Tuberculosis InfectionTUBILINCT06539455
Analysis of Liver Injury Risk Factors in a Multiethnic Population Treated With Antituberculosis Drugs
An observational study of Tuberculosis Infection, run by Stefania Cheli at 1 site in Italy.
Trial summary
Tuberculosis (TB) is the world's second leading cause of death from a single infectious agent after COVID-19. In 2022, TB was estimated to have affected 10.6 million people, of whom 1.3 million died because of it, despite the WHO's implementation of the "End TB" program. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Tuberculosis Infection
- What is being tested?
- standard anti-TB treatment
- How many people
- 127 participants
- Where
- 1 siteItaly
- Study dates
- 5 Jul 2024to 30 Sep 2024
- 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: Data collected from patients with confirmed tuberculosis, enrolled at the Department of Infectious Diseases of Luigi Sacco Hospital in Milan, Italy, between July 2020 and September 2023, will be analysed. Subjects were all followed up as outpatients at Tuberculosis Clinic at Luigi Sacco Hospital, some of them with previous inward stays at various hospitals in the Lombardy Region. The participants were given standard anti-TB treatment in line with international guidelines (RMP 10 mg/kg, INH 5 mg/kg), primarily administered orally, although intravenous administration was employed for inpatients as needed, and modified to oral administration as soon as possible. The other drugs of the standard regimen included standard daily doses of PZA (15-30 mg/kg) and EMB (15-20 mg/kg).
Who may be able to join
- adult patients (>18 years)
- patient who received standard initial therapy including INH (5mg/kg), RMP (10mg/kg), and PZA (25mg/kg) for patients with active TB disease
- treatment with first line anti-TB drugs, including rifampicin and isoniazid for patients with latent TBI
- normal serum ALT and bilirubin levels, no symptoms related to abnormal liver function prior to anti-TB drug treatment
- informed consent.
Who cannot join
- liver dysfunction, including biliary origin, before anti-TB therapy
- patients receiving non-standard treatment regimen initially (e.g., patients with severe pulmonary or extrapulmonary TB receiving large doses or more than four anti-TB drugs), 3) modified treatment regimen due to drug resistance or intolerance excluding first line anti-TB drugs
- 4) lactation or pregnancy 5) concomitant use of hepatotoxic drugs 6) abnormal hepatic function on laboratory testing before anti-TB 7) disease that was resistant to INH at the start of treatment 8) patients refusing to sign informed consent.
Trial locations and contacts
1 site in 1 country.
About this study
Tuberculosis (TB) is the world's second leading cause of death from a single infectious agent after COVID-19. In 2022, TB was estimated to have affected 10.6 million people, of whom 1.3 million died because of it, despite the WHO's implementation of the "End TB" program. Although the gold standard therapy is effective, it may lead to adverse events, among which hepatotoxicity is the most common. Due to its frequency, severity, and potential outcome, anti-TB drug-induced liver injury (DILI) is extremely concerning. Despite decades of use and the large number of patients exposed to anti-TB drugs worldwide, the pathogenesis underlying DILI remains poorly understood. Investigation of drug-related, host genetic, and environmental factors associated with hepatotoxicity susceptibility, as well as studies examining potential mechanisms causing DILI, may help clinicians develop strategies for reducing the incidence of hepatotoxicity. The aim of this study was to determine host- and drug-related risk factors and their association with hepatotoxicity in a multiethnic population in order to enable early identification of individuals with increased susceptibility to anti-TB DILI. An improved understanding of these factors may help to predict and prevent the occurrence of DILI and develop more effective treatments.
Read the detailed description
Tuberculosis (TB) is the world's second leading cause of death from a single infectious agent in 2022, after COVID-19. In 2022, TB disease was estimated to affect 10.6 million people, of whom 1.3 million died because of it, despite the WHO's adoption of the End TB Strategy. The standardised therapy involves a treatment regimen of isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA) for 2 months, then INH and RMP for at least an additional 4-7 months [3]. Even though 85% of TB cases are successfully treated, significant morbidity from treatment-related adverse events, such as hepatotoxicity, skin reactions, and gastrointestinal and neurological disorders, reduces the efficacy of therapy. In 11% of patients receiving INH, RMP, and PZA in combination, hepatotoxicity is the most frequent adverse effect that results in drug discontinuation. One of the most prevalent subtypes of idiosyncratic hepatotoxicity is caused by anti-TB drugs. There are many factors contributing to the development of liver injury that are related both to the drug and to the patient's characteristics. As to drug-related factors, acetylhydrazine, which is generated by NAT2, is widely considered a crucial INH metabolite that contributes to drug-induced liver injury (DILI). Given the importance of acetylation in INH metabolism, several studies have investigated NAT2 loss of function polymorphisms as possible risk factors for anti-TB DILI. In addition, advanced age, female gender, poor nutritional status, HBV or HCV infection, HIV infection, chronic liver disease, and alcoholism are environmental, physiological, and pathological factors contributing to anti-TB DILI incidence. Geographic and ethnic characteristics also play a role in the occurrence of DILI. This event is also ascribed to the polymorphisms observed at the level of genes encoding for metabolic enzymes. Of note, most studies available in the literature have been conducted in Asiatic geographical areas, where TB is considered of great concern due to its high incidence. Moreover, it is well known that the Chinese population is commonly composed of NAT2 rapid acetylators, showing a lower susceptibility to the development of anti-TB DILI. There is still considerable controversy and uncertainty regarding the potential role that the acetylator status of individuals (rapid or slow) may play in INH-induced hepatotoxicity, given the fact that the results of previous studies have shown such considerable variability.
Due to the impossibility of treating liver injury, the only recovery strategy is drug discontinuation in tuberculosis patients; its prevention is essential to avoiding this condition. To prevent the progression of the disease, increase the efficiency of treatment, and reduce mortality, screening patients for risk factors may be extremely useful. Consequently, the current study's aim is to determine the association between anti-TB DILI incidence and potential environmental, physiologic, and pathologic factors. Since 2020, a cohort of patients has been followed in the Department of Infectious Diseases of Luigi Sacco Hospital in Milan, Italy. Moreover, despite the multi-ethnic characterisation of the cohort enrolled in this study, the high prevalence of Caucasian patients (who also present a greater frequency of slow acetylators) may be provide a complementary perspective to previously published studies, mostly focusing on Asian populations. Based on this cohort, we performed a nested case-control study to understand the role of several drug- and host-related factors in DILI.
- Conditions
- Tuberculosis Infection
- Being tested
- standard anti-TB treatment
- Keywords
- isoniazide, rifampicin, drug-induced injury liver (DILI), slow acetylator, genotyping
- Medical subject headings
- Latent Tuberculosis, Chemical and Drug Induced Liver Injury
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
standard anti-TB treatmentDrug
standard anti-TB treatment in line with international guidelines (isoniazid , rifampin, ethambutol, and pyrazinamide)
| Study group | Role | What they receive |
|---|---|---|
| DILI group | Anti-TB DILI was defined by: 1) AST or ALT level > 5 times the ULN in patients with the absence of symptoms or with a total BIL level > 2 times the ULN; or 2) AST or ALT level > 3 times the ULN and total BIL level > 3 times the ULN in patients who show symptoms compatible with hepatitis. Receives: Drug: standard anti-TB treatment | |
| Non-DILI group | Subjects who had no hepatotoxicity events during the therapeutic regimen Receives: Drug: standard anti-TB treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
The occurrence of anti-TB DILI (number of participants with DILI)
Association between risk factors (drug- and host-related factors) and the incidence of DILI.
Evaluation of patient characteristics associated with the development of DILI. DILI was defined by: 1) AST or ALT level > 5 times the ULN in patients with absence of symptoms or with total BIL level > 2 times the ULN, or 2) AST or ALT level > 3 time the ULN and total BIL level > 3 times the ULN in patients who show symptoms compatible with hepatitis.
Measured: 6-12 month
Secondary outcomes (1)
The prevalence of early hepatotoxicity experience
Evaluate the characteristics of patients who first experienced anti-TB DILI.
Measured: 6-12 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Aug 2024
- Study start5 Jul 2024
- Primary completion30 Jul 2024
- Study completion30 Sep 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Tuberculosis InfectionStudies of the same condition, open and under way.
- 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
- Case-control
- Time perspective
- Retrospective
- Enrolment
- 127 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stefania Cheli
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Stefania Cheli, ASST Fatebenefratelli Sacco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06539455
- Sponsor's protocol ID
- TUBILI
- Acronym
- TUBILI
- Status last verified
- Aug 2024
- First submitted
- 30 Jul 2024
- Last updated
- 6 Aug 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Cheli S, Torre A, Schiuma M, Montrasio C, Civati A, Galimberti M, Battini V, Mariani I, Mosini G, Carnovale C, Radice S, Clementi E, Gori A, Antinori S. NAT2 Slow Acetylator Phenotype as a Significant Risk Factor for Hepatotoxicity Caused by Antituberculosis Drugs: Results From a Multiethnic Nested Case-Control Study. Clin Infect Dis. 2025 Aug 1;81(1):145-152. doi: 10.1093/cid/ciae583.
