Clinical trial NCT05221411: Tacrolimus Versus Mycophenolate for Autoimmune Hepatitis Patients With Incomplete Response on First Line Therapy
Official title: TAILOR Study: Tacrolimus Versus Mycophenolate for Autolmmune Hepatitis Patients With incompLete Response On First Line Therapy: a Randomized Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Autoimmune Hepatitis
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
First posted: 2022-02-03
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: 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

Primary outcomes:
measure: Complete biochemical remission
timeFrame: 52 weeks
Secondary outcomes:
measure: Safety and Tolerability
timeFrame: 52 weeks
measure: Proportion of patients with complete biochemical remission after 6 months
timeFrame: 24 weeks
measure: Proportion of patients with partial response
timeFrame: 52 weeks
measure: Proportion of patients with insufficient treatment response
timeFrame: 52 weeks
measure: Dose reduction of prednisone
timeFrame: 52 weeks
measure: Cessation rate of prednisone
timeFrame: 52 weeks
measure: Change of AST
timeFrame: 24 and 52 weeks
measure: Change of ALT
timeFrame: 24 and 52 weeks
measure: Change of IgG
timeFrame: 24 and 52 weeks
measure: Liver function
timeFrame: 24 and 52 weeks
measure: Fibrosis
timeFrame: 52 weeks
measure: Influence of liver disease on the quality of life
timeFrame: 52 weeks
measure: Treatment effect on health status
timeFrame: 52 weeks
measure: Cost-effectiveness based on empiric data obtained by this study.
timeFrame: 52 weeks
measure: Cost-effectiveness from a societal perspective
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
city: Den Bosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center +
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: Leiden University Medical Center
name: Bart van Hoek
role: PRINCIPAL_INVESTIGATOR
References: