Administration of Rifaximin to Improve Liver Regeneration and Outcome Following Major Liver Resection (ARROW)

Surgery is in almost all cases the only potentially curative treatment option for patients with primary or secondary malignancies of the liver. However, in most cases oncological resections ("R0-resections") can only be achieved by performing major liver resections (4 or more liver segments), which is related to considerable postoperative complications such as systemic infections and postoperative liver insufficiency (postresectional liver failure (PRLF)). Despite optimized preoperative and postoperative strategies of care presently, up to 32-55% of patients display severs postoperative complications (Clavien score ≥ 3a) and 5% even suffer from a severe PRLF. Recent observations in murine disease models as well as human patients suggested that postoperative alterations of hemodynamics within the portal vein tract as well as postoperative modulations of the immune response facilitates the translocation of gut bacteria in the blood, leading to systemic infections and sepsis. Moreover it became apparent that inflammatory mediators, released by the gut microbiota might negatively affect postoperative liver regeneration. Rifaximin (Xifaxan®) is a novel and potent, semisynthetic antibiotic that efficiently acts against most enteric bacteria and significantly reduced liver inflammation and liver fibrosis in animal studies. Moreover, Rifaximin is very well tolerated, even in patients with liver insufficiency.

Study Overview

• Status: Terminated
• Conditions: Malignant Liver Disease; Major Liver Resection
• Intervention / Treatment: Drug: XIFAXAN® (Rifaximin)

• Study Type: Interventional
• Enrollment (Anticipated): 96
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, 52074
    • RWTH Aachen University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients undergoing a liver resection of at least 4 segments
2. Age > 18 years < 80 years
3. BMI 18-40
4. Patients with ASA (American Society of Anesthesiologists) I-III
5. Written informed consent prior to study participation

Exclusion Criteria:

1. Patients with ASA IV-V
2. Contraindication for MRI (see 5.4.3)
3. Underlying chronic liver disease such as severe fibrosis or liver cirrhosis
4. Need for procedures additive to partial liver resection
5. Participation in other liver related trials
6. BMI > 40
7. Previous liver transplantation or porto-systemic shunt
8. Concomitant acute infectious diseases
9. Renal insufficiency
10. Hypersensitivity to Rifaximin
11. Concomitant HIPEC (hypertherme intraperitoneale chemoperfusion) treatment
12. ALPPS (associating liver partition and portal vein ligation for staged hepatectomy)
13. Pregnant females as determined by positive [serum or urine] hCG (human chorionic gonadotropin) test at Screening or prior to dosing. Participants of child-bearing age should use adequate contraception as defined in the study protocol.
14. Lactating females
15. The subject has a history of any other illness, which, in the opinion of the investigator, might pose an unacceptable risk by administering study medication.
16. The subject received an investigational drug within 30 days prior to inclusion into this study
17. The subject has any current or past medical condition and/or required medication to treat a condition that could affect the evaluation of the study
18. The subject is unwilling or unable to follow the procedures outlined in the protocol
19. The subject is mentally or legally incapacitated

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: film-coated Rifaximin (550 mg); (550 mg) tablet twice daily for at least 14 days but up to 28 days dependent on the need for a PVE and the period between PVE (portal vein embolization) or randomization and surgery. Preoperative Rifaximin treatment in case of a PVE will start the day after PVE and will last for 14-21 days. In case patients are not pre-treated with a PVE they will receive Rifaximin for 7-10 days prior to surgery. Regardless of PVE, patients will receive additional Rifaximin treatment the first 7 days postoperatively.	Drug: XIFAXAN® (Rifaximin); Other Names: NDA 22-554
No Intervention: standard therapy; Patients directed to the control group will not receive Rifaximin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of Rifaximin on postoperative liver function	LiMAx liver function percentage increase on postoperative day 7 in relation to LiMAx value on postoperative day 4 compared to a control group without Rifaximin treatment. LiMAx will be made after at least 14 days but up to 28 days of treatment (control group analogue) dependent on the need for a PVE and the period between PVE or randomization and surgery	Postoperative day 7 in relation to postoperative day 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
postoperative morbidity/Complications	Complications will be scored using the Clavien-Dindo scoring system and a liver-specific-composite-endpoint for the duration of hospital stay, an expected average of minimum 14 days	minimum 14 days after liver resection
Liver volume percentage increase	MRI volumetry: pre- and postoperative comperative measurements mainly based on suitable, preoperatively and routinely done MRI/CT-images. On postoperative day 7 as tudy related MRI will be done if no CT/MRI images available routinely done 1 day before or one day after visit 5	14 up to 21 days before liver resection at baseline and 7 days after the operation
liver function percentage increase	LiMAx-test: LiMAx liver function testing will be performed before surgery and on postoperative days 4 and 7 to evaluate functional recovery after liver resection.	14 up to 21 days before liver resection at baseline (all), on preoperative day 1 (PVE group only) and on postoperative day 4 and day 7 (all)
Time to functional recovery	The evaluation of time to functional recovery will start on POD 0 and will be scored daily until discharge from the hospital with the following criteria; Adequate pain control on oral analgesics only; Eating and drinking properly without the need of IV fluids; Independently mobile or mobile at preoperative level; Standard laboratory tests and liver function returning to normal level When all of these criteria are met, we consider a patient functional recovered.	minimum 14 days starting on operation day

Collaborators and Investigators

• Sponsor: RWTH Aachen University

Publications and helpful links

General Publications

• Bednarsch J, Czigany Z, Loosen SH, Heij L, Ruckgaber L, Maes H, Krause JP, Reen M, Toteva B, Vosdellen T, Bruners P, Lang SA, Ulmer TF, Roderburg C, Luedde T, Neumann UP. Perioperative rifaximin is not associated with enhanced functional and volumetric recovery after major liver resection. Sci Rep. 2021 Sep 9;11(1):17936. doi: 10.1038/s41598-021-97442-w.

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): November 20, 2020
• Study Completion (Actual): November 20, 2020

Study Registration Dates

• First Submitted: September 14, 2015
• First Submitted That Met QC Criteria: September 17, 2015
• First Posted (Estimate): September 21, 2015

Study Record Updates

• Last Update Posted (Actual): November 1, 2021
• Last Update Submitted That Met QC Criteria: October 28, 2021
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: inflammation; fibrosis; Rifaximin; Liver resection
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Anti-Infective Agents; Gastrointestinal Agents; Anti-Bacterial Agents; Rifaximin
• Other Study ID Numbers: CTC-A 13-129