PubMed 39727196
Study at a glance
From the registry record, last updated by the sponsor on 6 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Analysis of Liver Injury Risk Factors in a Multiethnic Population Treated With Antituberculosis Drugs
- ClinicalTrials.gov ID
- NCT06539455
- Acronym / sponsor ID
- TUBILI / TUBILI
- Conditions
- Tuberculosis Infection
- Keywords
- isoniazide, rifampicin, drug-induced injury liver (DILI), slow acetylator, genotyping
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 127 participants (actual)
- Lead sponsor
- Stefania CheliUniversity, hospital or other
- Study start
- 5 Jul 2024 (actual)
- Primary completion
- 30 Jul 2024 (actual)
- Study completion
- 30 Sep 2024 (estimated)
- First posted
- 6 Aug 2024 (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.
Tuberculosis (TB) is the world's second leading cause of death from a single infectious agent after COVID-19. In 2022, TB was estimated to have affected 10.6 million people, of whom 1.3 million died because of it, despite the WHO's implementation of the "End TB" program. Although the gold standard therapy is effective, it may lead to adverse events, among which hepatotoxicity is the most common. Due to its frequency, severity, and potential outcome, anti-TB drug-induced liver injury (DILI) is extremely concerning. Despite decades of use and the large number of patients exposed to anti-TB drugs worldwide, the pathogenesis underlying DILI remains poorly understood. Investigation of drug-related, host genetic, and environmental factors associated with hepatotoxicity susceptibility, as well as studies examining potential mechanisms causing DILI, may help clinicians develop strategies for reducing the incidence of hepatotoxicity. The aim of this study was to determine host- and drug-related risk factors and their association with hepatotoxicity in a multiethnic population in order to enable early identification of individuals with increased susceptibility to anti-TB DILI. An improved understanding of these factors may help to predict and prevent the occurrence of DILI and develop more effective treatments.
Detailed description
Tuberculosis (TB) is the world's second leading cause of death from a single infectious agent in 2022, after COVID-19. In 2022, TB disease was estimated to affect 10.6 million people, of whom 1.3 million died because of it, despite the WHO's adoption of the End TB Strategy. The standardised therapy involves a treatment regimen of isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA) for 2 months, then INH and RMP for at least an additional 4-7 months [3]. Even though 85% of TB cases are successfully treated, significant morbidity from treatment-related adverse events, such as hepatotoxicity, skin reactions, and gastrointestinal and neurological disorders, reduces the efficacy of therapy. In 11% of patients receiving INH, RMP, and PZA in combination, hepatotoxicity is the most frequent adverse effect that results in drug discontinuation. One of the most prevalent subtypes of idiosyncratic hepatotoxicity is caused by anti-TB drugs. There are many factors contributing to the development of liver injury that are related both to the drug and to the patient's characteristics. As to drug-related factors, acetylhydrazine, which is generated by NAT2, is widely considered a crucial INH metabolite that contributes to drug-induced liver injury (DILI). Given the importance of acetylation in INH metabolism, several studies have investigated NAT2 loss of function polymorphisms as possible risk factors for anti-TB DILI. In addition, advanced age, female gender, poor nutritional status, HBV or HCV infection, HIV infection, chronic liver disease, and alcoholism are environmental, physiological, and pathological factors contributing to anti-TB DILI incidence. Geographic and ethnic characteristics also play a role in the occurrence of DILI. This event is also ascribed to the polymorphisms observed at the level of genes encoding for metabolic enzymes. Of note, most studies available in the literature have been conducted in Asiatic geographical areas, where TB is considered of great concern due to its high incidence. Moreover, it is well known that the Chinese population is commonly composed of NAT2 rapid acetylators, showing a lower susceptibility to the development of anti-TB DILI. There is still considerable controversy and uncertainty regarding the potential role that the acetylator status of individuals (rapid or slow) may play in INH-induced hepatotoxicity, given the fact that the results of previous studies have shown such considerable variability.
