36 Weeks Short-Term Optimization Treatment of Glucocorticosteroid in the Patients With Chronic Recurrent DILI

NCT03266146 | Completed Phase 1 DMC

• 1 other identifier: BJ302-FGRXGB-003
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Drug-induced Liver Injury,Chronic

Keywords

Drug-induced Liver Injury; Recurrence; Methylprednisolone; Short-term

Outcome Measures

Primary Outcomes (1)

• 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.

  To analyze the clinical efficacy of glucocorticosteroid treatment

  From week 1 to week 60 or 72

Secondary Outcomes (2)

• The liver histological changes between two liver biopsies (baseline and treatment end)

  At week 0 and at week 36 week or 48 week

• Days of normalization or falling by half compared to admission of liver functions including serum levels of ALT, AST, TBIL,GGT and ALP.

  From week 1 to week 36 or 48

Study Arms (2)

36 Weeks Methylprednisolone

EXPERIMENTAL

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.

Drug: 36 Weeks Methylprednisolone

48 Weeks Methylprednisolone

EXPERIMENTAL

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.

Drug: 48 weeks Methylprednisolone

Interventions

36 Weeks Methylprednisolone DRUG

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.

Also known as: MEDROL,NDC0009-0056-02

36 Weeks Methylprednisolone

48 weeks Methylprednisolone DRUG

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.

Also known as: MEDROL,NDC0009-0056-02

48 Weeks Methylprednisolone

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;
• The time of recurrence is 1 or more than 1;
• The definition of recurrence, meet any of the following conditions:
• the level of serum AST or ALT is elevated more than 5 fold ULN;
• the level of serum AST or ALT is two times higher than before;
• 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

Beijing, 100039, China

Location

Related Publications (15)

• 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

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Huang A, Zhu Y, Liu S, Sun Y, Liu Z, Liang QS, Zhao J, Chang BX, Bi JF, Liu JT, Zhai XR, Xie H, Li N, Tian H, Han L, Zhuang Y, Ma H, Teng GJ, Zhang W, Aithal GP, Ji D, Zhao J, Zou Z. An optimized short-term steroid therapy for chronic drug-induced liver injury: A prospective randomized clinical trial. Liver Int. 2024 Jun;44(6):1435-1447. doi: 10.1111/liv.15899. Epub 2024 Mar 14.

  PMID: 38483145 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: August 26, 2017
• First Posted: August 29, 2017
• Study Start: September 2, 2017
• Primary Completion: January 31, 2023
• Study Completion: January 31, 2023
• Last Updated: February 15, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)