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Molecular Adsorbent Recirculating System (MARS®) in Hypoxic Hepatitis (MARS in HH)

Primary Purpose

Hypoxic Hepatitis, Ischemic Hepatitis, Shock Liver

Status
Unknown status
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
MARS
Sponsored by
Medical University of Vienna
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypoxic Hepatitis

Eligibility Criteria

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

Inclusion Criteria:

  • presence of severe hypoxic hepatitis with aminotransferase levels > 40 times the upper limit of normal
  • duration of hypoxic hepatitis more than 12 hours
  • age >/= 18 years

Exclusion Criteria:

  • age < 18 years
  • pregnancy
  • DNR - order
  • liver cirrhosis
  • Cardiopulmonary resuscitation with unknown neurological outcome and/or hypoxic brain damage
  • Expected survival of less than 24 hours

Sites / Locations

  • Medical University Vienna, Dpt. of Internal Medicine 3, Div. of Gastroenterology and HepatologyRecruiting
  • University Medical Center Hamburg-EppendorfRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Experimental

Arm Label

Control

MARS-Group

Arm Description

Patients with severe HH will be treated with standard medical therapy (i.e. vasopressor support with norepinephrine in refractory hypotension = RR mean < 65 mmHg, positive inotropic support with dobutamine if the central venous oxygen saturation < 70%, renal replacement therapy in case of severe metabolic acidosis and/or renal failure, antibiotic treatment in case of suspected or proven infection, mechanical ventilation in case of severe hypoxemia or hypercapnia and/or GCS <= 8.

20 patients will be allocated by randomization to the MARS arm. Additionally to standard medical therapy they will receive 4 MARS sessions on three consecutive days, MARS® therapy will be applied for at least 12 hours per session. Thereafter, MARS® treatment will be continued if the patient still has increasing aminotransferase levels, requires vasopressor support or suffers from cholestasis (defined as serum bilirubin levels > 5 mg/dL) for 3 sessions again. There will be a maximum of 7 MARS ® sessions per patient.

Outcomes

Primary Outcome Measures

difference of the indocyanine plasma disappearance rate (ICG-PDR)
The primary endpoint will be the difference of the indocyanine plasma disappearance rate (ICG-PDR) at day 7. Only in case of major differences in baseline values of ICG-PDR we will use the change from baseline to day 7 of ICG-PDR (delta ICG-PDR) as outcome. Assuming normal distribution of ICG-PDR, we will formally test the null-hypothesis of no difference between intervention group and control using an independent sample t-test. The assumption of a normal distribution will be founded on visually inspecting a histogram and using the Shapiro Wilks test for normal distribution. If the assumption of normality does not hold data will be compared using the Mann-Whitney U-test. A p-level of < 0.05 will be considered statistically significant. Furthermore a linear random coefficient model will be used to incorporate daily measurements of ICG-PDR during the course of the study in terms of a repeated measures design.

Secondary Outcome Measures

duration of vasopressor support
ICU - length of stay
hospital - length of stay
7-day mortality
28 day mortality
number of organ failure on day 7
number of organ failure on day 28
markers of liver function
especially occurrence of jaundice (defined as total bilirubin levels > 3 mg/dL) will be documented
number of vasopressor free days
systemic hemodynamics
systemic blood pressure, heart rate, cardiac index, central venous oxygen saturation, systemic vascular resistance index, global enddiastolic volume index, stroke volume variation, extravascular lung water index, pulse pressure variation, intrathoracic blood volume index, cardiac function index, central venous pressure
number of complications of HH
following complications will be encountered: cholestasis, secondary sclerosing cholangitis, hepatic encephalopathy grade 3 & 4, hypoglycemia, intraabdominal hypertension, new onset of infections, renal failure, hepatopulmonary syndrome
biomarkers
blood samples will be collected the assess markers of inflammation, markers of endothelial function, markers of cardiac function, markers of cholestasis, markers of liver cell necrosis etc
duration of mechanical ventilation
necessity of renal replacement therapy
duration of renal replacement therapy
90 days mortality

