Study setting {9}
This multicentre study will be conducted at the gastroenterology and hepatology outpatient clinics of seven academic centre and three large teaching hospitals in the Netherlands. Other Dutch hospitals can recruit patients and refer them to participating hospitals for screening and inclusion. A list of participating centre can be found at ClinicalTrials.gov under NCT05221411.
Eligibility criteria {10}
Inclusion criteria
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Patient is older than 18 years old
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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)[1, 2]
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Incomplete responder on at least a half year of first-line treatment, including azathioprine / 6-MP / 6-TG and prednisolone or budesonide
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ALT 1.5–10x ULN for at least 2 months
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Patient is capable of understanding the purpose and risks of the study, has been fully
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Informed and has given written informed consent to participate in the study
Exclusion criteria
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Presence of decompensated liver disease, defined as ascites, coagulopathy (INR > 1.5), encephalopathy, variceal bleed, hepato-pulmonal syndrome, hepatorenal syndrome or HCC in the past 6 months
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Signs of other liver diseases as metabolic dysfunction-associated steatotic liver disease (MASLD), Wilson disease, hemochromatosis, alcoholic liver disease or viral hepatitis B/C/D
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Clinical diagnosis of overlap / variant syndrome with PBC or PSC
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Liver transplantation in the medical history or currently on the waiting list for liver transplantation
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Incompliance with therapy during the last 12 months
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Active infections during inclusion including latent tuberculosis and HIV co-infection
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Allergic or hypersensitive to TAC or MMF
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An estimated glomerular filtration rate (eGFR) of < 60 mL/min
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Pregnancy or intention to become pregnant in the next 12 months
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Use of TAC or MMF in the past
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Malignancy in the medical history in the past five years, or current use of chemotherapy.
Who will take informed consent? {26a}
Patients are recruited at the outpatient clinics of all participating hospitals as well as in recruiting hospitals. They will be asked to participate by their treating physician. The local principal investigator will explain the study to potential study subjects. Subsequently, patients will receive a patients information form (PIF). After one week, patients will be contacted by the central study coordinator, to whom questions can be asked and by whom additional clarification can be given. After having given informed consent, a screening visit (Tx) will be planned.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Patients will provide informed consent for the collection of back-up samples of serum and plasma, that will be performed in several centres. These samples will be stored locally and will be used for central end-point analyses. Throughout the study, additional research questions may arise. Ancillary studies can be performed on blood samples.
Interventions
Explanation for the choice of comparators {6b}
Several retrospective studies have reported on the use of TAC as a second line therapy in autoimmune hepatitis. In several case series TAC was given to patients unresponsive to prednisone and/or AZA. The first study of TAC in AIH was performed by van Thiel et al[16]. They studied the use of TAC for induction treatment of AIH and found a decrease of ALT in 80% of the patients. In several subsequently (relatively) small case series TAC was given as second line therapy for AIH, whereas remission rates differed between 20–92% [14, 17–22].
The use of MMF for AIH, both in case of intolerance for first-line treatment and in case of
insufficient response, has been published by our group [23]. Retrospective cohort studies
indicate that in AIH patients with intolerance or insufficient response on first-line therapy, with MMF complete remission can be induced in 0–22% of patients [23–25]. One study reported a remarkable proportion of 57% remission with MMF[26]. There appeared to be a difference in remission rates between patients started on MMF for intolerance to first-line treatment or for insufficient response to first-line treatment [23–25].
Both TAC and MMF are mentioned as possible second-line therapy in guidelines and literature. In one paper CR on MMF was reported to be 22% in patients with an incomplete response, which is lower when compared to the CR rate in patients with intolerance to AZA[27]. A cohort of treatment naïve AIH patients has also been treated successfully with MMF[28–30].
Because of a more favourable profile of adverse effects, MMF should possibly be favoured as second-line treatment for AIH, and not TAC, although it might be less effective[31]. TAC could be more effective than MMF as second-line therapy for incomplete response. However, the aforementioned studies are all retrospective cohort studies. No randomized trials for second-line therapies for AIH have been performed.
