Efficacy and Safety of Glucocorticosteroid Treatment in the Patients With Chronic Recurrent DILI

NCT02651350 | Completed Phase 1 DMC

• 1 other identifier: BJ302-FGRXGB-001
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

This study is to observe the efficacy and safety of glucocorticosteroid treatment in the patients with chronic recurrent drug-induced liver injury (DILI).

Conditions

Drug-induced Liver Injury,Chronic

Keywords

Drug-induced Liver Injury; Recurrence; Methylprednisolone

Outcome Measures

Primary Outcomes (2)

• The relapse or recurrent rate of illness, namely, appearance of obviously abnormal liver function again during treatment and follow-up period

  The biochemical relapse rate was analyzed by either intention to treat (ITT) or per protocol set (PPS). Biochemical relapse was characterized either by the serum alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥ 3 × upper limits of normal (ULN) or alkaline phosphatase (ALP) ≥ 2 × ULN, or by at least 2 folds increase in serum ALT or AST or ALP from the abnormal index lately.

  At week 24

• The relapse or recurrent rate of illness, namely, appearance of obviously abnormal liver function again during treatment and follow-up period

  The biochemical relapse rate was analyzed by either intention to treat (ITT) or per protocol set (PPS). Biochemical relapse was characterized either by the serum alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥ 3 × upper limits of normal (ULN) or alkaline phosphatase (ALP) ≥ 2 × ULN, or by at least 2 folds increase in serum ALT or AST or ALP from the abnormal index lately.

  At week 72

Secondary Outcomes (3)

• Days of normalization of liver functions including serum levels of ALT, AST, TBIL,GGT and ALP.

  From week 1 to week 12

• The liver histological changes between two liver biopsies

  At week 0 and at week 48 week

• The number of participants with methylprednisolone treatment-related adverse events, such as severe osteopenia, uncontrolled hypertension

  At week 24 and at week 72

Study Arms (2)

Methylprednisolone

EXPERIMENTAL

Participants will receive methylprednisolone from week 0 through week 48 study visit in combination with standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil,or ursodeoxycholic acid (UDCA) in the first 12 weeks. Participants will then be followed until week 72 study visit.

Drug: Methylprednisolone; Drug: Standard Treatment

Standard Treatment

ACTIVE COMPARATOR

Participants will only receive standard treatment (namely,routine liver protection drugs) including reduced glutathione, glycyrrhizin, ademetionine, alprostadil,or ursodeoxycholic acid (UDCA) from week 0 through week 12 study visit. Participants will then be followed until week 72 study visit.

Drug: Standard Treatment

Interventions

Methylprednisolone DRUG

Participants 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 will also receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA) in the first 12 weeks.The total treatment duration will be 48 weeks. Follow-up duration is 24 weeks.

Also known as: MEDROL,NDC0009-0056-02

Methylprednisolone

Standard Treatment DRUG

Participants will only receive standard treatment,namely,routine liver protection drugs including reduced glutathione, glycyrrhizin, ademetionine, alprostadil,or ursodeoxycholic acid (UDCA) from week 0 through week 12 study visit. Participants will then be followed until week 72.

Also known as: Routine liver protection drugs

Methylprednisolone; Standard Treatment

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Meet with ACG clinic guidelines for diagnostic criteria of chronic DILI;
• Meet any of the following conditions:
• serum AST or ALT ≥ 10 fold ULN;
• serum AST or ALT ≥ 5 fold ULN and TBIL ≥ 2 fold ULN;
• liver histology indicates bridging necrosis or multiacinar necrosis or moderate or more inflammation or inflammation G3 or more;
• Women of childbearing age had a negative urine pregnancy test, and the subjects are willing to have no family planning during the study and to take effective measures;
• Voluntary participation, understanding and signing of informed consent, comply with the requirements of the research;

You may not qualify if:

• Patients with serious pre-existent comorbid conditions (vertebral compression fractures,psychosis,active peptic ulcer, brittle diabetes,uncontrolled hypertension;
• Patients with intolerances to prednisone;
• Patients with severe infection receiving antibiotics, anti-fungal,anti-viral therapy;
• Viral hepatitis,alcoholic or non-alcoholic liver disease,Wilson's disease or other inherited metabolic liver diseases.
• Pregnancy or desire of pregnancy;
• Breast-feeding;
• Liver cancer or other malignant tumor;

Sponsors & Collaborators

• Beijing 302 Hospital: lead

Study Sites (1)

Beijing 302 hospital,China

Beijing, Beijing Municipality, 100039, China

Location

Related Publications (12)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Wang JB, Huang A, Wang Y, Ji D, Liang QS, Zhao J, Zhou G, Liu S, Niu M, Sun Y, Tian H, Teng GJ, Chang BX, Bi JF, Peng XX, Xin S, Xie H, Ma X, Mao YM, Liangpunsakul S, Saxena R, Aithal GP, Xiao XH, Zhao J, Zou Z. Corticosteroid plus glycyrrhizin therapy for chronic drug- or herb-induced liver injury achieves biochemical and histological improvements: a randomised open-label trial. Aliment Pharmacol Ther. 2022 May;55(10):1297-1310. doi: 10.1111/apt.16902. Epub 2022 Mar 31.

  PMID: 35362188 DERIVED

MeSH Terms

Conditions

Chemical and Drug Induced Liver Injury, Chronic; Chemical and Drug Induced Liver Injury; Recurrence

Interventions

Methylprednisolone

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Poisoning

Intervention Hierarchy (Ancestors)

Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Zhengsheng Zou, Dr.

  Beijing 302 Hospital,China.

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 25, 2015
• First Posted: January 11, 2016
• Study Start: December 1, 2015
• Primary Completion: July 1, 2019
• Study Completion: July 1, 2019
• Last Updated: August 11, 2020

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)