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Methylprednisolone N Acetylcysteine in Hepatic Resections (MENHIR)

Primary Purpose

Ischemic Reperfusion Injury, Insufficiency; Hepatic, Postoperative, Liver Tumour

Status
Terminated
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Methylprednisolone
N-acetylcysteine
Sponsored by
Istituto Clinico Humanitas
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ischemic Reperfusion Injury focused on measuring N-Acetylcysteine, Methylprednisolone, Liver ischemia reperfusion injury, Pringle manoeuvre, Hepatic resection

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Any sex, any race, any ethnicity
  • Age > 18
  • Primary and secondary liver tumors
  • Normal renal function
  • Anticipated Pringle's length > 30 minutes

Exclusion Criteria:

  • Renal failure of any grade
  • ASA 4
  • Associate major surgery
  • Intraoperative bleeding > 1500 ml
  • Allergy to N-acetylcysteine or Methylprednisolone

Sites / Locations

  • Istituto Clinico Humanitas IRCCS

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

N-acetylcysteine

Methylprednisolone

Placebo

Arm Description

Patients were randomized to this arm will receive a bolus of N-acetylcysteine in an hour of 150 mg/kg after the beginning of the operation. After the bolus will start a 6-hour infusion of 50mg/kg/h of N-acetylcysteine.

Patients were randomized to this arm will receive a bolus of methylprednisolone in an hour of 500 mg after the beginning of the operation. After the bolus will start a 6-hour infusion of placebo (Ringer's acetate).

Patients were randomized to this arm will receive placebo (Ringer's acetate) in an hour after the beginning of the operation. After the bolus will start a 6-hour infusion of placebo (Ringer's acetate).

Outcomes

Primary Outcome Measures

A decrease of 100 UI/L of AST and ALT compared with placebo.
The primary endpoint of the study is the modulation of the IR injury made by NAC and/or MET in patients undergoing liver surgery. For this purpose a decrease of 100 UI/L of AST and ALT is expected compared with placebo.

Secondary Outcome Measures

Difference in total bilirubin expression.
This secondary endpoint want to assess difference in total bilirubin expression between the intervention groups and the placebo group.
Difference in blood transfusions.
This secondary endpoint want to assess difference in blood transfusion between the intervention groups and the placebo group.

Full Information

First Posted
November 7, 2012
Last Updated
November 9, 2013
Sponsor
Istituto Clinico Humanitas
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1. Study Identification

Unique Protocol Identification Number
NCT01726465
Brief Title
Methylprednisolone N Acetylcysteine in Hepatic Resections
Acronym
MENHIR
Official Title
Phase II Randomized Double Blind Trial of Methylprednisolone and N-acetylcysteine in Hepatic Resections.
Study Type
Interventional

2. Study Status

Record Verification Date
November 2013
Overall Recruitment Status
Terminated
Why Stopped
The first phase was completed
Study Start Date
November 2012 (undefined)
Primary Completion Date
October 2013 (Actual)
Study Completion Date
November 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Istituto Clinico Humanitas

