<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02971306</url>
  </required_header>
  <id_info>
    <org_study_id>G-CSF and NAC in AH</org_study_id>
    <nct_id>NCT02971306</nct_id>
  </id_info>
  <brief_title>G-CSF Plus NAC In Severe Alcoholic Hepatitis</brief_title>
  <official_title>Granulocyte Colony Stimulating Factor Plus N-Acetyl Cysteine In Severe Alcoholic Hepatitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Postgraduate Institute of Medical Education and Research</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Postgraduate Institute of Medical Education and Research</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Alcoholic hepatitis is related to very high mortality rate. About 40% of the patients are&#xD;
      died within first 6 months after the detection of the clinical syndrome. Therefore, it is&#xD;
      very essential for proper diagnosis and early treatment. In response to acute or chronic&#xD;
      liver damage, bone marrow derived stem cells can spontaneously populate liver and&#xD;
      differentiate into hepatic cells. Animal and human studies suggested that injured hepatocyte&#xD;
      may be replaced by pluripotent bone marrow cells. However, this hepatocyte repopulation is&#xD;
      highly dependent on varieties of liver injury and therapeutic conditions6. The studies has&#xD;
      suggested Granulocyte-colony stimulating factors (G-CSF) can regenerate hepatocyte by fusing&#xD;
      with hematopoietic cells, thereby enhancing the liver histology and survival rate.&#xD;
&#xD;
      G-CSF is a cytokine capable to regulate a number of functions in neutrophils. In three recent&#xD;
      studies mobilization of bone marrow stem cells induced by G-CSF was observed in patients with&#xD;
      alcoholic hepatitis. In two of this studies there was a survival benefit with the use of&#xD;
      G-CSF.&#xD;
&#xD;
      Alcoholism leads to decrease in endogenous antioxidant potential. Alcoholic liver disease&#xD;
      (ALD) patients show low endogenous antioxidants. Chronic ethanol consumption cause selective&#xD;
      deficiency in the availability of reduced glutathione (GSH) in mitochondria has been&#xD;
      reported. This is due to impaired functioning of GSH transporter from cytosol to&#xD;
      mitochondrial matrix. The effect on glutathione replenishing potential by N-acetyl cysteine&#xD;
      (NAC) can be used to reduce oxidative stress, which also has excellent safety profile.&#xD;
      Therefore, NAC can be used for severe alcoholic hepatitis treatment due to its therapeutic&#xD;
      potential factor. NAC also inhibit apoptosis and pro-inflammatory cytokine production. In a&#xD;
      study high doses of intravenous N-acetyl cysteine therapy for 14 days conferred neither&#xD;
      survival benefits nor early biological improvement in severe alcoholic hepatitis patients&#xD;
      with adequate nutritional support.However, these results must be viewed with caution, since&#xD;
      the study suffered from a lack of power. In a recent study, NAC and corticosteroids&#xD;
      combination therapy benefits among patients with severe acute alcoholic hepatitis in 1 month&#xD;
      survival, although the final outcome at 6 month survival was not improved. There are no&#xD;
      studies on the use of combination therapy of NAC plus G-CSF in patient with severe alcoholic&#xD;
      hepatitis.&#xD;
&#xD;
      Therefore we plan to study the safety and efficacy of combination therapy of G-CSF and NAC in&#xD;
      the patients with alcoholic hepatitis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with severe alcoholic hepatitis, admitted to Department of Hepatology PGIMER,&#xD;
      Chandigarh from July 2014 to December 2016 will be included in the study.&#xD;
&#xD;
      METHODS&#xD;
&#xD;
      This will be an open label trial. A randomization code is generated by random number table.&#xD;
      The patients will be randomized to receive standard medical therapy of pentoxifylline only as&#xD;
      control and combination therapy of Pentoxifylline with NAC and G-CSF as cases. There will be&#xD;
      one control and two cases as below:&#xD;
&#xD;
      1) Pentoxifylline (control) 2) Pentoxifylline+G-CSF (case 1) 3) Pentoxifylline+G-CSF +NAC&#xD;
      (case2) A) Pentoxifylline 400 mg thrice daily for 28 days A) Pentoxifylline 400 mg thrice&#xD;
      daily for 28 days plus G-CSF 5 mcg/kg every 12 hourly for consecutive 5 days A)&#xD;
      Pentoxifylline 400 mg thrice daily for 28 days plus G-CSF 5 mcg/kg every 12 hourly for 5 days&#xD;
