Clinical trial NCT02971306: G-CSF Plus NAC In Severe Alcoholic Hepatitis
Official title: Granulocyte Colony Stimulating Factor Plus N-Acetyl Cysteine In Severe Alcoholic Hepatitis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Alcoholic Hepatitis
Keywords: alcoholic hepatitis
alcoholic liver disease
jaundice
ascites
regeneration
Lead sponsor: PGIMER
Sponsor class: UNKNOWN
First posted: 2016-11-22
Enrollment: 60
Sex: MALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Eligibility criteria: 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

Primary outcomes:
measure: Primary end point- Survival at the end of 90 days
timeFrame: 90 days
Secondary outcomes:
measure: mobilization of CD34+ cells in peripheral blood
timeFrame: 6 days
measure: improvement in MELD score
timeFrame: 90 days
measure: Number of participants with treatment-related adverse events in the different treatment groups
timeFrame: 90 days
measure: improvement in modified Discriminant Factor
timeFrame: 90 days
measure: improvement in Child Turcotte Pugh score
timeFrame: 90 days
Other outcomes:
Locations:
city: Chandigarh
country: India
facility: Dept of Hepatology, PGIMER
Study officials:
References:
citation: 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.