Intervention description {11a}
Group one: Prolonged-release tacrolimus (Envarsus)
For this study, TAC will be used, preferably 0.75mg, 1mg and 4mg tablets of Envarsus® from Chiesi Pharmaceuticals. Envarsus is a once-daily prolonged release formulation with more stable tacrolimus levels [32, 33]. Patients in this arm will start with oral 0.07mg/kg/day of meltdose tacrolimus once daily. If Envarsus is unavailable, other forms of TAC (e.g., Advagraf, Adport, Dailiport, Prograft) may be used, with the appropriate dosing scheme, since different forms of TAC have different bioavailability. Tacrolimus has a narrow therapeutic window and highly variable pharmacokinetics. Therapeutic drug monitoring (TDM) will be performed to reach a target AUC of 160 µg*h/L (20% interval 128–196) tacrolimus. This is compatible with trough levels of 3.6–7.4 µg/l[34–36].
Tacrolimus can have several adverse effects. Due to a narrow therapeutic window, therapeutic drug monitoring is necessary to prevent underexposure, which can result in reduced effect, and overexposure, which can lead to side effects including hypertension, tremor, headache, renal toxicity and hyperkalaemia. Like with any other immunosuppressive drug, there is an increases risk of infections.
Group 2: mycophenolate mofetil (Cellcept®)
For this study, 500mg tablets of CellCept® from F. Hoffmann-La Roche AG Pharmaceuticals will be used. If not available, generic forms of MMF may be used. Patients in the MMF arm will receive a maximum total dose of 2000mg daily, split-dose. Patients will commence with a dose of 500mg twice daily. When tolerated, doses will be titrated to 1000mg twice daily after week 2. Most common adverse effects are gastrointestinal toxicity, leukopenia, thrombopenia and increased risk of infections.
Criteria for discontinuing or modifying allocated interventions {11b}
Subjects can leave the study at any point during the follow-up. Investigators can decide to withdraw a subject from the study when:
In case of severe adverse effects or eGFR < 50ml/min, the dose of study medication will be halved. If severe side effects persist despite halving the dose, study medication will be discontinued. If the eGFR is < 40ml/min, study medication will also be discontinued. In case study medication is discontinued, all follow-up visits and assessments will still be performed with the exception of the therapeutic drug monitoring.
If loss of remission, defined as ALT > 1-3x ULN after reaching CR, occurs or when ALT reaches 3-10x ULN during the study, corticosteroid dose will be increased to the dose at screening, while trial participation can be continued as per discretion of the treating physician.
Strategies to improve adherence to interventions {11c}
TAC and MMF will be packed and labelled as study medication according to Good Manufacturing Practice (GMP) guidelines by the pharmacy of the Leiden University Medical Center (LUMC). Local study investigators will perform drug-accountability using a drug-accountability log. Patients will be asked to take their medication and empty boxes to the close-out visit to control compliance. Additionally, the Basel Assessment of Adherence to immunosuppressive medIcations Scale (BAASIS) will be used to check compliance. The questionnaires will be filled out during each clinic visit or will be sent electronically by e-mail. Reminders will be sent after 14 days.
Relevant concomitant care permitted or prohibited during the trial {11d}
New medication may be prescribed at the discretion of the treating physician. No new immunosuppressants may be used, besides the corticosteroids already in use at screening. If a flare of AIH (ALT > 10x ULN) occurs during the study period patients will receive the standard of care by the treating physician and trial participation will end.
Study subjects are not allowed to participate in other trials investigating pharmaceutical agents for AIH.
Provisions for post-trial care {30}
Participants who suffer harm from participating in the study are covered by the liability insurance of the LUMC with a maximum of €650.000 per subject, €5.000.000 per study and €7.500.000 per year. The insurance applies to the damage that becomes apparent during the study or within 4 years after the end of the study.
Outcomes {12}
Primary outcome
Proportion of patients with CR after 12 months of treatment with TAC compared to patients with MMF treatment in AIH patients with incomplete remission to at least six months of first-line treatment.
CR is defined as ALT, AST and IgG below the upper limit of normal. The endpoint will be expressed as a hazard ration with 95% confidence interval.
Secondary outcomes
The secondary objectives are:
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Safety and Tolerability - Number and severity of side effects; Rate of stopping treatment due to side effects; serum creatinine & potassium; Blood pressure; Blood glucose levels and incidence of new onset diabetes; Number of (opportunistic) infections; tremor; diarrhoea
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Proportion of patients with CR after 6 months
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Cumulative corticosteroid dose
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Change of AST, ALT and IgG at 6 and 12 months versus baseline and between groups at the same time points
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Liver function: Total bilirubin, albumin, INR and MELD-score after 6 and 12 months between groups
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Fibrosis: Liver stiffness as measured by elastography and blood fibrosis markers (Enhanced Liver Fibrosis test)
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Quality of life (questionnaires) using the validated liver disease symptom index (LDSI), short-form 36 (SF-36) and EQ5D
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Cost-effectiveness: using modified Productivity Cost Questionnaire (iPCQ) and Medical Consumption Questionnaire (iMCQ) questionnaires
Participant timeline {13}
A schematic overview of study visits and assessments is shown in Table 1. The total duration of the study will be the undefined period of time between screening and start of the investigative product and 12 months follow-up.