      plus NAC 300 mg/kg on day 1 (150 mg/kg in 250 ml of 5% dextrose over a minute of 30&#xD;
      minutes,50 mg/kg in 500ml 5% dextrose over a period of 4 hours, 100mg /kg in 1000 ml of 5%&#xD;
      dextrose over a period of 16 hours ) and on day 2 through 5 100mg /kg/day in 1000ml of&#xD;
      glucose solution.&#xD;
&#xD;
      This will be a single time therapy. Patients will be admitted in the department of hepatology&#xD;
      and will be assessed everyday clinically as well as by laboratory tests during therapy to&#xD;
      assess safety and effects of treatment.&#xD;
&#xD;
        1. Total leukocytes count will be assessed daily.&#xD;
&#xD;
        2. Circulating CD 34 positive cells will be measured on day 0 and 6 of G-CSF therapy.&#xD;
&#xD;
        3. In addition, ultrasonography will be performed at day 1 and 6 in order to evaluate&#xD;
           difference in spleen size and portal vein flow.&#xD;
&#xD;
        4. Biochemical, coagulation, and hematological parameters (Liver function tests, Renal&#xD;
           Function Tests, Prothrombin Time, International Normalised Ratio, etc.) will be&#xD;
           monitored periodically, daily for 1 week, then weekly for 1month and monthly for three&#xD;
           month.&#xD;
&#xD;
      All patients will be followed at weekly interval for 1 month and then monthly for 3 months.&#xD;
&#xD;
      Outcome:&#xD;
&#xD;
      Primary Objectives:&#xD;
&#xD;
      Survival at 3 months&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
      Mobilisation of CD34 positive cells in peripheral blood. Clinical/biochemical improvement in&#xD;
      liver function profile. Improvement in prognostic scores-Maddrey's Discriminant function,&#xD;
      MELD score, and Child score.&#xD;
&#xD;
      Safety and efficacy of G-CSF and NAC in alcoholic hepatitis&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>July 2014</start_date>
  <completion_date type="Anticipated">December 2017</completion_date>
  <primary_completion_date type="Anticipated">December 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Primary end point- Survival at the end of 90 days</measure>
    <time_frame>90 days</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>mobilization of CD34+ cells in peripheral blood</measure>
    <time_frame>6 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>improvement in MELD score</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with treatment-related adverse events in the different treatment groups</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>improvement in modified Discriminant Factor</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>improvement in Child Turcotte Pugh score</measure>
    <time_frame>90 days</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Alcoholic Hepatitis</condition>
  <arm_group>
    <arm_group_label>Standard Medical therapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>standard medical therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>G-CSF</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>standard medical therapy plus G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>G-CSF and NAC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>standard medical therapy</intervention_name>
    <description>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.</description>
    <arm_group_label>G-CSF</arm_group_label>
    <arm_group_label>G-CSF and NAC</arm_group_label>
    <arm_group_label>Standard Medical therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>G-CSF</intervention_name>
    <description>G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days</description>
    <arm_group_label>G-CSF</arm_group_label>
    <arm_group_label>G-CSF and NAC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>n-Acetylcysteine</intervention_name>
    <description>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</description>
    <arm_group_label>G-CSF and NAC</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Alcoholic hepatitis patients:&#xD;
&#xD;
          1. More than 10 years of heavy alcohol consumption (mean intake ≈ 100 g/day).&#xD;
&#xD;
          2. Elevated aspartate aminotransferase level (but &lt;500 IU per millilitre) and Ratio&#xD;
             ofAST/ALT≥2 times&#xD;
&#xD;
          3. Elevated serum total bilirubin level ≥ 5 mgdL (86 μmol/L)&#xD;
&#xD;
          4. Elevated INR(≥1.5) and&#xD;
&#xD;
          5. Neutrophilia. Patient with Maddrey's DF of≥ 32 will be included in the study, with or&#xD;
             without biopsy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Age &lt; 18 and &gt; 75 years&#xD;
