Autoimmune HepatitisNCT03711669
Biomarkers to Predict the Success of Immunosuppression Withdrawal in Autoimmune Hepatitis
An observational study of Autoimmune Hepatitis, run by Hospital Clinic of Barcelona at 2 sites in Spain.
Trial summary
Autoimmune hepatitis (AIH) is an inflammatory, chronic and recurrent liver disease of unknown etiology that can lead to cirrhosis or acute liver failure. It is a rare disease affecting 16 cases every 100,000 persons in Europe, mainly in women in every age group. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Autoimmune Hepatitis
- What is being tested?
- Immunosuppression withdrawal
- Type of treatment
- Lifestyle or therapy programme
- How many people
- 96 participants
- Where
- 2 sitesSpain
- Study dates
- 10 Jan 2018to Apr 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients diagnosed with type 1 AIH with biochemical remission of at least 3 years that are under immunosuppressive treatment followed in Hospital Clinic Barcelona. Patients with type 2 AIH are excluded because of their proved high risk of recurrence.
Who may be able to join
- Diagnosis of type 1 AIH.
- AST/ALT within normal limits the 3 years prior inclusion.
- normal levels of IgG.
- > 18 years-old.
Who cannot join
- Presence of biochemical alterations during the 3 years prior diagnosis.
- Coexistence of another autoimmune disease that requires IS.
- Prednisone doses over 7.5mg/day.
- Biopsy prior starting withdrawal with a Knodell score over 3/16.
- Positivity for hepatitis B virus, hepatitis C virus or human immunodeficiency virus.
- Pregnancy.
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- Glomerular filtrate <35ml/min.
- Not being able to attend follow-up visits.
- Use of drugs or alcohol abuse.
Trial locations and contacts
2 sites in 1 country.
Spain2 sites, 2 recruiting
- Recruiting
Hospital Clinic Barcelona
Barcelona, 08036
Maria C Londoño, MD, PhD
- Recruiting
Hospital del Mar
Barcelona
Montserrat Garcia-Retortillo
About this study
Official title: Identification of Biomarkers That Help to Predict Success of Immunosuppression Withdrawal in Patients With Type 1 Autoimmune Hepatitis
Autoimmune hepatitis (AIH) is an inflammatory, chronic and recurrent liver disease of unknown etiology that can lead to cirrhosis or acute liver failure. It is a rare disease affecting 16 cases every 100,000 persons in Europe, mainly in women in every age group. It is characteristic the presence of high levels of aminotransferases, hypergammaglobulinemia and high titres of autoantibodies, as well as interface hepatitis in the biopsy.
Due to the autoimmune etiology of AIH, treatment is based on immunosuppressive strategies, mainly prednisone and azathioprine regimens which make possible to achieve remission in approximately 75% of cases with moderate or severe hepatocellular inflammation.
Read more
Remission is defined as a normalization in aminotransferases, immunoglobulin G (IgG) and resolution histological inflammation (this last one comes after biochemical remission). It has also been observed that there is a restoration in number and function of Tregs after achieving remission.
The rates of recurrence after withdrawing it varies from 30-87% depending on the studies and their follow-up. It is usual to maintain treatment indefinitely in clinical practice. This strategy implies maintaining treatment for long periods of time in patients that could be available to maintain sustained remission, exposing them to adverse effects. From all these, we think it is important to be able to identify patients who will be able to maintain biochemical and histological remission without immunosuppression (IS), which still is not known in this disease's management.
Some observational and retrospective studies have identified some parameters that could imply a higher risk of recurrence after stopping treatment such as high levels of aminotransferases and IgG, less time of remission before withdrawal (specifically less than 2 years) or presence of interface hepatitis in a biopsy prior discontinuation of treatment. However, the accuracy of these parameters is low and as a result, management of this disease has not changed much over the past decades, still having patients under prolonged treatment unnecessarily.
For the previously mentioned reasons, there is a need to identify new biomarkers that allow clinicians selecting patients with AIH in whom treatment could be stopped avoiding its costs and adverse effects. At the same time, it would help to understand the immunopathogenesis of AIH and identification of new therapeutic targets.
Read the detailed description
Study design: This is a prospective not controlled, not randomized, unicentric study to establish predictive biomarkers for a safe and effective treatment withdrawal in patients with type 1 AIH.
Length of the study: Screening is expected to take a year. Treatment withdrawal will be done gradually over a period of 6 months and there will be a follow-up of 18 months.
Sample size: The rate of recurrence has been around 36% in some studies. However, this rate is uncertain and it depends on the studied population and the afterwards follow-up. That is why investigators have calculated the sample size with the confidence interval of this rate and a 10% precision which was of 87 patients. Expecting 10% of losses, the final sample size is 96 patients.
Patients: Investigators will select 96 patients diagnosed with type 1 AIH with biochemical remission of at least 3 years that are under immunosuppressive treatment followed in Hospital Clinic Barcelona. Patients with type 2 AIH are excluded because of their proved high risk of recurrence. Other inclusion and exclusion criteria are the following:
Treatment withdrawal: IS will be tapered gradually over a period of 6 months. Azathioprine will be stopped during the first 3 months, reducing the dose 50% every month. Prednisone will be tapered 2.5mg monthly until total withdrawal. During withdrawal and the first year after stopping treatment patients will undergo laboratory tests on a monthly basis, afterwards, follow-up will be done every 3 months until the end of the project.
Sustained remission: Patients that after stopping treatment maintain AST/ALT under 2 times the upper normal limit.
Recurrence: Patients who do not fulfil previous criteria.
Data collection:
- Demographic variables: age, sex, time from diagnosis to treatment withdrawal, laboratory information such as aminotransferases, gamma-glutamyl transferase (GGT), alkaline phosphatase (AP) and autoantibodies.
- Histological sample at the moment of inclusion in which the following analysis will be performed: usual staining techniques to evaluate the presence of portal inflammation, interface hepatitis and fibrosis. Expression of a group of genes involved in liver rejection (CXCL9, CXCL10, FoxP3, TK1, CD74, MMP9) will be evaluated with quantitative polymerase chain reaction (qPCR) in RNA of the tissue samples cryopreserved at -80ºC. Immunochemical staining to quantify the number of lymphocytes CD4+, CD8+ and Tregs.
- The following variables will be evaluated in blood samples collected at the inclusion and in every follow-up visit:
- Flux cytometry: Frequency and characteristics of Tregs (CD4+, CD25+, CD127- and FoxP3). The intracellular stain of CTLA-4 will be evaluated as well.
- Stimulation with interleukin 2 (IL2) to study Tregs response (measured by the expression of pSTAT5 after 20minutes of stimulation and the afterwards production of IL10).
- Autoantibodies titers: antinuclear autoantibodies (ANA), anti-smooth muscle antibody(ASMA), anti-liver kidney microsome type 1 (antiLKM), anti-soluble liver antigen (antiSLA) and immunoglobulins levels.
Statistical analysis: Categorical variables will be compared with Chi or Fisher tests. Quantitative variables will be analyzed with non-parametric tests (Mann-Whitney for independent samples and Wilcoxon for paired samples). To quantify the expression of genes in blood and tissue sample the Ct of the gene will be normalized with the 3 "housekeeping" (18S, HPRT, GAPDH) to generate the delta Ct. Results will be expressed as a relative expression of the cDNA of the study and the calibrated sample. Differences of <0.05 will be considered as statistically significant. Data analysis will be performed with Stata vs 15.1.
Ambition: Investigator's hypothesis is that those patients affected with type 1 AIH able to maintain remission after treatment withdrawal will express distinctive serological and histological biomarkers, making possible the identification of patients that could benefit from stopping treatment in the future avoiding its costs and adverse effects. At the same time, it would help to understand the immunopathogenesis of AIH and the identification of new therapeutic targets. Therefore, changing the natural history of this disease where there has been little advance in this field in the past decades.
- Conditions
- Autoimmune Hepatitis
- Being tested
- Immunosuppression withdrawal
- Keywords
- autoimmune hepatitis, disease flare, treatment withdrawal
- Medical subject headings
- Hepatitis, Autoimmune
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Immunosuppression withdrawalBehavioural
IS will be tapered gradually over a period of 6 months. Azathioprine will be stopped during the first 3 months, reducing the dose 50% every month. Prednisone will be tapered 2.5mg monthly until total withdrawal. During withdrawal and the first year after stopping treatment patients will undergo laboratory tests on a monthly basis, afterwards follow-up will be done every 3 months until the end of the project.
What is being measured
The primary outcome is the main question the study is designed to answer.
Remission rate after treatment withdrawal
Patients that after stopping treatment maintain aspartate aminotransferase (AST) and alanine aminotransferase (ALT) under 2 times the upper normal limit at the end of the study
Measured: Through study completion (average 1.5 years)
Secondary outcomes (1)
Adverse outcomes after treatment withdrawal (descriptive)
Evaluation of complications that take place after treatment withdrawal: need of hospitalization if there is a flare or diagnosis of 'de novo' autoimmune diseases or worsening symptoms such as asthenia or arthralgias.