Sample size {14}
A sample size calculation is based on the log-rank test for comparing two groups, a follow-up of 12 months and the assumption of exponential survival times. The expected difference between groups was formulated in terms of relative risk derived from the expected cumulative incidences in the two groups according to previous literature. Papers on MMF for insufficient response in EU and North-America - reported 13%, 21% and 34% CR respectively - and review of the literature on TAC in adult AIH patients was also taken into account. Assuming proportions of CR at the end of follow-up of 0.22 in the MMF group and 0.53 in the TAC group with a two-sided α of 0.05 significance level and power of 1-β = 0.8 to determine difference in proportions of 0.31, results, in N = 38 patients per group. Taking into account a 10% loss to follow-up (e.g. due to side effects), this results in N = 43 patients per group. Thus, we aim to include a total of 86 patients.
Recruitment {15}
Recruitment will take place at regular outpatient clinic visits. Patients will be approached by their treating physician. Study visits will take place during regular outpatient clinic visits, providing a low threshold for participation in follow-up.
Assignment of interventions: allocation
Sequence generation {16a}
Participants will be randomised 1:1, with a variable block randomization (block size 4, 6, 8) between azathioprine or MMF, stratified for the presence of cirrhosis (yes/no), based on recent vibration-controlled transient elastography (VCTE) (> 16kPa) or liver biopsy (Metavir F4), using the electronic case report form (eCRF) by Castor Electronic Data Management (Castor EDC).
Concealment mechanism {16b}
Participants, treating physicians, local and central study coordinators are blinded for the randomisation process, but not for medication use during the study (because of the need for blood level monitoring of TAC) and not for the outcome of individual participants.
Implementation {16c}
Randomisation will be done by the central study coordinator. Assessors of the final outcome will be blinded. The allocation sequence is unknown to the central study coordinator.
Assignment of interventions: Blinding
Who will be blinded {17a}
The design of this study is open-label. This entails that only the outcome assessors will be blinded during analyses. The assigned study arm will be known for both patients and all research staff (including the primary caregiver and principal investigator).
Procedure for unblinding if needed {17b}
As this is an open-label study, unblinding of participants, local and central study coordinators and primary caregiver will not be required.
Data collection and management
Plans for assessment and collection of outcomes {18a}
At the screening visit, data on demographics, medical history and medication use is collected after obtaining informed consent. Simultaneously laboratory assessments are done, including screening for systemic infections and pharmacogenetics, and VCTE is performed. After inclusion, participants visit the outpatient at different timepoints (table 1). During these visits, laboratory tests are done, TDM is done using area under the curve measurements (visits T2 and T12) or trough levels (only for TAC on visits T24, T36, T52), and (serious) adverse events ((S)AEs) are reviewed. During specified study visits, health related quality of life (HRQoL) questionnaires are administered and VCTE is done.
Plans to promote participant retention and complete follow-up {18b}
Participants visit the outpatient clinic at an interval of three months, as per standard of care in most participating centre. Patients who are referred from a recruiting centre can visit the participating centre at a six-monthly interval, having the remaining study visits in the recruiting centre as part of standard care. Patients who withdraw from the study due to (severe) side effects of toxicity, follow-up visits will be performed with the exception of TDM. No additional data of patients discontinuing treatment for other reasons will be collected.
Data management {19}
All data will be entered electronically in case report forms in Castor EDC. Data are collected by the site personnel or the coordinating investigator. After signing informed consent, participants will receive a trial identification number.
Confidentiality {27}
All data and specimens will be entered and stored in a coded fashion. The code key will be kept at the participating sites. Access will be limited to involved researchers, who are responsible for the processing of the data. The dataset analysed during the current study and statistical code can be requested through the principle investigator of the sponsor site.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
At screening, weeks 24 and 52, additional serum samples will be taken for central end-point analyses. All biological specimens stored during the study are stored for possible additional analyses at a later stage.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Statistical methods for primary and secondary outcomes
Intention-to-treat analysis will be used throughout the study for primary and secondary endpoints. All randomised patients will be included in the intention-to-treat analysis. CR at 12 months will be reported as percentage. A Kaplan-Meyer survival analysis with log-rank test will be performed to assess the rapidity of reaching CR. Time to CR will be censored at 12 months. In the unlikely event that a subject is withdrawn from the study due to liver-related mortality or liver transplantation, a competing risk analysis according to Fine & Grey will be performed.
