<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/NCT03266146</url>
  </required_header>
  <id_info>
    <org_study_id>BJ302-FGRXGB-003</org_study_id>
    <nct_id>NCT03266146</nct_id>
  </id_info>
  <brief_title>36 Weeks Short-Term Optimization Treatment of Glucocorticosteroid in the Patients With Chronic Recurrent DILI</brief_title>
  <official_title>The Efficacy and Safety of 36 Weeks Short-Term Optimization Treatment of Glucocorticosteroid in the Patients With Chronic Recurrent Drug-Induced Liver Injury</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Beijing 302 Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Beijing 302 Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is to observe the efficacy and safety of 36 weeks short-term optimization&#xD;
      treatment of glucocorticosteroid in the patients with chronic recurrent drug-induced liver&#xD;
      injury (DILI).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Drug-induced liver injury (DILI) refers to liver diseases caused by drugs and toxic&#xD;
      substances. DILI is a clinical event that can be associated with severe outcomes such as&#xD;
      acute liver failure. Up to now, approximately 1100 drugs, herbal products, vitamins and&#xD;
      illicit compounds are associated with liver injury. Recently, the incidence of DILI is&#xD;
      rising. In our hospital, hospitalized patients with DILI was increased from 1.39% in 2002 to&#xD;
      2.31% in 2006, and further up to 3.17% in 2011, which indicated 2.3-folds increase over last&#xD;
      ten years. About 20% patients with acute DILI are prone to chronic liver disease. For&#xD;
      patients with chronic recurrent DILI, routine liver protective treatment was difficult to&#xD;
      rescue abnormal liver functions. Moreover, increasing health care costs seriously affect the&#xD;
      patient's quality of life. Glucocorticosteroids can inhibit the non-specific inflammation and&#xD;
      permeability of the capillary bile duct, limit the activation of T lymphocytes, and&#xD;
      selectively inhibit B lymphocytes to produce antibodies, thus preventing or delaying the&#xD;
      immune-induced liver injury. In our pre-clinical trials (NCT02651350), we found that the rate&#xD;
      of recurrence of the glucocorticoid treatment group was significant lower (&lt;10%) than the&#xD;
      control group (about 50%) (P &lt;0.001) and there was significant difference of liver&#xD;
      histological change during baseline and treatment end between the glucocorticoid treatment&#xD;
      group and the control group. Meanwhile, we did not find obvious glucocorticoid's side effect&#xD;
      in the glucocorticoid treatment group. At the same time, we found that there was good effect&#xD;
      in 36 weeks glucocorticoid treatment in several patients. Therefore, we shall design two&#xD;
      groups on the basis of the ratio of 1:1, namely, 36 weeks of glucocorticoid treatment group&#xD;
      and 48 weeks of glucocorticoid treatment group in order to evaluate the efficacy and safety&#xD;
      of 36 weeks short-term optimization treatment of glucocorticosteroid in the patients with&#xD;
      chronic recurrent DILI.&#xD;
&#xD;
      Participants in 36 weeks of glucocorticoid treatment group will receive methylprednisolone,&#xD;
      48mg/d for the 1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by&#xD;
      16mg/d for 20 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until&#xD;
      drug withdrawal. Participants in 36 weeks of glucocorticoid treatment group also will receive&#xD;
      standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or&#xD;
      ursodeoxycholic acid (UDCA).Participants will then be followed for 24 weeks. Participants in&#xD;
      48 weeks of glucocorticoid treatment group will receive methylprednisolone, 48mg/d for the&#xD;
      1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by 16mg/d for 32&#xD;
      weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal.&#xD;
      Participants in glucocorticoid 48 weeks of treatment group also will receive standard&#xD;
      treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil,or&#xD;
      ursodeoxycholic acid (UDCA).Participants will then be followed for 24 weeks.&#xD;
&#xD;
      The efficacy and safety of 36 weeks short-term optimization treatment of glucocorticosteroid&#xD;
      in the patients with chronic recurrent DILI will be observed and compared with 48 weeks&#xD;
      glucocorticosteroid treatment during the treatment and follow-up period.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 2, 2017</start_date>
