, Radboud University Medical Center, Universitaire Ziekenhuizen Leuven, University Medical Center Groningen

Countries where clinical trial is conducted

Belgium,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Health related Quality of life	Health related Quality of life, measured by EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) questionnaire	One year
Other	Disease rrelated Quality of life	Health related Quality of life, Liver Disease Symptom Index (LDSI) 2.0 questionnaire.	One year
Other	Cost-effectiveness	Cost-effectiveness, measured by a combined questionnaire, based on institute for Medical Technology Assessment (iMTA) Productivity Cost Questionnaire (iPCQ)/Medical Consumption Questionnaire (iMCQ)	One year
Primary	post-TIPS Hepatic Encephalopathy	post-TIPS Hepatic Encephalopathy	First 3 months after TIPS placement
Secondary	Mortality	Mortality	90 days
Secondary	Transplant free survival	Transplant free survival	One year
Secondary	time to development of post-TIPS HE episode(s)	time to development of post-TIPS HE episode(s)	One year
Secondary	development of a second episode of post-TIPS HE	development of a second episode of post-TIPS HE	3 months
Secondary	development of post-TIPS HE between 3-12 months after TIPS placement	development of post-TIPS HE between 3-12 months after TIPS placement	3-12 months
Secondary	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	One year
Secondary	change in one-minute animal naming test compared to baseline	change in one-minute animal naming test compared to baseline	One year
Secondary	differences in molecular composition of peripheral / portal blood samples	differences in molecular composition of peripheral / portal blood samples at TIPS placement	One year
Secondary	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;	One year