Alcoholic HepatitisPhase 4NCT02971306
G-CSF Plus NAC In Severe Alcoholic Hepatitis
A Phase 4 study testing standard medical therapy, G-CSF and n-Acetylcysteine in people with Alcoholic Hepatitis, run by Post Graduate Institute of Medical Education and Research, Chandigarh at 1 site in India.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years, men only
- Conditions the study is for
- Alcoholic Hepatitis
- What is being tested?
- standard medical therapy, G-CSF and n-Acetylcysteine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 1 siteIndia
- Study dates
- Jul 2014to Dec 2017
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 12Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
India1 site, 1 recruiting
- Recruiting
Dept of Hepatology, PGIMER
Chandigarh, 160012
Virendra Singh, MD, DM, +911722756338, virendrasingh100@hotmail.com
About this study
Official title: 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.
Read more
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.
Read the 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:
- 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.
- Total leukocytes count will be assessed daily.
- Circulating CD 34 positive cells will be measured on day 0 and 6 of G-CSF therapy.
- In addition, ultrasonography will be performed at day 1 and 6 in order to evaluate difference in spleen size and portal vein flow.
- 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
- Conditions
- Alcoholic Hepatitis
- Being tested
- standard medical therapy, G-CSF, n-Acetylcysteine
- Keywords
- alcoholic hepatitis, alcoholic liver disease, jaundice, ascites, regeneration
- Medical subject headings
- Hepatitis, Alcoholic, Liver Diseases, Alcoholic, Jaundice, Ascites
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
standard medical therapyDrug
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-CSFDrug
G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days
n-AcetylcysteineDrug
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
| Study group | Role | What they receive |
|---|---|---|
| Standard Medical therapy | Active comparator | standard medical therapy Receives: Drug: standard medical therapy |
| G-CSF | Experimental | standard medical therapy plus G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days Receives: 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) Receives: Drug: standard medical therapy; Drug: G-CSF; Drug: n-Acetylcysteine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Primary end point- Survival at the end of 90 days
Measured: 90 days
Secondary outcomes (5)
mobilization of CD34+ cells in peripheral blood
Measured: 6 days
improvement in MELD score
Measured: 90 days
Number of participants with treatment-related adverse events in the different treatment groups
Measured: 90 days
improvement in modified Discriminant Factor
Measured: 90 days
improvement in Child Turcotte Pugh score
Measured: 90 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Nov 2016 (estimated)
- Study startJul 2014
- Primary completionDec 2017 (estimated)
- Study completionDec 2017 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Alcoholic HepatitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Post Graduate Institute of Medical Education and Research, Chandigarh
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr.Virendra Singh, Post Graduate Institute of Medical Education and Research, Chandigarh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02971306
- Sponsor's protocol ID
- G-CSF and NAC in AH
- Status last verified
- Sep 2017
- First submitted
- 9 Nov 2016
- Last updated
- 19 Sep 2017
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 29391265
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Granulocyte Colony Stimulating Factor Plus N-Acetyl Cysteine In Severe Alcoholic Hepatitis
- ClinicalTrials.gov ID
- NCT02971306
- Acronym / sponsor ID
- G-CSF and NAC in AH
- Conditions
- Alcoholic Hepatitis
- Keywords
- alcoholic hepatitis, alcoholic liver disease, jaundice, ascites, regeneration
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Post Graduate Institute of Medical Education and Research, ChandigarhUniversity, hospital or other
- Study start
- Jul 2014
- Primary completion
- Dec 2017 (estimated)
- Study completion
- Dec 2017 (estimated)
- First posted
- 22 Nov 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
- Total leukocytes count will be assessed daily.
- Circulating CD 34 positive cells will be measured on day 0 and 6 of G-CSF therapy.
- In addition, ultrasonography will be performed at day 1 and 6 in order to evaluate difference in spleen size and portal vein flow.
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Standard Medical therapy | Active comparator | Drug: standard medical therapystandard medical therapy |
| G-CSF | Experimental | Drug: standard medical therapy, Drug: G-CSFstandard medical therapy plus G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days |
| G-CSF and NAC | Experimental | Drug: standard medical therapy, Drug: G-CSF, Drug: n-Acetylcysteinestandard 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) |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| standard medical therapyStandard 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 and NAC, Standard Medical therapy |
| G-CSFG-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days | Drug | G-CSF, G-CSF and NAC |
| n-Acetylcysteinen-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 | Drug | G-CSF and NAC |
Primary outcome
Primary end point- Survival at the end of 90 days
Time frame: 90 days
5 secondary outcomes
mobilization of CD34+ cells in peripheral blood
Time frame: 6 days
improvement in MELD score
Time frame: 90 days
Number of participants with treatment-related adverse events in the different treatment groups
Time frame: 90 days
improvement in modified Discriminant Factor
Time frame: 90 days
improvement in Child Turcotte Pugh score
Time frame: 90 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2017.
- Derived from this study: PubMed 29391265Singh 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.
- Individual participant dataSharing planned: No
Related trials for Alcoholic Hepatitis
RecruitingPhase 2
Study to Evaluate ALN-CIDEB in Adults With Fibrotic Metabolic Dysfunction-Associated Steatohepatitis (MASH)
Metabolic Dysfunction-Associated Steatohepatitis (MASH)
RecruitingObservational study
"Constitution of a Biological Collection to Establish Preclinical Translational Models for the Study of Tumors and Chronic Liver Diseases".
Chronic Liver Disease and Cirrhosis, Liver Cancer
RecruitingPhase 3
Study to Evaluate the Safety and Efficacy of Larsucosterol in Participants With Alcohol-associated Hepatitis (AH)
Hepatitis
RecruitingObservational study
Blood Collection Biorepository for Liver Disease Research
Non-Alcoholic Steatohepatitis(NASH), Hepatitis C
RecruitingPhase 2
Liver Cirrhosis Network Rosuvastatin Efficacy and Safety for Cirrhosis in the United States
Cirrhosis, Cirrhosis, Liver
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing standard medical therapy, G-CSF and n-Acetylcysteine in people with Alcoholic Hepatitis, run by Post Graduate Institute of Medical Education and Research, Chandigarh at 1 site in India.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 19 Sep 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Virendra Singh, MD, DM (+911722756338, virendrasingh100@hotmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Primary end point- Survival at the end of 90 days (time frame: 90 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02971306, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2017.