  <completion_date type="Actual">January 31, 2023</completion_date>
  <primary_completion_date type="Actual">January 31, 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</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>Recurrence rate of illness, namely, appearance of obviously abnormal liver function again during treatment and follow-up period. The definition of recurrence: The level of AST or ALT is elevated more than 5 fold ULN or is two times higher than before.</measure>
    <time_frame>From week 1 to week 60 or 72</time_frame>
    <description>To analyze the clinical efficacy of glucocorticosteroid treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The liver histological changes between two liver biopsies (baseline and treatment end)</measure>
    <time_frame>At week 0 and at week 36 week or 48 week</time_frame>
    <description>To analyze the clinical efficacy of glucocorticosteroid treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Days of normalization or falling by half compared to admission of liver functions including serum levels of ALT, AST, TBIL,GGT and ALP.</measure>
    <time_frame>From week 1 to week 36 or 48</time_frame>
    <description>To analyze the clinical efficacy of glucocorticosteroid treatment</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">90</enrollment>
  <condition>Drug-induced Liver Injury,Chronic</condition>
  <arm_group>
    <arm_group_label>36 Weeks Methylprednisolone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants in 36 weeks of glucocorticoid treatment group will receive methylprednisolone, 48mg/d for the 1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by 16mg/d for 20 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal. Participants in 36 weeks of glucocorticoid treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA). Participants will then be followed for 24 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>48 Weeks Methylprednisolone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants in 48 weeks of glucocorticoid treatment group will receive methylprednisolone, 48mg/d for the 1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by 16mg/d for 32 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal. Participants in glucocorticoid 48 weeks of treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA). Participants will then be followed for 24 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>36 Weeks Methylprednisolone</intervention_name>
    <description>Participants in 36 weeks of glucocorticoid treatment group will receive methylprednisolone, 48mg/d for the 1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by 16mg/d for 20 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal. Participants in 36 weeks of glucocorticoid treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA).The total treatment duration will be 36 weeks. Follow-up duration is 24 weeks.</description>
    <arm_group_label>36 Weeks Methylprednisolone</arm_group_label>
    <other_name>MEDROL,NDC0009-0056-02</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>48 weeks Methylprednisolone</intervention_name>
    <description>Participants in 48 weeks of glucocorticoid treatment group will receive methylprednisolone, 48mg/d for the 1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by 16mg/d for 32 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal. Participants in 36 weeks of glucocorticoid treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA).The total treatment duration will be 48 weeks. Follow-up duration is 24 weeks.</description>
    <arm_group_label>48 Weeks Methylprednisolone</arm_group_label>
    <other_name>MEDROL,NDC0009-0056-02</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Meet with ACG clinic guidelines for diagnostic criteria of chronic DILI;&#xD;
&#xD;
          2. The time of recurrence is 1 or more than 1;&#xD;
&#xD;
             The definition of recurrence, meet any of the following conditions:&#xD;
&#xD;
               -  the level of serum AST or ALT is elevated more than 5 fold ULN;&#xD;
&#xD;
               -  the level of serum AST or ALT is two times higher than before;&#xD;
&#xD;
          3. Meet any of the following conditions:&#xD;
&#xD;
               -  serum AST or ALT ≥ 10 fold ULN;&#xD;
&#xD;
               -  serum AST or ALT ≥ 5 fold ULN and TBIL ≥ 2 fold ULN;&#xD;
&#xD;
               -  liver histology indicates bridging necrosis or multiacinar necrosis or moderate&#xD;
                  or more inflammation or inflammation G3 or more;&#xD;
&#xD;
          4. Women of childbearing age had a negative urine pregnancy test, and the subjects are&#xD;
