Induction of Remission in Autoimmune Hepatitis With Azathioprine vs. MMF

NCT06650124 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: 12/8/2023-ACAD/E-12745/992
• Study Type: interventional
• Target: 108
• Locations: 0 countries
• Sites: N/A

Brief Summary

The goal of this clinical trial is to determine the effectiveness of azathioprine (AZA) versus mycophenolate mofetil (MMF) in inducing remission in treatment-naive patients with autoimmune hepatitis (AIH). The main questions it aims to answer are: Does MMF combined with prednisolone lead to higher remission rates compared to AZA with prednisolone after 24 weeks? Is MMF associated with fewer adverse events than AZA in these patients? Researchers will compare two treatment arms (MMF vs. AZA) to see if MMF leads to improved remission rates and safety outcomes. Primary Outcome Measure: Biochemical remission: The primary outcome is the normalization of liver enzymes (AST, ALT) and IgG levels at 24 weeks. Secondary Outcome Measures: Safety and adverse events: Monitoring and comparing the incidence and severity of side effects between the two groups. Treatment adherence: Evaluating how well patients stick to their assigned treatment regimens. Improvement in quality of life: Assessing changes in the patient's quality of life using validated questionnaires. Reversal of fibrosis: Measured by liver stiffness using Fibroscan, aiming for no progression of fibrosis. Participants will: Receive either MMF or AZA, alongside a tapering dose of prednisolone. Be monitored regularly through clinic visits, laboratory tests, and safety assessments to track remission and any adverse events.

Conditions

Autoimmune Hepatitis

Keywords

utoimmune Hepatitis (AIH); Azathioprine (AZA); Mycophenolate Mofetil (MMF); Induction of Remission

Outcome Measures

Primary Outcomes (1)

• Biochemical Remission at 24 Weeks

  Definition: Normalization of liver enzymes (ALT, AST) and immunoglobulin G (IgG) levels. Time Frame: Measured at 24 weeks of treatment. Purpose: To evaluate the effectiveness of mycophenolate mofetil (MMF) versus azathioprine (AZA) in achieving biochemical remission in treatment-naive autoimmune hepatitis (AIH) patients.

  24 weeks

Secondary Outcomes (4)

• Incidence and Severity of Adverse Events

  24 weeks.

• Treatment Adherence

  24 weeks.

• Quality of Life Improvement

  24 weeks.

• Change in Liver Fibrosis

  24 weeks.

Study Arms (2)

Azathioprine + Prednisolone Arm

ACTIVE COMPARATOR

Azathioprine + Prednisolone Arm Participants will receive azathioprine (AZA) in combination with prednisolone as part of their treatment regimen.

Drug: Azathioprine + Prednisolone

Mycophenolate Mofetil + Prednisolone Arm

ACTIVE COMPARATOR

Mycophenolate Mofetil + Prednisolone Arm Participants will receive mycophenolate mofetil (MMF) in combination with prednisolone as part of their treatment regimen.

Drug: Mycophenolate Mofetil + Prednisolone Participants will receive mycophenolate mofetil in combination.

Interventions

Mycophenolate Mofetil + Prednisolone Participants will receive mycophenolate mofetil in combination. DRUG

Participants in this arm will receive mycophenolate mofetil (MMF) starting at 1,000 mg/day for the first two weeks, increasing to 2,000 mg/day thereafter. This will be combined with prednisolone, beginning at 40-60 mg/day, with a tapering dose to 5-10 mg/day after 4-8 weeks, depending on the patient's response. MMF works by inhibiting inosine monophosphate dehydrogenase, which decreases lymphocyte proliferation, thereby reducing immune-mediated liver damage in autoimmune hepatitis. Prednisolone, a corticosteroid, is included to control inflammation during the induction phase of treatment. This intervention lasts for 24 weeks, with monitoring for biochemical remission (normalization of liver enzymes and IgG levels) and adverse events to assess the treatment's safety and efficacy.

Mycophenolate Mofetil + Prednisolone Arm

Azathioprine + Prednisolone DRUG

In this arm, participants will receive azathioprine (AZA) starting at 50 mg/day for the first two weeks, followed by an increase to 100 mg/day. This dose will be combined with prednisolone, starting at 40-60 mg/day, with the dosage tapering to 5-10 mg/day after 4-8 weeks, depending on patient response. Azathioprine works as an immunosuppressive agent by inhibiting DNA synthesis in rapidly dividing immune cells, thereby reducing liver inflammation in autoimmune hepatitis. Prednisolone, a corticosteroid, is included to control inflammation during the initial treatment phase. The intervention lasts for 24 weeks with regular monitoring for biochemical remission, defined as normalization of liver enzymes (AST, ALT) and IgG levels, as well as the occurrence of adverse events to assess safety and tolerability.