Due to the impossibility of treating liver injury, the only recovery strategy is drug discontinuation in tuberculosis patients; its prevention is essential to avoiding this condition. To prevent the progression of the disease, increase the efficiency of treatment, and reduce mortality, screening patients for risk factors may be extremely useful. Consequently, the current study's aim is to determine the association between anti-TB DILI incidence and potential environmental, physiologic, and pathologic factors. Since 2020, a cohort of patients has been followed in the Department of Infectious Diseases of Luigi Sacco Hospital in Milan, Italy. Moreover, despite the multi-ethnic characterisation of the cohort enrolled in this study, the high prevalence of Caucasian patients (who also present a greater frequency of slow acetylators) may be provide a complementary perspective to previously published studies, mostly focusing on Asian populations. Based on this cohort, we performed a nested case-control study to understand the role of several drug- and host-related factors in DILI.
Study design
- Observational model
- Case-control
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| DILI group | – | Drug: standard anti-TB treatmentAnti-TB DILI was defined by: 1) AST or ALT level > 5 times the ULN in patients with the absence of symptoms or with a total BIL level > 2 times the ULN; or 2) AST or ALT level > 3 times the ULN and total BIL level > 3 times the ULN in patients who show symptoms compatible with hepatitis. |
| Non-DILI group | – | Drug: standard anti-TB treatmentSubjects who had no hepatotoxicity events during the therapeutic regimen |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Data collected from patients with confirmed tuberculosis, enrolled at the Department of Infectious Diseases of Luigi Sacco Hospital in Milan, Italy, between July 2020 and September 2023, will be analysed. Subjects were all followed up as outpatients at Tuberculosis Clinic at Luigi Sacco Hospital, some of them with previous inward stays at various hospitals in the Lombardy Region. The participants were given standard anti-TB treatment in line with international guidelines (RMP 10 mg/kg, INH 5 mg/kg), primarily administered orally, although intravenous administration was employed for inpatients as needed, and modified to oral administration as soon as possible. The other drugs of the standard regimen included standard daily doses of PZA (15-30 mg/kg) and EMB (15-20 mg/kg).
Key inclusion criteria (5 listed)
- adult patients (>18 years)
- patient who received standard initial therapy including INH (5mg/kg), RMP (10mg/kg), and PZA (25mg/kg) for patients with active TB disease
- treatment with first line anti-TB drugs, including rifampicin and isoniazid for patients with latent TBI
- normal serum ALT and bilirubin levels, no symptoms related to abnormal liver function prior to anti-TB drug treatment
- informed consent.
Key exclusion criteria (3 listed)
- liver dysfunction, including biliary origin, before anti-TB therapy
- patients receiving non-standard treatment regimen initially (e.g., patients with severe pulmonary or extrapulmonary TB receiving large doses or more than four anti-TB drugs), 3) modified treatment regimen due to drug resistance or intolerance excluding first line anti-TB drugs
- 4) lactation or pregnancy 5) concomitant use of hepatotoxic drugs 6) abnormal hepatic function on laboratory testing before anti-TB 7) disease that was resistant to INH at the start of treatment 8) patients refusing to sign informed consent.
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 |
|---|---|---|
| standard anti-TB treatmentstandard anti-TB treatment in line with international guidelines (isoniazid , rifampin, ethambutol, and pyrazinamide) | Drug | DILI group, Non-DILI group |
Primary outcome
The occurrence of anti-TB DILI (number of participants with DILI)
Time frame: 6-12 month
Association between risk factors (drug- and host-related factors) and the incidence of DILI. Evaluation of patient characteristics associated with the development of DILI. DILI was defined by: 1) AST or ALT level > 5 times the ULN in patients with absence of symptoms or with total BIL level > 2 times the ULN, or 2) AST or ALT level > 3 time the ULN and total BIL level > 3 times the ULN in patients who show symptoms compatible with hepatitis.
1 secondary outcome
The prevalence of early hepatotoxicity experience
Time frame: 6-12 month
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Aug 2024.
- Derived from this study: PubMed 39727196Cheli S, Torre A, Schiuma M, Montrasio C, Civati A, Galimberti M, Battini V, Mariani I, Mosini G, Carnovale C, Radice S, Clementi E, Gori A, Antinori S. NAT2 Slow Acetylator Phenotype as a Significant Risk Factor for Hepatotoxicity Caused by Antituberculosis Drugs: Results From a Multiethnic Nested Case-Control Study. Clin Infect Dis. 2025 Aug 1;81(1):145-152. doi: 10.1093/cid/ciae583.
- Individual participant dataSharing planned: No
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Tuberculosis Infection, run by Stefania Cheli at 1 site in Italy.
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 5 inclusion and 3 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 6 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. 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?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The occurrence of anti-TB DILI (number of participants with DILI) (time frame: 6-12 month). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06539455, which also lists 1 linked publication.
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 6 Aug 2024.