Granulocyte Colony Stimulating Factor Four Week Plus N-Acetyl Cysteine in Severe Alcoholic Hepatitis

Sponsor

Postgraduate Institute of Medical Education and Research (Other)

Overall Status

Completed

CT.gov ID

NCT05840640

Collaborator

(none)

Enrollment

Location

Arms

40.9

Actual Duration (Months)

1.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Alcoholic hepatitis is related to very high mortality rate. About 40% of the patients 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 conditions. The studies have 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 these 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 acute 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 4 weeks of NAC plus G-CSF in patient with severe alcoholic hepatitis.

Therefore the investigators plan to study the safety and efficacy of combination therapy of G-CSF and 4 weeks of NAC in the patients with alcoholic hepatitis.

Condition or Disease	Intervention/Treatment	Phase
Alcoholic Hepatitis	Drug: Standard Medical Therapy Drug: G-CSF Drug: G-CSF and NAC	Phase 4

Study Design

Study Type:

Interventional

Actual Enrollment :

66 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Open label randomizedOpen label randomized

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Granulocyte Colony Stimulating Factor Four Week Plus N-Acetyl Cysteine in Severe Alcoholic Hepatitis

Actual Study Start Date :

Oct 1, 2017

Actual Primary Completion Date :

Feb 28, 2021

Actual Study Completion Date :

Feb 28, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Standard Medical therapy Standard medical therapy involves primary treatment with 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: Standard Medical Therapy Standard medical therapy involves primary treatment with 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 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 standard medical therapy plus G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days
Experimental: G-CSF and NAC Standard Medical Therapy plus G-CSF with intravenous 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 followed by oral NAC from days 6 to 28)	Drug: Standard Medical Therapy Standard medical therapy involves primary treatment with 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 standard medical therapy plus G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days Drug: G-CSF and NAC Standard Medical Therapy plus G-CSF with intravenous 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 followed by oral NAC from days 6 to 28)

Arm

Intervention/Treatment

Active Comparator: Standard Medical therapy

Standard medical therapy involves primary treatment with 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: Standard Medical Therapy

Experimental: G-CSF

Standard Medical Therapy plus G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days

Drug: Standard Medical Therapy

Drug: G-CSF

standard medical therapy plus G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days

Experimental: G-CSF and NAC

Standard Medical Therapy plus G-CSF with intravenous 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 followed by oral NAC from days 6 to 28)

Drug: Standard Medical Therapy

Drug: G-CSF

standard medical therapy plus G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days

Drug: G-CSF and NAC

Outcome Measures

Primary Outcome Measures

Survival at the end of 90 days [90 days]

Secondary Outcome Measures

Number of CD34+ cells in peripheral blood [6 days]
Change in MELD score [90 days]
Change in modified Maddrey's Discriminant Function at 90 days. [90 days]
Modified Maddrey's Discriminant Function will be calculated using the following formula: [4.6 × (prothrombin time of patient - prothrombin time of control) + serum bilirubin in mg/dl] Modified Maddrey's Discriminant Function is a validated and well-established parameter for assessing the severity and prognosis of alcoholic hepatitis.
Change in Child Turcotte Pugh score [90 days]
Number of participants with treatment-related adverse events in the different treatment groups [90 days]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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