             willing to have no family planning during the study and to take effective measures;&#xD;
&#xD;
          5. Voluntary participation, understanding and signing of informed consent, comply with&#xD;
             the requirements of the research.&#xD;
&#xD;
             -&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with serious pre-existent comorbid conditions (vertebral compression&#xD;
             fractures,psychosis,active peptic ulcer, brittle diabetes,uncontrolled hypertension;&#xD;
&#xD;
          2. Patients with intolerances to prednisone;&#xD;
&#xD;
          3. Patients with severe infection receiving antibiotics, anti-fungal,anti-viral therapy;&#xD;
&#xD;
          4. Viral hepatitis,alcoholic or non-alcoholic liver disease,Wilson's disease or other&#xD;
             inherited metabolic liver diseases.&#xD;
&#xD;
          5. Pregnancy or desire of pregnancy;&#xD;
&#xD;
          6. Breast-feeding;&#xD;
&#xD;
          7. Liver cancer or other malignant tumor.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Zhengsheng Zou, Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Beijing 302 Hospital,China.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Beijing 302 hospital</name>
      <address>
        <city>Beijing</city>
        <zip>100039</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ; Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014 Jul;109(7):950-66; quiz 967. doi: 10.1038/ajg.2014.131. Epub 2014 Jun 17.</citation>
    <PMID>24935270</PMID>
  </reference>
  <reference>
    <citation>Moreno L, Sanchez-Delgado J, Vergara M, Casas M, Miquel M, Dalmau B. Recurrent drug-induced liver injury (DILI) with ciprofloxacin and amoxicillin/clavulanic. Rev Esp Enferm Dig. 2015 Dec;107(12):767-8. doi: 10.17235/reed.2015.3810/2015.</citation>
    <PMID>26671593</PMID>
  </reference>
  <reference>
    <citation>Tencate V, Komorowski R, Cronin D, Hong J, Gawrieh S. A case study: refractory recurrent autoimmune hepatitis following liver transplantation in two male patients. Transplant Proc. 2014 Jan-Feb;46(1):298-300. doi: 10.1016/j.transproceed.2013.09.028.</citation>
    <PMID>24507072</PMID>
  </reference>
  <reference>
    <citation>Lucena MI, Kaplowitz N, Hallal H, Castiella A, Garcia-Bengoechea M, Otazua P, Berenguer M, Fernandez MC, Planas R, Andrade RJ. Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis. J Hepatol. 2011 Oct;55(4):820-7. doi: 10.1016/j.jhep.2010.12.041. Epub 2011 Feb 19.</citation>
    <PMID>21338638</PMID>
  </reference>
  <reference>
    <citation>Suzuki A, Brunt EM, Kleiner DE, Miquel R, Smyrk TC, Andrade RJ, Lucena MI, Castiella A, Lindor K, Bjornsson E. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology. 2011 Sep 2;54(3):931-9. doi: 10.1002/hep.24481. Epub 2011 Aug 8.</citation>
    <PMID>21674554</PMID>
  </reference>
  <reference>
    <citation>Weiler-Normann C, Schramm C. Drug induced liver injury and its relationship to autoimmune hepatitis. J Hepatol. 2011 Oct;55(4):747-9. doi: 10.1016/j.jhep.2011.02.024. Epub 2011 Mar 9. No abstract available.</citation>
    <PMID>21396413</PMID>
  </reference>
  <reference>
    <citation>Bessone F, Lucena MI, Roma MG, Stephens C, Medina-Caliz I, Frider B, Tsariktsian G, Hernandez N, Bruguera M, Gualano G, Fassio E, Montero J, Reggiardo MV, Ferretti S, Colombato L, Tanno F, Ferrer J, Zeno L, Tanno H, Andrade RJ. Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases. Liver Int. 2016 Feb;36(2):302-10. doi: 10.1111/liv.12899. Epub 2015 Jul 16.</citation>
    <PMID>26104271</PMID>
  </reference>
  <reference>
    <citation>Sugimoto K, Ito T, Yamamoto N, Shiraki K. Seven cases of autoimmune hepatitis that developed after drug-induced liver injury. Hepatology. 2011 Nov;54(5):1892-3. doi: 10.1002/hep.24513. Epub 2011 Aug 9. No abstract available.</citation>
    <PMID>21725992</PMID>
  </reference>
  <reference>
    <citation>Fujiwara K, Yokosuka O. Histological discrimination between autoimmune hepatitis and drug-induced liver injury. Hepatology. 2012 Feb;55(2):657. doi: 10.1002/hep.24768. No abstract available.</citation>
    <PMID>22038865</PMID>
  </reference>
  <reference>
    <citation>Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, Vierling JM; American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010 Jun;51(6):2193-213. doi: 10.1002/hep.23584. No abstract available.</citation>
    <PMID>20513004</PMID>
  </reference>
  <reference>
    <citation>Fontana RJ, Hayashi PH, Gu J, Reddy KR, Barnhart H, Watkins PB, Serrano J, Lee WM, Chalasani N, Stolz A, Davern T, Talwakar JA; DILIN Network. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014 Jul;147(1):96-108.e4. doi: 10.1053/j.gastro.2014.03.045. Epub 2014 Mar 27.</citation>