Azathioprine + Prednisolone Arm

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis: Confirmed diagnosis of autoimmune hepatitis (AIH) based on clinical, biochemical, and histological findings.
• Biochemical markers: Elevated liver enzymes, specifically AST and ALT, indicating liver inflammation.
• Treatment-naive: Patients must be treatment-naive, meaning they have not received prior immunosuppressive therapy for AIH.
• Willingness to participate: Patients must provide informed consent and be willing to comply with all study-related procedures and follow-ups. -

You may not qualify if:

• Acute liver failure: Patients presenting with acute liver failure at baseline will be excluded.
• Low blood counts: Patients with a platelet count less than 50,000/mm³ or total leukocyte count (TLC) less than 3,000/mm³ will not be eligible.
• Previous treatment: Patients who have already received immunosuppressive or disease-modifying therapy for AIH or related conditions.
• Pregnancy or lactation: Pregnant or lactating women will be excluded to avoid potential risks to the mother or fetus.
• Hepatocellular carcinoma (HCC) or malignancy: Any patients with evidence of hepatocellular carcinoma or other active malignancies.
• Medication allergies: Patients with known allergies to azathioprine, mycophenolate mofetil (MMF), or prednisolone will be excluded.
• Non-consent: Patients who are not willing to participate in the study or unable to provide informed consent.

Sponsors & Collaborators

• Institute of Liver and Biliary Sciences, India: lead

Related Publications (9)

• Snijders RJALM, Stoelinga AEC, Gevers TJG, Pape S, Biewenga M, Tushuizen ME, Verdonk RC, de Jonge HJM, Vrolijk JM, Bakker SF, Vanwolleghem T, de Boer YS, Baven Pronk MAMC, Beuers U, van der Meer AJ, Gerven NMFV, Sijtsma MGM, van Eijck BC, van IJzendoorn MC, van Herwaarden M, van den Brand FF, Korkmaz KS, van den Berg AP, Guichelaar MMJ, Levens AD, van Hoek B, Drenth JPH; Dutch Autoimmune Hepatitis Working Group. An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis. J Hepatol. 2024 Apr;80(4):576-585. doi: 10.1016/j.jhep.2023.11.032. Epub 2023 Dec 14.

  PMID: 38101756 BACKGROUND

• Santiago P, Schwartz I, Tamariz L, Levy C. Systematic review with meta-analysis: mycophenolate mofetil as a second-line therapy for autoimmune hepatitis. Aliment Pharmacol Ther. 2019 Apr;49(7):830-839. doi: 10.1111/apt.15157. Epub 2019 Feb 13.

  PMID: 30761563 BACKGROUND

• Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zuckerman E, Bahr MJ, Gunther R, Hultcrantz RW, Spengler U, Lohse AW, Szalay F, Farkkila M, Prols M, Strassburg CP; European AIH-BUC-Study Group. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology. 2010 Oct;139(4):1198-206. doi: 10.1053/j.gastro.2010.06.046. Epub 2010 Jun 22.

  PMID: 20600032 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

• Czaja AJ. Current and future treatments of autoimmune hepatitis. Expert Rev Gastroenterol Hepatol. 2009 Jun;3(3):269-91. doi: 10.1586/egh.09.15.

  PMID: 19485809 BACKGROUND

• Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: Standard treatment and systematic review of alternative treatments. World J Gastroenterol. 2017 Sep 7;23(33):6030-6048. doi: 10.3748/wjg.v23.i33.6030.

  PMID: 28970719 BACKGROUND

• Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, Dokmeci AK, Gane E, Hou JL, Jafri W, Jia J, Kim JH, Lai CL, Lee HC, Lim SG, Liu CJ, Locarnini S, Al Mahtab M, Mohamed R, Omata M, Park J, Piratvisuth T, Sharma BC, Sollano J, Wang FS, Wei L, Yuen MF, Zheng SS, Kao JH. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016 Jan;10(1):1-98. doi: 10.1007/s12072-015-9675-4. Epub 2015 Nov 13.

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• Makol A, Watt KD, Chowdhary VR. Autoimmune hepatitis: a review of current diagnosis and treatment. Hepat Res Treat. 2011;2011:390916. doi: 10.1155/2011/390916. Epub 2011 May 15.

  PMID: 21760995 BACKGROUND

• Czaja AJ, Freese DK; American Association for the Study of Liver Disease. Diagnosis and treatment of autoimmune hepatitis. Hepatology. 2002 Aug;36(2):479-97. doi: 10.1053/jhep.2002.34944. No abstract available.

  PMID: 12143059 BACKGROUND

MeSH Terms

Conditions

Hepatitis, Autoimmune

Interventions

Mycophenolic Acid; Azathioprine; Prednisolone

Condition Hierarchy (Ancestors)

Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Thionucleosides; Sulfur Compounds; Mercaptopurine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Central Study Contacts

Babu Lal Meena, DM Hepatology

CONTACT

+91-9781100898; drbabupgi@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: nterventional Study Model: Parallel Assignment Study Type: Interventional (Clinical Trial) Study Model: Parallel Assignment - Participants are randomly assigned to one of two groups (either receiving azathioprine or mycophenolate mofetil) and remain in their assigned group for the entire study. Masking: Double-blind (both participants and investigators are unaware of which treatment is being administered to prevent bias). Allocation: Randomized - Patients are randomly allocated to one of the two treatment groups.

Study Record Dates

• First Submitted: October 17, 2024
• First Posted: October 21, 2024
• Study Start: November 1, 2024
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: November 7, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share