All parameters will be summarised by treatment group using descriptive statistics. Mean, standard deviation, median and range will be used for continuous variables. Counts and percentages will be used for categorical variables. For normally distributed continuous variables student T-test will be used, for not normally distributed continuous variables Mann Whitney U test will be used. For categorical variables Chi-square test or Fishers exact test will be used. For repeated measurements paired T-test and Wilcoxon signed rank test will be used where appropriate. Confounding will be tested where appropriate.
The economic evaluation comparing the MMF and TAC policies will include a trial-based cost-effectiveness analysis (1-year healthcare costs per complete biochemical remission) and a model-based cost-utility analysis (life-long societal costs per QALY, calculated from the EQ-5D-5L).
Statistical analyses will be performed with Statistical Package for Social Sciences (SPSS), version 24.0 or higher. Two-sided tests will be used and p-values < 0.05 will be deemed significant.
Interim analyses {21b}
No interim analysis is planned in this study. Safety of the interventions will be monitored by registering (serious) adverse events. In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there is sufficient ground that continuation of the study will jeopardise subject health or safety.
Methods for additional analyses (e.g. subgroup analyses) {20b}
No subgroup analysis will be performed in this study.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
In the event of missing data, this will be dealt with accordingly using additional statistical analyses (e.g. imputation). The primary analysis will be an intention-to-treat analysis. Every patient who has received at least one dose of study medication will be included in the ITT analysis.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
After publication of the final manuscript, data may be available upon reasonable request. The dataset analysed during the current study and statistical code can then be requested through the principle investigator of the sponsor site, as is the full protocol.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
Leiden University Medical Center is the coordinating centre of this study. Both the principle investigator and the coordinating investigator are employed by the coordinating centre. The coordinating investigator is responsible for the day-to-day support of participating and recruiting sites. Additionally, data collection and analyses will be done once the study is finished. The principle investigator is updated on the study weekly. Additionally, the Dutch Autoimmune Hepatitis Working Group (DAIHWG) is updated biannually on the study’s progress during meetings. The DAIHWG consists of hepatologists with an interest for AIH from various (study) sites.
Composition of the data monitoring committee, its role and reporting structure {21a}
It was not deemed necessary by the medical ethical committee to constitute an independent data safety management board for this study.
Adverse event reporting and harms {22}
AEs are defined as any undesirable experience occurring to a subject during the
study, whether or not considered related to the investigational product. All adverse events
reported spontaneously by the subject or observed by the investigator or his staff will be
recorded. A SAE is any untoward medical occurrence or effect that (a) results in death; (b) is life threatening (at the time of the event); (c) requires hospitalisation or prolongation of existing inpatients’ hospitalisation; (d) results in persistent or significant disability or incapacity; (e) is a congenital anomaly or birth defect; (f) that required medical or surgical intervention to preclude of any other important medical event that did not result in any of the outcomes listed above due to medical or surgical intervention but could have based upon appropriate medical judgement. Elective hospital admissions are not considered SAEs. The principle investigator of the participating site will report the SAE to the coordinating investigator within 24 hours. The latter will report the medical ethical committee via Toetsingonline.nl within 7 (death) or 15 (life threatening event) days.
Frequency and plans for auditing trial conduct {23}
The TAILOR study is monitored at all participating sites by a set monitor assigned by the LUMC. Monitoring will be performed at set intervals determined in the monitoring plan. This interval is initially set once every year, taking into consideration the recruitment status and protocol adherence. The (internal) monitor may decide to intensify the monitoring interval. Auditing upon invitation of the hospital may occur, when deemed necessary. The frequency of auditing is unknown.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Substantial amendments will be submitted to the medical ethical committee of the LUMC before implementation, with the exception of amendments for immediate safety of participants. Important protocol modifications, influencing patients, will be communicated to the central and local ethics committees as appropriate.
Dissemination plans {31a}
Collected data will not yet be made available, since recruitment is still ongoing. The results of this trial will be submitted for publication in a scientific journal. In addition the results will be presented in the ClinicalTrials.gov database. Outcomes of this study will be shared with the scientific community, patients representatives, sponsor and patients through conferences, meetings, newsletters and through other relevant media.