    <PMID>24681128</PMID>
  </reference>
  <reference>
    <citation>Stine JG, Chalasani NP. Drug Hepatotoxicity: Environmental Factors. Clin Liver Dis. 2017 Feb;21(1):103-113. doi: 10.1016/j.cld.2016.08.008. Epub 2016 Oct 13.</citation>
    <PMID>27842766</PMID>
  </reference>
  <reference>
    <citation>Hayashi PH, Rockey DC, Fontana RJ, Tillmann HL, Kaplowitz N, Barnhart HX, Gu J, Chalasani NP, Reddy KR, Sherker AH, Hoofnagle JH; Drug-Induced Liver Injury Network (DILIN) Investigators. Death and liver transplantation within 2 years of onset of drug-induced liver injury. Hepatology. 2017 Oct;66(4):1275-1285. doi: 10.1002/hep.29283. Epub 2017 Aug 26.</citation>
    <PMID>28543844</PMID>
  </reference>
  <reference>
    <citation>Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, Watkins PB, Navarro V, Barnhart H, Gu J, Serrano J; United States Drug Induced Liver Injury Network. Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. Gastroenterology. 2015 Jun;148(7):1340-52.e7. doi: 10.1053/j.gastro.2015.03.006. Epub 2015 Mar 6.</citation>
    <PMID>25754159</PMID>
  </reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>August 26, 2017</study_first_submitted>
  <study_first_submitted_qc>August 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 29, 2017</study_first_posted>
  <last_update_submitted>February 13, 2023</last_update_submitted>
  <last_update_submitted_qc>February 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Drug-induced Liver Injury</keyword>
  <keyword>Recurrence</keyword>
  <keyword>Methylprednisolone</keyword>
  <keyword>Short-term</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chemical and Drug Induced Liver Injury</mesh_term>
    <mesh_term>Chemical and Drug Induced Liver Injury, Chronic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methylprednisolone</mesh_term>
    <mesh_term>Methylprednisolone Acetate</mesh_term>
    <mesh_term>Methylprednisolone Hemisuccinate</mesh_term>
    <mesh_term>Prednisolone</mesh_term>
    <mesh_term>Prednisolone acetate</mesh_term>
    <mesh_term>Prednisolone hemisuccinate</mesh_term>
    <mesh_term>Prednisolone phosphate</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/NCT03266146
org study id: BJ302-FGRXGB-003
nct id: NCT03266146
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study is to observe the efficacy and safety of 36 weeks short-term optimization
      treatment of glucocorticosteroid in the patients with chronic recurrent drug-induced liver
      injury (DILI).
Drug-induced liver injury (DILI) refers to liver diseases caused by drugs and toxic
      substances. DILI is a clinical event that can be associated with severe outcomes such as
      acute liver failure. Up to now, approximately 1100 drugs, herbal products, vitamins and
      illicit compounds are associated with liver injury. Recently, the incidence of DILI is
      rising. In our hospital, hospitalized patients with DILI was increased from 1.39% in 2002 to
      2.31% in 2006, and further up to 3.17% in 2011, which indicated 2.3-folds increase over last
      ten years. About 20% patients with acute DILI are prone to chronic liver disease. For
      patients with chronic recurrent DILI, routine liver protective treatment was difficult to
      rescue abnormal liver functions. Moreover, increasing health care costs seriously affect the
      patient's quality of life. Glucocorticosteroids can inhibit the non-specific inflammation and
      permeability of the capillary bile duct, limit the activation of T lymphocytes, and
      selectively inhibit B lymphocytes to produce antibodies, thus preventing or delaying the
      immune-induced liver injury. In our pre-clinical trials (NCT02651350), we found that the rate
      of recurrence of the glucocorticoid treatment group was significant lower (<10%) than the
      control group (about 50%) (P <0.001) and there was significant difference of liver
      histological change during baseline and treatment end between the glucocorticoid treatment
      group and the control group. Meanwhile, we did not find obvious glucocorticoid's side effect
      in the glucocorticoid treatment group. At the same time, we found that there was good effect
      in 36 weeks glucocorticoid treatment in several patients. Therefore, we shall design two
      groups on the basis of the ratio of 1:1, namely, 36 weeks of glucocorticoid treatment group
      and 48 weeks of glucocorticoid treatment group in order to evaluate the efficacy and safety
      of 36 weeks short-term optimization treatment of glucocorticosteroid in the patients with
      chronic recurrent DILI.