Full Information

First Posted
September 16, 2012
Last Updated
September 21, 2016
Sponsor
Medical University of Vienna
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1. Study Identification

Unique Protocol Identification Number
NCT01690845
Brief Title
Molecular Adsorbent Recirculating System (MARS®) in Hypoxic Hepatitis
Acronym
MARS in HH
Official Title
Molecular Adsorbent Recirculating System (MARS®) for the Treatment of Patients With Hypoxic Hepatitis - a Prospective Randomized Controlled Clinical Study
Study Type
Interventional

2. Study Status

Record Verification Date
September 2016
Overall Recruitment Status
Unknown status
Study Start Date
June 2012 (undefined)
Primary Completion Date
June 2017 (Anticipated)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Medical University of Vienna

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Hypoxic hepatitis (HH) is reported to be the most frequent cause of elevated aminotransferase levels in hospital. Up to 10 % of critically ill patients develop HH during the course of their intensive care unit (ICU) stay. Occurrence of HH is a life threatening event and ICU-mortality is reported to be up to 60%. Early therapeutic intervention is of central prognostic importance in patients with HH to improve the hemodynamic impairment as early as possible, to reduce hyperammonemia and hepatic encephalopathy, to avoid progression of organ failure and to improve outcome. Studies reported that Molecular Adsorbent Recirculating System (MARS®) therapy improved the hemodynamic situation in patients with acute and acute on chronic liver failure. The study hypothesis is that MARS® therapy in critically ill patients with severe HH improves hepatic hemodynamics and function and consecutively the course of the disease. 40 patients with suffering of severe HH with aminotransferase levels > 40 times the upper limit of normal of more than 12 hours will be randomized 1:1 to MARS® therapy (n=20) or conventional therapy (n=20). 4 MARS®-sessions will be performed on three consecutive days, each for at least 12 hours. Treatment will be continued under special circumstances. The maximum duration of the treatment phase is 7 days. The primary endpoint is the difference of the indocyanine plasma disappearance rate at day 7. The expected duration of the study is 2 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoxic Hepatitis, Ischemic Hepatitis, Shock Liver, Hypoxic Liver Injury, Acute Liver Failure

