G-CSF Plus NAC In Severe Alcoholic Hepatitis

NCT02971306 | Unknown Phase 4 DMC

• 1 other identifier: G-CSF and NAC in AH
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Alcoholic Hepatitis

Keywords

alcoholic hepatitis; alcoholic liver disease; jaundice; ascites; regeneration

Outcome Measures

Primary Outcomes (1)

• Primary end point- Survival at the end of 90 days

  90 days

Secondary Outcomes (5)

• mobilization of CD34+ cells in peripheral blood

  6 days

• improvement in MELD score

  90 days

• Number of participants with treatment-related adverse events in the different treatment groups

  90 days

• improvement in modified Discriminant Factor

  90 days

• improvement in Child Turcotte Pugh score

  90 days

Study Arms (3)

Standard Medical therapy

ACTIVE COMPARATOR

standard medical therapy

Drug: standard medical therapy

G-CSF

EXPERIMENTAL

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

Drug: standard medical therapy; Drug: G-CSF

G-CSF and NAC

EXPERIMENTAL

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; Drug: G-CSF; Drug: n-Acetylcysteine

Interventions

standard medical therapy DRUG

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.

G-CSF; G-CSF and NAC; Standard Medical therapy

G-CSF DRUG

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

G-CSF; G-CSF and NAC

n-Acetylcysteine DRUG

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

G-CSF and NAC

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Post Graduate Institute of Medical Education and Research, Chandigarh: lead

Study Sites (1)

Dept of Hepatology, PGIMER

Chandigarh, 160012, India

RECRUITING

Related Publications (1)

• Singh V, Keisham A, Bhalla A, Sharma N, Agarwal R, Sharma R, Singh A. Efficacy of Granulocyte Colony-Stimulating Factor and N-Acetylcysteine Therapies in Patients With Severe Alcoholic Hepatitis. Clin Gastroenterol Hepatol. 2018 Oct;16(10):1650-1656.e2. doi: 10.1016/j.cgh.2018.01.040. Epub 2018 Jan 31.

  PMID: 29391265 DERIVED

MeSH Terms

Conditions

Hepatitis, Alcoholic; Liver Diseases, Alcoholic; Jaundice; Ascites

Interventions

Granulocyte Colony-Stimulating Factor; Acetylcysteine

Condition Hierarchy (Ancestors)

Hepatitis; Liver Diseases; Digestive System Diseases; Alcohol-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Hyperbilirubinemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Skin Manifestations; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids

Central Study Contacts

Virendra Singh, MD, DM

CONTACT

+911722756338; virendrasingh100@hotmail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Hepatology

Study Record Dates

• First Submitted: November 9, 2016
• First Posted: November 22, 2016
• Study Start: July 1, 2014
• Primary Completion: December 1, 2017
• Study Completion: December 1, 2017
• Last Updated: September 19, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)