      Participants in 36 weeks of glucocorticoid treatment group will receive methylprednisolone,
      48mg/d for the 1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by
      16mg/d for 20 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until
      drug withdrawal. Participants in 36 weeks of glucocorticoid treatment group also will receive
      standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or
      ursodeoxycholic acid (UDCA).Participants will then be followed for 24 weeks. Participants in
      48 weeks of glucocorticoid treatment group will receive methylprednisolone, 48mg/d for the
      1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by 16mg/d for 32
      weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal.
      Participants in glucocorticoid 48 weeks of treatment group also will receive standard
      treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil,or
      ursodeoxycholic acid (UDCA).Participants will then be followed for 24 weeks.

      The efficacy and safety of 36 weeks short-term optimization treatment of glucocorticosteroid
      in the patients with chronic recurrent DILI will be observed and compared with 48 weeks
      glucocorticosteroid treatment during the treatment and follow-up period.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Recurrence rate of illness, namely, appearance of obviously abnormal liver function again during treatment and follow-up period. The definition of recurrence: The level of AST or ALT is elevated more than 5 fold ULN or is two times higher than before.
time frame: From week 1 to week 60 or 72
description: To analyze the clinical efficacy of glucocorticosteroid treatment
measure: The liver histological changes between two liver biopsies (baseline and treatment end)
time frame: At week 0 and at week 36 week or 48 week
description: To analyze the clinical efficacy of glucocorticosteroid treatment
measure: Days of normalization or falling by half compared to admission of liver functions including serum levels of ALT, AST, TBIL,GGT and ALP.
time frame: From week 1 to week 36 or 48
description: To analyze the clinical efficacy of glucocorticosteroid treatment
arm group label: 36 Weeks Methylprednisolone
arm group type: Experimental
description: Participants in 36 weeks of glucocorticoid treatment group will receive methylprednisolone, 48mg/d for the 1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by 16mg/d for 20 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal. Participants in 36 weeks of glucocorticoid treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA). Participants will then be followed for 24 weeks.
arm group label: 48 Weeks Methylprednisolone
arm group type: Experimental
description: Participants in 48 weeks of glucocorticoid treatment group will receive methylprednisolone, 48mg/d for the 1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by 16mg/d for 32 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal. Participants in glucocorticoid 48 weeks of treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA). Participants will then be followed for 24 weeks.
intervention type: Drug
intervention name: 36 Weeks Methylprednisolone
description: Participants in 36 weeks of glucocorticoid treatment group will receive methylprednisolone, 48mg/d for the 1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by 16mg/d for 20 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal. Participants in 36 weeks of glucocorticoid treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA).The total treatment duration will be 36 weeks. Follow-up duration is 24 weeks.
arm group label: 36 Weeks Methylprednisolone
other name: MEDROL,NDC0009-0056-02
intervention type: Drug
intervention name: 48 weeks Methylprednisolone
description: Participants in 48 weeks of glucocorticoid treatment group will receive methylprednisolone, 48mg/d for the 1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by 16mg/d for 32 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal. Participants in 36 weeks of glucocorticoid treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA).The total treatment duration will be 48 weeks. Follow-up duration is 24 weeks.
arm group label: 48 Weeks Methylprednisolone
other name: MEDROL,NDC0009-0056-02
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Zhengsheng Zou, Dr.
role: Principal Investigator
affiliation: Beijing 302 Hospital,China.
facility: 
country: China
citation: Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ; Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014 Jul;109(7):950-66; quiz 967. doi: 10.1038/ajg.2014.131. Epub 2014 Jun 17.
PMID: 24935270
citation: Moreno L, Sanchez-Delgado J, Vergara M, Casas M, Miquel M, Dalmau B. Recurrent drug-induced liver injury (DILI) with ciprofloxacin and amoxicillin/clavulanic. Rev Esp Enferm Dig. 2015 Dec;107(12):767-8. doi: 10.17235/reed.2015.3810/2015.
PMID: 26671593
citation: Tencate V, Komorowski R, Cronin D, Hong J, Gawrieh S. A case study: refractory recurrent autoimmune hepatitis following liver transplantation in two male patients. Transplant Proc. 2014 Jan-Feb;46(1):298-300. doi: 10.1016/j.transproceed.2013.09.028.
