Tacrolimus Versus Mycophenolate for Autoimmune Hepatitis Patients With Incomplete Response on First Line Therapy

NCT05221411 | Unknown Phase 4 DMC

• 3 other identifiers: P21.0892021-003420-33NL78216.058.21
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 6

Brief Summary

Rationale: The combination of azathioprine and prednisone is the first-line treatment for autoimmune hepatitis (AIH), a chronic inflammatory disease of the liver. Complete biochemical remission (CR) is the first treatment goal in autoimmune hepatitis. CR is determined by AST and ALT and IgG within the reference range. CR is not reached in a substantial proportion of AIH patients: after one year 50%, after three years around 20% did not achieve CR. Without CR ongoing hepatitis leads to progression towards fibrosis and eventually (decompensated) cirrhosis. Not achieving CR is the most important risk factor for the need for liver transplantation or liver related death, independent of age and presence of cirrhosis. Tacrolimus (TAC) and mycophenolate mofetil (MMF) are frequently used to prevent rejection in kidney and liver transplant patients. In AIH patients with insufficient response or intolerance to first-line therapy in retrospective cohort studies with MMF 0-57% and with TAC 20-95% CR was reached. Objective: The aim of this study is to compare the effectiveness of TAC with MMF as a second line treatment for AIH. Proportion of patients with CR after 12 months of treatment will be the primary outcome parameter to determine effectivity. Study design: Randomized open-label two arm study. Patients will be randomized between treatment with TAC or MMF. Study population: Patients with AIH with an incomplete response (no CR) to first-line treatment are eligible for this study. Intervention: In the TAC group baseline treatment will be replaced by tacrolimus. In the MMF group baseline treatment will be replaced by MMF. The current dose of prednisolone, or at least 5 mg daily, will be continued in both arms. After achieving CR prednisolone will be tapered according to protocol. Main study parameters/endpoints: Difference in proportion of patients with CR at 12 months (normalization of ALT, AST and IgG) between the TAC and MMF treatment group. Secondary parameters:

• Safety and tolerability of TAC and MMF treatments
• Difference in proportion of patients with CR at 6 months (normalization of ALT, AST and IgG) between the TAC and MMF treatment group.
• Difference in ALT, AST and IgG at 6 and 12 months versus baseline
• Difference in fibrogenesis and fibrosis parameters between groups and before and after treatment
• Difference in quality of life between groups and before and after treatment

Conditions

Autoimmune Hepatitis

Outcome Measures

Primary Outcomes (1)

• Complete biochemical remission

  The proportion of patients with CR after 12 months of treatment with TAC compared to MMF in patients with AIH with an incomplete response to first-line treatment.

  52 weeks

Secondary Outcomes (15)

• Safety and Tolerability

  52 weeks

• Proportion of patients with complete biochemical remission after 6 months

  24 weeks

• Proportion of patients with partial response

  52 weeks

• Proportion of patients with insufficient treatment response

  52 weeks

• Dose reduction of prednisone

  52 weeks

Study Arms (2)

Mycofenolate Mofetil

EXPERIMENTAL

Patients in the mycophenolate mofetil (MMF) arm will receive MMF for a total of 12 months (if tolerated)

Drug: Mycophenolate Mofetil

Tacrolimus (Envarsus)

EXPERIMENTAL

Patients in the tacrolimus (TAC) arm will receive treatment with meltdose TAC for a total of 12 months (if tolerated)

Drug: Tacrolimus

Interventions

Mycophenolate Mofetil DRUG

Mycophenolate mofetil will be started at a dose 500mg twice daily. When tolerated and an AUC within range, patients will be titrated to 1000mg twice daily at week two.

Also known as: Cellcept

Mycofenolate Mofetil

Tacrolimus DRUG

Meltdose tacrolimus will be started at a dose of 0.07 mg/kg/day. The drug will be taken orally once-daily in the morning. Dose will be adjusted to reach target AUC and trough levels.

Also known as: Envarsus

Tacrolimus (Envarsus)

Eligibility Criteria

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

You may qualify if:

• Patient is older than 18 years old
• Probable or definite auto immune hepatitis according to the original or simplified IAIHG criteria (\>10 points pre-treatment on the original criteria or \>6 points on the simplified criteria)(2, 3)
• Incomplete responder on at least a half year of first-line treatment, with at least last 6 months azathioprine / 6-MP) / 6-TG and prednisolone or budesonide, and ALT 1.5 - 10x ULN for at least 2 months
• Patient is capable of understanding the purpose and risks of the study, has been fully informed and has given written informed consent to participate in the study

You may not qualify if:

• Presence of decompensated liver disease, defined as ascites, coagulopathy (INR \>1.5), encephalopathy, variceal bleed, hepatopulmonal syndrome, hepatorenal syndrome or HCC in the past 6 months
• Signs of other liver diseases as NAFLD, Wilson disease, hemochromatosis, alcoholic liver disease or hepatitis B/C/D
• Clinical diagnosis of overlap / variant syndrome with PBC or PSC
• Liver transplantation in the medical history or currently on the waiting list for liver transplantation
• Incompliance with therapy during the last 12 months
• Allergic or hypersensitive to tacrolimus or MMF
• An estimated glomerular filtration rate (eGFR) of \<60 mL/min
• Pregnancy or intention to become pregnant in the next 12 months
• Use of TAC or MMF in the past
• Malignancy in the medical history

Sponsors & Collaborators

• Leiden University Medical Center: lead

Study Sites (6)

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, Netherlands

NOT YET RECRUITING

Reinier de Graaf Gasthuis

Delft, Netherlands

NOT YET RECRUITING

Medisch Spectrum Twente

Enschede, Netherlands

NOT YET RECRUITING

Leiden University Medical Center

Leiden, Netherlands

RECRUITING

Maastricht University Medical Center +

Maastricht, Netherlands

NOT YET RECRUITING

University Medical Center Utrecht

Utrecht, Netherlands

NOT YET RECRUITING

Related Publications (1)

• Stoelinga AEC, Tushuizen ME, van den Hout WB, Girondo MDMR, de Vries ES, Levens AD, Moes DAR, Gevers TJG, van der Meer S, Brouwer HT, de Jonge HJM, de Boer YS, Beuers UHW, van der Meer AJ, van den Berg AP, Guichelaar MMJ, Drenth JPH, van Hoek B; Dutch Autoimmune Hepatitis Group. Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial. Trials. 2024 Jan 17;25(1):61. doi: 10.1186/s13063-023-07832-w.

  PMID: 38233878 DERIVED

MeSH Terms

Conditions

Hepatitis, Autoimmune

Interventions

Mycophenolic Acid; Tacrolimus

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; Macrolides; Lactones

Study Officials

• Bart van Hoek

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anna Stoelinga

CONTACT

+31 6 30 29 11 71; a.e.c.stoelinga@lumc.nl

Bart van Hoek

CONTACT

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. dr.

Study Record Dates

• First Submitted: January 7, 2022
• First Posted: February 3, 2022
• Study Start: January 19, 2022
• Primary Completion: January 1, 2023
• Study Completion: January 1, 2024
• Last Updated: February 3, 2022

Record last verified: 2022-01

Locations

NL (6)