&#xD;
          2. Hepatocellular carcinoma or portal vein thrombosis&#xD;
&#xD;
          3. Refusal to participate in the study&#xD;
&#xD;
          4. Serum creatinine &gt;1.0 mg%&#xD;
&#xD;
          5. Hepatic encephalopathy- grade 3 or 4&#xD;
&#xD;
          6. Upper gastrointestinal bleed in last ten days&#xD;
&#xD;
          7. Uncontrolled bacterial infection&#xD;
&#xD;
          8. Human immunodeficiency virus, Hepatitis B virus, Hepatitis C virus seropositivity,&#xD;
             Autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha1-antitrypsin deficiency&#xD;
&#xD;
          9. Pregnancy&#xD;
&#xD;
         10. Glucocorticoid treatment&#xD;
&#xD;
         11. Significant co-morbidity&#xD;
&#xD;
         12. Previous known hypersensitivity to G-CSF/NAC&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Virendra Singh, MD, DM</last_name>
    <phone>+911722756338</phone>
    <email>virendrasingh100@hotmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Dept of Hepatology, PGIMER</name>
      <address>
        <city>Chandigarh</city>
        <zip>160012</zip>
        <country>India</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Virendra Singh, MD, DM</last_name>
      <phone>+911722756338</phone>
      <email>virendrasingh100@hotmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>November 9, 2016</study_first_submitted>
  <study_first_submitted_qc>November 18, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2016</study_first_posted>
  <last_update_submitted>September 18, 2017</last_update_submitted>
  <last_update_submitted_qc>September 18, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 19, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Postgraduate Institute of Medical Education and Research</investigator_affiliation>
    <investigator_full_name>Dr.Virendra Singh</investigator_full_name>
    <investigator_title>Professor of Hepatology</investigator_title>
  </responsible_party>
  <keyword>alcoholic hepatitis</keyword>
  <keyword>alcoholic liver disease</keyword>
  <keyword>jaundice</keyword>
  <keyword>ascites</keyword>
  <keyword>regeneration</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
    <mesh_term>Hepatitis, Alcoholic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetylcysteine</mesh_term>
    <mesh_term>N-monoacetylcystine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02971306
org study id: G-CSF and NAC in AH
nct id: NCT02971306
lead sponsor: 
has dmc: Yes
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.
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
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Primary end point- Survival at the end of 90 days
time frame: 90 days
measure: mobilization of CD34+ cells in peripheral blood
time frame: 6 days
measure: improvement in MELD score
time frame: 90 days
measure: Number of participants with treatment-related adverse events in the different treatment groups
time frame: 90 days
measure: improvement in modified Discriminant Factor
time frame: 90 days
measure: improvement in Child Turcotte Pugh score
time frame: 90 days
arm group label: Standard Medical therapy
arm group type: Active Comparator
description: standard medical therapy
arm group label: G-CSF
arm group type: Experimental
description: standard medical therapy plus G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days
arm group label: G-CSF and NAC
arm group type: Experimental
description: 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)
intervention type: Drug
intervention name: standard medical therapy
description: 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.
arm group label: G-CSF
arm group label: G-CSF and NAC
arm group label: Standard Medical therapy
intervention type: Drug
intervention name: G-CSF
description: G-CSF- 5μg/Kg s.c every 12 hours for 5 consecutive days
arm group label: G-CSF
arm group label: G-CSF and NAC
intervention type: Drug
intervention name: n-Acetylcysteine
description: 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
arm group label: G-CSF and NAC
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Virendra Singh, MD, DM
phone: +911722756338
email: virendrasingh100@hotmail.com
facility: 
status: Recruiting
contact: 
country: India
responsible party type: Principal Investigator
investigator affiliation: Postgraduate Institute of Medical Education and Research
investigator full name: Dr.Virendra Singh
investigator title: Professor of Hepatology
mesh term: Hepatitis A
mesh term: Hepatitis
mesh term: Hepatitis, Alcoholic
mesh term: Acetylcysteine
mesh term: N-monoacetylcystine
sharing ipd: No