PMID: 24507072
citation: Lucena MI, Kaplowitz N, Hallal H, Castiella A, Garcia-Bengoechea M, Otazua P, Berenguer M, Fernandez MC, Planas R, Andrade RJ. Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis. J Hepatol. 2011 Oct;55(4):820-7. doi: 10.1016/j.jhep.2010.12.041. Epub 2011 Feb 19.
PMID: 21338638
citation: Suzuki A, Brunt EM, Kleiner DE, Miquel R, Smyrk TC, Andrade RJ, Lucena MI, Castiella A, Lindor K, Bjornsson E. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology. 2011 Sep 2;54(3):931-9. doi: 10.1002/hep.24481. Epub 2011 Aug 8.
PMID: 21674554
citation: Weiler-Normann C, Schramm C. Drug induced liver injury and its relationship to autoimmune hepatitis. J Hepatol. 2011 Oct;55(4):747-9. doi: 10.1016/j.jhep.2011.02.024. Epub 2011 Mar 9. No abstract available.
PMID: 21396413
citation: Bessone F, Lucena MI, Roma MG, Stephens C, Medina-Caliz I, Frider B, Tsariktsian G, Hernandez N, Bruguera M, Gualano G, Fassio E, Montero J, Reggiardo MV, Ferretti S, Colombato L, Tanno F, Ferrer J, Zeno L, Tanno H, Andrade RJ. Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases. Liver Int. 2016 Feb;36(2):302-10. doi: 10.1111/liv.12899. Epub 2015 Jul 16.
PMID: 26104271
citation: Sugimoto K, Ito T, Yamamoto N, Shiraki K. Seven cases of autoimmune hepatitis that developed after drug-induced liver injury. Hepatology. 2011 Nov;54(5):1892-3. doi: 10.1002/hep.24513. Epub 2011 Aug 9. No abstract available.
PMID: 21725992
citation: Fujiwara K, Yokosuka O. Histological discrimination between autoimmune hepatitis and drug-induced liver injury. Hepatology. 2012 Feb;55(2):657. doi: 10.1002/hep.24768. No abstract available.
PMID: 22038865
citation: Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, Vierling JM; American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010 Jun;51(6):2193-213. doi: 10.1002/hep.23584. No abstract available.
PMID: 20513004
citation: Fontana RJ, Hayashi PH, Gu J, Reddy KR, Barnhart H, Watkins PB, Serrano J, Lee WM, Chalasani N, Stolz A, Davern T, Talwakar JA; DILIN Network. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014 Jul;147(1):96-108.e4. doi: 10.1053/j.gastro.2014.03.045. Epub 2014 Mar 27.
PMID: 24681128
citation: Stine JG, Chalasani NP. Drug Hepatotoxicity: Environmental Factors. Clin Liver Dis. 2017 Feb;21(1):103-113. doi: 10.1016/j.cld.2016.08.008. Epub 2016 Oct 13.
PMID: 27842766
citation: Hayashi PH, Rockey DC, Fontana RJ, Tillmann HL, Kaplowitz N, Barnhart HX, Gu J, Chalasani NP, Reddy KR, Sherker AH, Hoofnagle JH; Drug-Induced Liver Injury Network (DILIN) Investigators. Death and liver transplantation within 2 years of onset of drug-induced liver injury. Hepatology. 2017 Oct;66(4):1275-1285. doi: 10.1002/hep.29283. Epub 2017 Aug 26.
PMID: 28543844
citation: Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, Watkins PB, Navarro V, Barnhart H, Gu J, Serrano J; United States Drug Induced Liver Injury Network. Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. Gastroenterology. 2015 Jun;148(7):1340-52.e7. doi: 10.1053/j.gastro.2015.03.006. Epub 2015 Mar 6.
PMID: 25754159
responsible party type: Sponsor
mesh term: Chemical and Drug Induced Liver Injury
mesh term: Chemical and Drug Induced Liver Injury, Chronic
mesh term: Methylprednisolone
mesh term: Methylprednisolone Acetate
mesh term: Methylprednisolone Hemisuccinate
mesh term: Prednisolone
mesh term: Prednisolone acetate
mesh term: Prednisolone hemisuccinate
mesh term: Prednisolone phosphate
sharing ipd: No