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

Primary Purpose

Malignant Liver Disease, Major Liver Resection

Status
Terminated
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
XIFAXAN® (Rifaximin)
Sponsored by
RWTH Aachen University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Liver Disease focused on measuring Liver resection, fibrosis, inflammation, Rifaximin

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • RWTH Aachen University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

film-coated Rifaximin (550 mg)

standard therapy

Arm Description

(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.

Patients directed to the control group will not receive Rifaximin.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
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
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.
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.

Full Information

First Posted
September 14, 2015
Last Updated
October 28, 2021
Sponsor
RWTH Aachen University
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1. Study Identification

Unique Protocol Identification Number
NCT02555293
Brief Title
Administration of Rifaximin to Improve Liver Regeneration and Outcome Following Major Liver Resection
Acronym
ARROW
Official Title
Administration of Rifaximin to Improve Liver Regeneration and Outcome Following Major Liver Resection
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Terminated
Why Stopped
Prematurely terminated due to organisational reasons
Study Start Date
February 2016 (undefined)
Primary Completion Date
November 20, 2020 (Actual)
Study Completion Date
November 20, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
RWTH Aachen University

4. Oversight

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Liver Disease, Major Liver Resection
Keywords
Liver resection, fibrosis, inflammation, Rifaximin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
96 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
film-coated Rifaximin (550 mg)
Arm Type
Experimental
Arm Description
(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.
Arm Title
standard therapy
Arm Type
No Intervention
Arm Description
Patients directed to the control group will not receive Rifaximin.
Intervention Type
Drug
Intervention Name(s)
XIFAXAN® (Rifaximin)
Other Intervention Name(s)
NDA 22-554
Primary Outcome Measure Information:
Title
Effect of Rifaximin on postoperative liver function
Description
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
Time Frame
Postoperative day 7 in relation to postoperative day 4
Secondary Outcome Measure Information:
Title
postoperative morbidity/Complications
Description
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
Time Frame
minimum 14 days after liver resection
Title
Liver volume percentage increase
Description
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
Time Frame
14 up to 21 days before liver resection at baseline and 7 days after the operation
Title
liver function percentage increase
Description
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.
Time Frame
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)
Title
Time to functional recovery
Description
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.
Time Frame
minimum 14 days starting on operation day

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients undergoing a liver resection of at least 4 segments Age > 18 years < 80 years BMI 18-40 Patients with ASA (American Society of Anesthesiologists) I-III Written informed consent prior to study participation Exclusion Criteria: Patients with ASA IV-V Contraindication for MRI (see 5.4.3) Underlying chronic liver disease such as severe fibrosis or liver cirrhosis Need for procedures additive to partial liver resection Participation in other liver related trials BMI > 40 Previous liver transplantation or porto-systemic shunt Concomitant acute infectious diseases Renal insufficiency Hypersensitivity to Rifaximin Concomitant HIPEC (hypertherme intraperitoneale chemoperfusion) treatment ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) 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. Lactating females 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. The subject received an investigational drug within 30 days prior to inclusion into this study 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 The subject is unwilling or unable to follow the procedures outlined in the protocol The subject is mentally or legally incapacitated
Facility Information:
Facility Name
RWTH Aachen University
City
Aachen
ZIP/Postal Code
52074
Country
Germany

12. IPD Sharing Statement

Citations:
PubMed Identifier
34504196
Citation
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.
Results Reference
derived

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

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