Measured: Through study completion (average 1.5 years)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Oct 2018
- Study start10 Jan 2018
- Primary completionJan 2021 (estimated)
- Study completionApr 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Autoimmune HepatitisStudies of the same condition, open and under way.
- More trials run by Hospital Clinic of BarcelonaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 96 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospital Clinic of Barcelona
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Maria Londoño, Hospital Clinic of Barcelona
- Investigators
- Maria C Londoño, MD, PhD, Principal investigator, Hospital Clinic of Barcelona
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03711669
- Sponsor's protocol ID
- PI17/00955
- Status last verified
- Feb 2020
- First submitted
- 4 Oct 2018
- Last updated
- 12 Feb 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: IPD are to be shared with researchers participating in the study.
Study at a glance
From the registry record, last updated by the sponsor on 12 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Identification of Biomarkers That Help to Predict Success of Immunosuppression Withdrawal in Patients With Type 1 Autoimmune Hepatitis
- ClinicalTrials.gov ID
- NCT03711669
- Acronym / sponsor ID
- PI17/00955
- Conditions
- Autoimmune Hepatitis
- Keywords
- autoimmune hepatitis, disease flare, treatment withdrawal
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 96 participants (estimated)
- Lead sponsor
- Hospital Clinic of BarcelonaUniversity, hospital or other
- Study start
- 10 Jan 2018 (actual)
- Primary completion
- Jan 2021 (estimated)
- Study completion
- Apr 2021 (estimated)
- First posted
- 18 Oct 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Autoimmune hepatitis (AIH) is an inflammatory, chronic and recurrent liver disease of unknown etiology that can lead to cirrhosis or acute liver failure. It is a rare disease affecting 16 cases every 100,000 persons in Europe, mainly in women in every age group. It is characteristic the presence of high levels of aminotransferases, hypergammaglobulinemia and high titres of autoantibodies, as well as interface hepatitis in the biopsy.
Due to the autoimmune etiology of AIH, treatment is based on immunosuppressive strategies, mainly prednisone and azathioprine regimens which make possible to achieve remission in approximately 75% of cases with moderate or severe hepatocellular inflammation.
Remission is defined as a normalization in aminotransferases, immunoglobulin G (IgG) and resolution histological inflammation (this last one comes after biochemical remission). It has also been observed that there is a restoration in number and function of Tregs after achieving remission.
The rates of recurrence after withdrawing it varies from 30-87% depending on the studies and their follow-up. It is usual to maintain treatment indefinitely in clinical practice. This strategy implies maintaining treatment for long periods of time in patients that could be available to maintain sustained remission, exposing them to adverse effects. From all these, we think it is important to be able to identify patients who will be able to maintain biochemical and histological remission without immunosuppression (IS), which still is not known in this disease's management.
Some observational and retrospective studies have identified some parameters that could imply a higher risk of recurrence after stopping treatment such as high levels of aminotransferases and IgG, less time of remission before withdrawal (specifically less than 2 years) or presence of interface hepatitis in a biopsy prior discontinuation of treatment. However, the accuracy of these parameters is low and as a result, management of this disease has not changed much over the past decades, still having patients under prolonged treatment unnecessarily.
For the previously mentioned reasons, there is a need to identify new biomarkers that allow clinicians selecting patients with AIH in whom treatment could be stopped avoiding its costs and adverse effects. At the same time, it would help to understand the immunopathogenesis of AIH and identification of new therapeutic targets.
Detailed description
Study design: This is a prospective not controlled, not randomized, unicentric study to establish predictive biomarkers for a safe and effective treatment withdrawal in patients with type 1 AIH.
Length of the study: Screening is expected to take a year. Treatment withdrawal will be done gradually over a period of 6 months and there will be a follow-up of 18 months.
Sample size: The rate of recurrence has been around 36% in some studies. However, this rate is uncertain and it depends on the studied population and the afterwards follow-up. That is why investigators have calculated the sample size with the confidence interval of this rate and a 10% precision which was of 87 patients. Expecting 10% of losses, the final sample size is 96 patients.
Patients: Investigators will select 96 patients diagnosed with type 1 AIH with biochemical remission of at least 3 years that are under immunosuppressive treatment followed in Hospital Clinic Barcelona. Patients with type 2 AIH are excluded because of their proved high risk of recurrence. Other inclusion and exclusion criteria are the following:
Treatment withdrawal: IS will be tapered gradually over a period of 6 months. Azathioprine will be stopped during the first 3 months, reducing the dose 50% every month. Prednisone will be tapered 2.5mg monthly until total withdrawal. During withdrawal and the first year after stopping treatment patients will undergo laboratory tests on a monthly basis, afterwards, follow-up will be done every 3 months until the end of the project.
