G-CSF Plus NAC In Severe Alcoholic Hepatitis

September 18, 2017 updated by: Dr.Virendra Singh, Postgraduate Institute of Medical Education and Research

Granulocyte Colony Stimulating Factor Plus N-Acetyl Cysteine In Severe Alcoholic Hepatitis

Alcoholic hepatitis is related to very high mortality rate. About 40% of the patients are died within first 6 months after the detection of the clinical syndrome. Therefore, it is very essential for proper diagnosis and early treatment. In response to acute or chronic liver damage, bone marrow derived stem cells can spontaneously populate liver and differentiate into hepatic cells. Animal and human studies suggested that injured hepatocyte may be replaced by pluripotent bone marrow cells. However, this hepatocyte repopulation is highly dependent on varieties of liver injury and therapeutic conditions6. The studies has suggested Granulocyte-colony stimulating factors (G-CSF) can regenerate hepatocyte by fusing with hematopoietic cells, thereby enhancing the liver histology and survival rate.

G-CSF is a cytokine capable to regulate a number of functions in neutrophils. In three recent studies mobilization of bone marrow stem cells induced by G-CSF was observed in patients with alcoholic hepatitis. In two of this studies there was a survival benefit with the use of G-CSF.

Alcoholism leads to decrease in endogenous antioxidant potential. Alcoholic liver disease (ALD) patients show low endogenous antioxidants. Chronic ethanol consumption cause selective deficiency in the availability of reduced glutathione (GSH) in mitochondria has been reported. This is due to impaired functioning of GSH transporter from cytosol to mitochondrial matrix. The effect on glutathione replenishing potential by N-acetyl cysteine (NAC) can be used to reduce oxidative stress, which also has excellent safety profile. Therefore, NAC can be used for severe alcoholic hepatitis treatment due to its therapeutic potential factor. NAC also inhibit apoptosis and pro-inflammatory cytokine production. In a study high doses of intravenous N-acetyl cysteine therapy for 14 days conferred neither survival benefits nor early biological improvement in severe alcoholic hepatitis patients with adequate nutritional support.However, these results must be viewed with caution, since the study suffered from a lack of power. In a recent study, NAC and corticosteroids combination therapy benefits among patients with severe acute alcoholic hepatitis in 1 month survival, although the final outcome at 6 month survival was not improved. There are no studies on the use of combination therapy of NAC plus G-CSF in patient with severe alcoholic hepatitis.

Therefore we plan to study the safety and efficacy of combination therapy of G-CSF and NAC in the patients with alcoholic hepatitis.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Patients with severe alcoholic hepatitis, admitted to Department of Hepatology PGIMER, Chandigarh from July 2014 to December 2016 will be included in the study.

METHODS

This will be an open label trial. A randomization code is generated by random number table. The patients will be randomized to receive standard medical therapy of pentoxifylline only as control and combination therapy of Pentoxifylline with NAC and G-CSF as cases. There will be one control and two cases as below:

1) Pentoxifylline (control) 2) Pentoxifylline+G-CSF (case 1) 3) Pentoxifylline+G-CSF +NAC (case2) A) Pentoxifylline 400 mg thrice daily for 28 days A) Pentoxifylline 400 mg thrice daily for 28 days plus G-CSF 5 mcg/kg every 12 hourly for consecutive 5 days A) Pentoxifylline 400 mg thrice daily for 28 days plus G-CSF 5 mcg/kg every 12 hourly for 5 days plus NAC 300 mg/kg on day 1 (150 mg/kg in 250 ml of 5% dextrose over a minute of 30 minutes,50 mg/kg in 500ml 5% dextrose over a period of 4 hours, 100mg /kg in 1000 ml of 5% dextrose over a period of 16 hours ) and on day 2 through 5 100mg /kg/day in 1000ml of glucose solution.

This will be a single time therapy. Patients will be admitted in the department of hepatology and will be assessed everyday clinically as well as by laboratory tests during therapy to assess safety and effects of treatment.

  1. Total leukocytes count will be assessed daily.
  2. Circulating CD 34 positive cells will be measured on day 0 and 6 of G-CSF therapy.
  3. In addition, ultrasonography will be performed at day 1 and 6 in order to evaluate difference in spleen size and portal vein flow.
  4. Biochemical, coagulation, and hematological parameters (Liver function tests, Renal Function Tests, Prothrombin Time, International Normalised Ratio, etc.) will be monitored periodically, daily for 1 week, then weekly for 1month and monthly for three month.

All patients will be followed at weekly interval for 1 month and then monthly for 3 months.

Outcome:

Primary Objectives:

Survival at 3 months

Secondary Objectives:

Mobilisation of CD34 positive cells in peripheral blood. Clinical/biochemical improvement in liver function profile. Improvement in prognostic scores-Maddrey's Discriminant function, MELD score, and Child score.