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a prospective double-blind randomized phase II clinical trial, with two groups of intervention (one with administration of N-acetylcysteine and the other with administration of methylprednisolone), and one group of placebo. The purpose of this study is to investigate the role of N-acetylcysteine and Methylprednisolone in the modulation of warm ischemia of the liver during hepatic resection. In fact to avoid massive blood loss in liver surgery, continuous or intermittent vascular clamping of the hepatic hilum ('Pringle maneuver') is generally used with good results. However, as a consequence, ischemia and subsequent reperfusion result in complex metabolic, immunological, and microvascular changes, which together might contribute to hepatocellular damage and dysfunction. This phenomenon, known as ischemia-reperfusion (IR) injury of the liver, is a complex multi-path process leading to the activation of some inflammatory pathways. Any patient candidate to liver resection will be enrolled in the study based on the aforementioned criteria. The primary objective of the study is to assess the real efficacy of Methylprednisolone and N-acetylcysteine in reducing the secondary damage from ischemia reperfusion injury in liver resection and in reducing inflammatory response. Secondary objective of the study is whether the reduction of ischemia-reperfusion injury results in: lower incidence of postoperative liver failure, improvement of postoperative liver function, and reduction of blood components transfusions. The randomization will be done the day before the operation. The drugs will be prepared in a blind fashion by the hospital pharmacy. The hospital pharmacy will provide to each patient a drip to make bolus of about an hour before the start of the liver resection and a syringe pump for an infusion of approximately 6 hours. If the patient is enrolled and randomized in the placebo arm, he/she will receive 250 ml of glucose 5% plus the infusion of 100 ml of glucose 5% If the patient is randomized in the Methylprednisolone arm, he/she will receive a dose of 500 mg in 250 ml of glucose 5% plus 100 mg of glucose 5%. If the patient is randomized in the N-acetylcysteine arm, he/she will receive a dose of 150 mg/kg in 250 ml of glucose 5% plus N-acetylcysteine 50 mg/kg in 100 ml glucose 5%. Systematic sampling of liver function tests will be done the day before the operation, at the end of the operation, as well as in postoperative day 1, 3, 5 and 7.
Detailed Description
Elective liver resection is performed mainly for benign and malignant liver tumors. The malignant tumors may arise primarily within the liver (hepatocellular carcinoma and cholangiocarcinoma) or represent metastases from malignancies of other organs. During hepatic resection, the risk of severe intraoperative bleeding represents a major risk. To avoid massive blood loss, continuous or intermittent vascular clamping of the hepatic artery and portal vein ('Pringle maneuver') is an efficient method to reduce hemorrhage. However, as a consequence, ischemia and subsequent reperfusion result in complex metabolic, immunological, and microvascular changes, which together might contribute to hepatocellular damage and dysfunction. This phenomenon, known as ischemia-reperfusion (IR) injury of the liver, is a complex multi-path process leading to the activation of inflammatory pathways, in which cellular injury results from events occurring during both the ischemic and reperfusion phases. The key mechanism of tissue injury is the intense and excessive inflammatory response to reperfusion. Although initially considered a condition mediated by innate immune responses, IR injury also triggers adaptive immunity, such as activated Kupffer cells that express cytokines and chemokines thereby leading to further neutrophils activation and recruitment. Neutrophils inflict tissue damage on the liver through the generation of some reactive oxygen-species (ROS) and of some proteolytic enzymes. Various methods and many pharmacological agents have been attempted to decrease the IR injury associated with prolonged duration of vascular occlusion, no one is a standard of care in protocols for liver resection. After a tough review of the literature we considered the most promising data on two drugs: N-acetylcysteine (NAC) and Methylprednisolone (MET). NAC seems more active in ischemic phase and in the early reperfusion period. In fact when blood flow is interrupted cellular adenosine triphosphate (ATP) is depleted and there is a buildup of adenosine monophosphate, which is catabolized to hypoxanthine that is oxidized to xanthine by the enzyme xanthine oxidase, generating ROS in the process. Glutathione (GSH), that is an antioxidant present in the liver, offers protection against oxygen free radicals. During hypoxia, GSH stores are consumed, which predisposes to oxidative injury. N-acetylcysteine (NAC) serves as a precursor to GSH and can replenish intracellular GSH stores, it directly scavenge hydrogen peroxide. It has also been shown to impair the chemo taxis and generation of oxygen radicals by human phagocytic cells through an anti-inflammatory action, inhibit cytokine-mediated induction of nitric oxide synthase in human hepatocytes in vitro and have probably an anti-inflammatory mechanism of hepatoprotection against oxidative injury from nitric oxide (NO). So there is a substantial body of experimental work evaluating the role of NAC in liver I/R injury, but these studies are small in terms of patients, and more importantly they utilize a widely disparate range of protocols of administration. Yet, there is only one small study describing the outcome of a randomized controlled trial in patients undergoing liver resection. Thus, we decide, after the 'a priori' sample power calculation, to investigate the effect of NAC in patients submitted to hepatic resection systematically performed with the 'Pringle maneuver' using the same loading dose and subsequent infusion of some Randomized Clinical Trial in liver transplantation. Together with NAC we decide to investigate the effects of MET, which is a glucocorticoid steroid that acts as an anti-inflammatory agent, reducing inflammatory markers and apoptotic cell count in experimental liver IR injury. To our knowledge, there are only three published studies that evaluated the role of MET in liver resection, but only one of those was associated to a significant decrease of transaminase enzymes (AST and ALT). The basic hypothesis is that the protective effects of Methylprednisolone may become more apparent as the extent of liver resection and/or the duration of vascular occlusion increases. Therefore, the investigators designed a randomized controlled trial with adequate sample size with the aim to recognize in the intervention groups, one with NAC and one with MET, a statistically significant reduction of ALT and AST (100U/L) compared with the placebo group. No stratifications are planned. Two comparisons are planned Experimental (MET+NAC) vs. Standard and MET vs. NAC. A randomization ratio MET:NAC:STD=1:1:1 is planned; for the Experimental (EXP) Vs Standard (STD) comparison the allocation ratio is therefore 2:1. In order to verify the superiority of EXP (MET+NAC) it was assumed that with the standard treatment the mean value of ALT was 800 units with a standard deviation (SD) of 100, as reported in literature. the investigators decided to consider of interest a reduction of 100 for the experimental treatments leading to consider a value of 700 as desirable. Considering α value of 0.025 (one-sided) and a power of 90%, a total of 48 evaluable patients are required (16 in each arm). If the test results in a statistical significant advantage for EXP arms (MET+NAC), the study will continue the accrual for MET and NAC only, with the aim of comparing MET vs. NAC, considering a difference of interest of 50 units, with α value of 0.05 (two-sided) and a power of 80%. Further 94 Pts need to be enrolled for a total of 126 evaluable patients available for the comparison of MET vs. NAC. The total sample size will be 142 (63 treated with MET, 63 treated with NAC and 16 treated with standard therapy).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ischemic Reperfusion Injury, Insufficiency; Hepatic, Postoperative, Liver Tumour
Keywords
N-Acetylcysteine, Methylprednisolone, Liver ischemia reperfusion injury, Pringle manoeuvre, Hepatic resection