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Control
Arm Type
No Intervention
Arm Description
Patients with severe HH will be treated with standard medical therapy (i.e. vasopressor support with norepinephrine in refractory hypotension = RR mean < 65 mmHg, positive inotropic support with dobutamine if the central venous oxygen saturation < 70%, renal replacement therapy in case of severe metabolic acidosis and/or renal failure, antibiotic treatment in case of suspected or proven infection, mechanical ventilation in case of severe hypoxemia or hypercapnia and/or GCS <= 8.
Arm Title
MARS-Group
Arm Type
Experimental
Arm Description
20 patients will be allocated by randomization to the MARS arm. Additionally to standard medical therapy they will receive 4 MARS sessions on three consecutive days, MARS® therapy will be applied for at least 12 hours per session. Thereafter, MARS® treatment will be continued if the patient still has increasing aminotransferase levels, requires vasopressor support or suffers from cholestasis (defined as serum bilirubin levels > 5 mg/dL) for 3 sessions again. There will be a maximum of 7 MARS ® sessions per patient.
Intervention Type
Device
Intervention Name(s)
MARS
Other Intervention Name(s)
Molecular adsorbent recirculating system (MARS®)
Intervention Description
Molecular adsorbent recirculating system (MARS®) can be used in patients with acute liver failure for bridging to liver transplantation. Studies reported that MARS® therapy improved the hemodynamic situation in patients with acute and acute on chronic liver failure. Several groups observed an increase in arterial pressure, systemic vascular resistance index, a decrease in portal pressure and improvement of renal blood flow. Furthermore, studies demonstrated that MARS therapy reduces ammonia levels and improves hepatic encephalopathy.
Primary Outcome Measure Information:
Title
difference of the indocyanine plasma disappearance rate (ICG-PDR)
Description
The primary endpoint will be the difference of the indocyanine plasma disappearance rate (ICG-PDR) at day 7. Only in case of major differences in baseline values of ICG-PDR we will use the change from baseline to day 7 of ICG-PDR (delta ICG-PDR) as outcome. Assuming normal distribution of ICG-PDR, we will formally test the null-hypothesis of no difference between intervention group and control using an independent sample t-test. The assumption of a normal distribution will be founded on visually inspecting a histogram and using the Shapiro Wilks test for normal distribution. If the assumption of normality does not hold data will be compared using the Mann-Whitney U-test. A p-level of < 0.05 will be considered statistically significant. Furthermore a linear random coefficient model will be used to incorporate daily measurements of ICG-PDR during the course of the study in terms of a repeated measures design.
Time Frame
Days 1-7
Secondary Outcome Measure Information:
Title
duration of vasopressor support
Time Frame
1-28
Title
ICU - length of stay
Time Frame
1-28
Title
hospital - length of stay
Time Frame
1-90
Title
7-day mortality
Time Frame
7 days
Title
28 day mortality
Time Frame
28 days
Title
number of organ failure on day 7
Time Frame
7 days
Title
number of organ failure on day 28
Time Frame
28 days
Title
markers of liver function
Description
especially occurrence of jaundice (defined as total bilirubin levels > 3 mg/dL) will be documented
Time Frame
1-28
Title
number of vasopressor free days
Time Frame
28 days
Title
systemic hemodynamics
Description
systemic blood pressure, heart rate, cardiac index, central venous oxygen saturation, systemic vascular resistance index, global enddiastolic volume index, stroke volume variation, extravascular lung water index, pulse pressure variation, intrathoracic blood volume index, cardiac function index, central venous pressure
Time Frame
7 days
Title
number of complications of HH
Description
following complications will be encountered: cholestasis, secondary sclerosing cholangitis, hepatic encephalopathy grade 3 & 4, hypoglycemia, intraabdominal hypertension, new onset of infections, renal failure, hepatopulmonary syndrome
Time Frame
1-28
Title
biomarkers
Description
blood samples will be collected the assess markers of inflammation, markers of endothelial function, markers of cardiac function, markers of cholestasis, markers of liver cell necrosis etc
Time Frame
0-28
Title
duration of mechanical ventilation
Time Frame
1-28
Title
necessity of renal replacement therapy
Time Frame
1-28
Title
duration of renal replacement therapy
Time Frame
1-28
Title
90 days mortality
Time Frame
90 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: presence of severe hypoxic hepatitis with aminotransferase levels > 40 times the upper limit of normal duration of hypoxic hepatitis more than 12 hours age >/= 18 years Exclusion Criteria: age < 18 years pregnancy DNR - order liver cirrhosis Cardiopulmonary resuscitation with unknown neurological outcome and/or hypoxic brain damage Expected survival of less than 24 hours
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Valentin Fuhrmann, Prof
Phone
0043140400
Ext
4741
Email
valentin.fuhrmann@meduniwien.ac.at
First Name & Middle Initial & Last Name or Official Title & Degree
Thomas Horvatits, MD
Phone
0043140400
Ext
4741
Email
thomas.horvatits@meduniwien.ac.at
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Valentin Fuhrmann, Prof
Organizational Affiliation
Medical University Vienna
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medical University Vienna, Dpt. of Internal Medicine 3, Div. of Gastroenterology and Hepatology
City
Vienna
ZIP/Postal Code
1090
Country
Austria
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Valentin Fuhrmann, Prof
Phone
0043140400
Ext
4741
Email
valentin.fuhrmann@meduniwien.ac.at
First Name & Middle Initial & Last Name & Degree
Thomas Horvatitis, MD
Phone
0043140400
Ext
4741
Email
thomas.horvatitis@meduniwien.ac.at
First Name & Middle Initial & Last Name & Degree
Valentin Fuhrmann, Prof
Facility Name
University Medical Center Hamburg-Eppendorf
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stefan Kluge, Prof

12. IPD Sharing Statement

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Molecular Adsorbent Recirculating System (MARS®) in Hypoxic Hepatitis

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