Safety and efficacy of G-CSF and NAC in alcoholic hepatitis

Study Type

Interventional

Enrollment (Anticipated)

60

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • India
      • Chandigarh, India, 160012

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

Alcoholic hepatitis patients:

  1. More than 10 years of heavy alcohol consumption (mean intake ≈ 100 g/day).
  2. Elevated aspartate aminotransferase level (but <500 IU per millilitre) and Ratio ofAST/ALT≥2 times
  3. Elevated serum total bilirubin level ≥ 5 mgdL (86 μmol/L)
  4. Elevated INR(≥1.5) and
  5. Neutrophilia. Patient with Maddrey's DF of≥ 32 will be included in the study, with or without biopsy.

Exclusion Criteria:

  1. Age < 18 and > 75 years
  2. Hepatocellular carcinoma or portal vein thrombosis
  3. Refusal to participate in the study
  4. Serum creatinine >1.0 mg%
  5. Hepatic encephalopathy- grade 3 or 4
  6. Upper gastrointestinal bleed in last ten days
  7. Uncontrolled bacterial infection
  8. Human immunodeficiency virus, Hepatitis B virus, Hepatitis C virus seropositivity, Autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha1-antitrypsin deficiency
  9. Pregnancy
  10. Glucocorticoid treatment
  11. Significant co-morbidity
  12. Previous known hypersensitivity to G-CSF/NAC

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Standard Medical therapy
standard medical therapy
Drug: standard medical therapy
Standard medical therapy involves primary treatment with pentoxifylline at a dose of 400 mg three times a day and normal hospital nutrition (1800 to 2000 kcal per day). Diuretics, sodium restriction and albumin for treatment of ascites or fresh frozen plasma for coagulopathy or antibiotics for any focus of infection as spontaneous bacterial peritonitis (SBP), pneumonia, cellulitis, and urinary tract infection as indicated.
Experimental: G-CSF
standard medical therapy plus G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days
Drug: standard medical therapy
Standard medical therapy involves primary treatment with pentoxifylline at a dose of 400 mg three times a day and normal hospital nutrition (1800 to 2000 kcal per day). Diuretics, sodium restriction and albumin for treatment of ascites or fresh frozen plasma for coagulopathy or antibiotics for any focus of infection as spontaneous bacterial peritonitis (SBP), pneumonia, cellulitis, and urinary tract infection as indicated.
Drug: G-CSF
G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days
Experimental: G-CSF and NAC
standard medical therapy plus G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days plus NAC (day 1: NAC at 150, 50, and 100 mg/kg in 250, 500, and 1000 ml of 5% glucose solution over 30 minutes, 4 hours, and 16 hours, respectively; days 2 through 5: 100 mg/kg/day in 1000 ml of 5% glucose solution)
Drug: standard medical therapy
Standard medical therapy involves primary treatment with pentoxifylline at a dose of 400 mg three times a day and normal hospital nutrition (1800 to 2000 kcal per day). Diuretics, sodium restriction and albumin for treatment of ascites or fresh frozen plasma for coagulopathy or antibiotics for any focus of infection as spontaneous bacterial peritonitis (SBP), pneumonia, cellulitis, and urinary tract infection as indicated.
Drug: G-CSF
G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days
Drug: n-Acetylcysteine
n-Acetylcysteine at 150, 50, and 100 mg/kg in 250, 500, and 1000 ml of 5% glucose solution over 30 minutes, 4 hours, and 16 hours, respectively; days 2 through 5: 100 mg/kg/day in 1000 ml of 5% glucose solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Primary end point- Survival at the end of 90 days
Time Frame: 90 days
90 days

Secondary Outcome Measures

Outcome Measure
Time Frame
mobilization of CD34+ cells in peripheral blood
Time Frame: 6 days
6 days
improvement in MELD score
Time Frame: 90 days
90 days
Number of participants with treatment-related adverse events in the different treatment groups
Time Frame: 90 days
90 days
improvement in modified Discriminant Factor
Time Frame: 90 days
90 days
improvement in Child Turcotte Pugh score
Time Frame: 90 days
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Postgraduate Institute of Medical Education and Research

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2014

Primary Completion (Anticipated)

December 1, 2017

Study Completion (Anticipated)

December 1, 2017

Study Registration Dates

First Submitted

November 9, 2016

First Submitted That Met QC Criteria

November 18, 2016

First Posted (Estimate)

November 22, 2016

Study Record Updates

Last Update Posted (Actual)

September 19, 2017

Last Update Submitted That Met QC Criteria

September 18, 2017

Last Verified

September 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • G-CSF and NAC in AH

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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