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

January 21, 2022 updated by: Bart van Hoek, Leiden University Medical Center

TAILOR Study: Tacrolimus Versus Mycophenolate for Autolmmune Hepatitis Patients With incompLete Response On First Line Therapy: a Randomized Trial

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

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

86

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Bart van Hoek

Study Locations

  • Netherlands
      • Delft, Netherlands
        • Not yet recruiting
        • Reinier de Graaf Gasthuis
        • Contact:
          • Hans Brouwer
      • Den Bosch, Netherlands
        • Not yet recruiting
        • Jeroen Bosch Ziekenhuis
        • Contact:
          • Henk-Marijn de Jonge
      • Enschede, Netherlands
        • Not yet recruiting
        • Medisch Spectrum Twente
        • Contact:
          • Maureen Guichelaar
      • Leiden, Netherlands
        • Recruiting
        • Leiden University Medical Center
        • Contact:
          • Bart van Hoek
      • Maastricht, Netherlands
        • Not yet recruiting
        • Maastricht University Medical Center +
        • Contact:
          • Tom Gevers
      • Utrecht, Netherlands
        • Not yet recruiting
        • University Medical Center Utrecht
        • Contact:
          • Suzanne van der Meer

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • Active infections during inclusion including latent tuberculosis and HIV co-infection
  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Mycofenolate Mofetil
Patients in the mycophenolate mofetil (MMF) arm will receive MMF for a total of 12 months (if tolerated)
Drug: Mycophenolate Mofetil
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.
Other Names:
  • Cellcept
Experimental: Tacrolimus (Envarsus)
Patients in the tacrolimus (TAC) arm will receive treatment with meltdose TAC for a total of 12 months (if tolerated)
Drug: Tacrolimus
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.
Other Names:
  • Envarsus

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Complete biochemical remission
Time Frame: 52 weeks
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety and Tolerability
Time Frame: 52 weeks
Number and severity of side effects; Rate of stopping treatment due to side effects; serum creatinin & potassium; Blood pressure; Blood glucose levels and incidence of new onset diabetes; Number of (opportunistic) infections; tremor; diarrhea
52 weeks
Proportion of patients with complete biochemical remission after 6 months
Time Frame: 24 weeks
Defined as ALT, AST and IgG below the upper limit of normal
24 weeks
Proportion of patients with partial response
Time Frame: 52 weeks
defined as decrease of AST and ALT, but no normalization
52 weeks
Proportion of patients with insufficient treatment response
Time Frame: 52 weeks
less than 25% reduction in ALT after 6 and 12 months treatment
52 weeks
Dose reduction of prednisone
Time Frame: 52 weeks
Difference between dose at inclusion and dose at the end of study
52 weeks
Cessation rate of prednisone
Time Frame: 52 weeks
The number of patients able to completely withdraw from corticosteroids
52 weeks
Change of AST
Time Frame: 24 and 52 weeks
at 6 and 12 months versus baseline and between groups at the same time points
24 and 52 weeks
Change of ALT
Time Frame: 24 and 52 weeks
at 6 and 12 months versus baseline and between groups at the same time points
24 and 52 weeks
Change of IgG
Time Frame: 24 and 52 weeks
at 6 and 12 months versus baseline and between groups at the same time points
24 and 52 weeks
Liver function
Time Frame: 24 and 52 weeks
Total bilirubin, albumin, INR and MELD-score after 6 and 12 months between groups
24 and 52 weeks
Fibrosis
Time Frame: 52 weeks
Liver stiffness as measured by elastography and blood fibrosis markers (ELF)
52 weeks
Influence of liver disease on the quality of life
Time Frame: 52 weeks
using the validated liver disease symptom index (LDSI)
52 weeks
Treatment effect on health status
Time Frame: 52 weeks
using the validated EQ5D
52 weeks
Cost-effectiveness based on empiric data obtained by this study.
Time Frame: 52 weeks
Economic evaluation including a cost-effectiveness evaluation
52 weeks
Cost-effectiveness from a societal perspective
Time Frame: 52 weeks
Economic evaluation including a cost-utility evaluation (costs per QALY)
52 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Leiden University Medical Center

Investigators

  • Principal Investigator: Bart van Hoek, Leiden University Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 19, 2022

Primary Completion (Anticipated)

January 1, 2023

Study Completion (Anticipated)

January 1, 2024

Study Registration Dates

First Submitted

January 7, 2022

First Submitted That Met QC Criteria

January 21, 2022

First Posted (Actual)

February 3, 2022

Study Record Updates

Last Update Posted (Actual)

February 3, 2022

Last Update Submitted That Met QC Criteria

January 21, 2022

Last Verified

January 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P21.089
  • 2021-003420-33 (EudraCT Number)
  • NL78216.058.21 (Other Identifier: CCMO)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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