Sustained remission: Patients that after stopping treatment maintain AST/ALT under 2 times the upper normal limit.
Recurrence: Patients who do not fulfil previous criteria.
Data collection:
- Demographic variables: age, sex, time from diagnosis to treatment withdrawal, laboratory information such as aminotransferases, gamma-glutamyl transferase (GGT), alkaline phosphatase (AP) and autoantibodies.
- Histological sample at the moment of inclusion in which the following analysis will be performed: usual staining techniques to evaluate the presence of portal inflammation, interface hepatitis and fibrosis. Expression of a group of genes involved in liver rejection (CXCL9, CXCL10, FoxP3, TK1, CD74, MMP9) will be evaluated with quantitative polymerase chain reaction (qPCR) in RNA of the tissue samples cryopreserved at -80ºC. Immunochemical staining to quantify the number of lymphocytes CD4+, CD8+ and Tregs.
- The following variables will be evaluated in blood samples collected at the inclusion and in every follow-up visit:
- Flux cytometry: Frequency and characteristics of Tregs (CD4+, CD25+, CD127- and FoxP3). The intracellular stain of CTLA-4 will be evaluated as well.
- Stimulation with interleukin 2 (IL2) to study Tregs response (measured by the expression of pSTAT5 after 20minutes of stimulation and the afterwards production of IL10).
- Autoantibodies titers: antinuclear autoantibodies (ANA), anti-smooth muscle antibody(ASMA), anti-liver kidney microsome type 1 (antiLKM), anti-soluble liver antigen (antiSLA) and immunoglobulins levels.
Statistical analysis: Categorical variables will be compared with Chi or Fisher tests. Quantitative variables will be analyzed with non-parametric tests (Mann-Whitney for independent samples and Wilcoxon for paired samples). To quantify the expression of genes in blood and tissue sample the Ct of the gene will be normalized with the 3 "housekeeping" (18S, HPRT, GAPDH) to generate the delta Ct. Results will be expressed as a relative expression of the cDNA of the study and the calibrated sample. Differences of <0.05 will be considered as statistically significant. Data analysis will be performed with Stata vs 15.1.
Ambition: Investigator's hypothesis is that those patients affected with type 1 AIH able to maintain remission after treatment withdrawal will express distinctive serological and histological biomarkers, making possible the identification of patients that could benefit from stopping treatment in the future avoiding its costs and adverse effects. At the same time, it would help to understand the immunopathogenesis of AIH and the identification of new therapeutic targets. Therefore, changing the natural history of this disease where there has been little advance in this field in the past decades.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients diagnosed with type 1 AIH with biochemical remission of at least 3 years that are under immunosuppressive treatment followed in Hospital Clinic Barcelona. Patients with type 2 AIH are excluded because of their proved high risk of recurrence.
Key inclusion criteria (4 listed)
- Diagnosis of type 1 AIH.
- AST/ALT within normal limits the 3 years prior inclusion.
- normal levels of IgG.
- > 18 years-old.
Key exclusion criteria (9 listed)
- Presence of biochemical alterations during the 3 years prior diagnosis.
- Coexistence of another autoimmune disease that requires IS.
- Prednisone doses over 7.5mg/day.
- Biopsy prior starting withdrawal with a Knodell score over 3/16.
- Positivity for hepatitis B virus, hepatitis C virus or human immunodeficiency virus.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Immunosuppression withdrawalIS will be tapered gradually over a period of 6 months. Azathioprine will be stopped during the first 3 months, reducing the dose 50% every month. Prednisone will be tapered 2.5mg monthly until total withdrawal. During withdrawal and the first year after stopping treatment patients will undergo laboratory tests on a monthly basis, afterwards follow-up will be done every 3 months until the end of the project. | Behavioural | – |
Primary outcome
Remission rate after treatment withdrawal
Time frame: Through study completion (average 1.5 years)
Patients that after stopping treatment maintain aspartate aminotransferase (AST) and alanine aminotransferase (ALT) under 2 times the upper normal limit at the end of the study
1 secondary outcome
Adverse outcomes after treatment withdrawal (descriptive)
Time frame: Through study completion (average 1.5 years)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Feb 2020.
- Individual participant dataSharing planned: No. IPD are to be shared with researchers participating in the study.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Maria C Londoño, MD, PhD principal investigator
Hospital Clinic of Barcelona
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Autoimmune Hepatitis, run by Hospital Clinic of Barcelona at 2 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 12 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Maria C Londoño, MD,PhD (+34 932275753 ext. 2845, mlondono@clinic.cat), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Remission rate after treatment withdrawal (time frame: Through study completion (average 1.5 years)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Feb 2020.