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare Provider
Allocation
Randomized
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
N-acetylcysteine
Arm Type
Experimental
Arm Description
Patients were randomized to this arm will receive a bolus of N-acetylcysteine in an hour of 150 mg/kg after the beginning of the operation. After the bolus will start a 6-hour infusion of 50mg/kg/h of N-acetylcysteine.
Arm Title
Methylprednisolone
Arm Type
Experimental
Arm Description
Patients were randomized to this arm will receive a bolus of methylprednisolone in an hour of 500 mg after the beginning of the operation. After the bolus will start a 6-hour infusion of placebo (Ringer's acetate).
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients were randomized to this arm will receive placebo (Ringer's acetate) in an hour after the beginning of the operation. After the bolus will start a 6-hour infusion of placebo (Ringer's acetate).
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone
Other Intervention Name(s)
methylprednisolone sodium succinate
Intervention Description
Methylprednisolone is a glucocorticoid, which is an adrenocortical steroid. The chemical name for methylprednisolone is pregna-1,4-diene-3,20-dione, 11,17,21-trihydroxy-6-methyl-, (6α,11β)-and the molecular weight is 374.48. It is an analog of naturally occurring glucocorticoid (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Methylprednisolone is used for their potent anti-inflammatory effects in disorders of many organ systems, it modify the body's immune responses to diverse stimuli. The usual dosage of medication varies in relation to pathology for which is prescribed: normally varies from about 40-60 mg per day up to very high doses of 30 mg/kg bolus as used in spinal cord injury.
Intervention Type
Drug
Intervention Name(s)
N-acetylcysteine
Other Intervention Name(s)
N-acetyl cysteine
Intervention Description
Acetylcysteine is the N-acetyl derivative of the naturally occurring amino acid, L-cysteine. Chemically, it is N-acetyl-L-cysteine. The compound is a white crystalline powder which melts at 104°-110°C and has a very slight odor. Acetylcysteine may form cysteine, disulfides, and conjugates in vivo (N, N'-diacetylcysteine, N-acetylcysteine- cysteine, N-acetylcysteine-glutathione, N-acetylcysteine-protein, etc). No metabolites were identified. Acetylcysteine likely protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite.
Primary Outcome Measure Information:
Title
A decrease of 100 UI/L of AST and ALT compared with placebo.
Description
The primary endpoint of the study is the modulation of the IR injury made by NAC and/or MET in patients undergoing liver surgery. For this purpose a decrease of 100 UI/L of AST and ALT is expected compared with placebo.
Time Frame
Systematic sampling of liver function tests the day before the operation, at the end of the operation, as well as in postoperative day 1, 3, 5 and 7
Secondary Outcome Measure Information:
Title
Difference in total bilirubin expression.
Description
This secondary endpoint want to assess difference in total bilirubin expression between the intervention groups and the placebo group.
Time Frame
Systematic sampling of liver function tests the day before the operation, at the end of the operation, as well as in postoperative day 1, 3, 5 and 7
Title
Difference in blood transfusions.
Description
This secondary endpoint want to assess difference in blood transfusion between the intervention groups and the placebo group.
Time Frame
Systematic sampling of liver function tests the day before the operation, at the end of the operation, as well as in postoperative day 1, 3, 5 and 7

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Any sex, any race, any ethnicity Age > 18 Primary and secondary liver tumors Normal renal function Anticipated Pringle's length > 30 minutes Exclusion Criteria: Renal failure of any grade ASA 4 Associate major surgery Intraoperative bleeding > 1500 ml Allergy to N-acetylcysteine or Methylprednisolone
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Guido Torzilli, PhD
Organizational Affiliation
Facoltà di Medicina e Chirurgia dell'Università degli Studi di Milano
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Giovanni Bordone, PhD
Organizational Affiliation
Facoltà di Medicina e Chirurgia dell'Università degli Studi di Milano
Official's Role
Principal Investigator
Facility Information:
Facility Name
Istituto Clinico Humanitas IRCCS
City
Rozzano
State/Province
Milano
ZIP/Postal Code
20089
Country
Italy

12. IPD Sharing Statement

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Methylprednisolone N Acetylcysteine in Hepatic Resections

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