Drug-Induced Liver Injury
Conditions
Keywords
Drug Induced Hepatitis (DIH), Toxic Liver, Drug Induced Liver Injury (DILI)
Brief summary
We will conduct a randomized placebo controlled trial to determine whether administration of intravenous (IV) NAC to participants with TB DIH, in dosages similar to that used in paracetamol poisoning, can improve recovery from hepatotoxicity.
Detailed description
South Africa has a huge tuberculosis (TB) disease burden, with 948 per 100 000 people diagnosed with TB in 2008. TB drug induced hepatitis (DIH) is a common adverse effect of TB therapy that causes significant patient morbidity and prolonged hospital stays. N-Acetylcysteine (NAC) has been extensively studied and used for many years in the treatment of paracetamol-induced hepatotoxicity, with good evidence of efficacy and safety. NAC has also been used in other forms of liver injury and drug toxicity. It has not previously been used in the management of TB DIH. We will screen all patients with clinical hepatitis on TB treatment admitted to New Somerset and Groote Schuur hospitals and aim to recruit 100 participants over 3 years. We will randomise 50 participants to receive an IV loading dose of 150mg/kg of NAC over 60 minutes followed by 50mg/kg IV over 4 hours by continuous infusion and finally 100mg/kg IV over 16 hours. Fifty participants will be randomised to receive placebo. The primary outcome will be time to normalisation of liver function (ALT\<100). We will also determine the effect of NAC on duration of hospitalization, rate of recovery from liver failure, all cause mortality, and describe adverse effects of IV NAC in this patient population.
Interventions
DRUGIV N-acetylcysteine (NAC)
DRUGWater
Sponsors
Medical Research Council, South Africa
University of Cape Town
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults \> 18 years old * Diagnosed with pulmonary or extrapulmonary tuberculosis based on symptoms, radiological features and/or laboratory evidence. * On first line antituberculous therapy * Diagnosed with TB DIH
Exclusion criteria
* Patients with a diagnosis of acute viral hepatitis based on a positive anti-HAV, IgM, anti- HBcIgM, or confirmed hepatitis C infection * Patients known to be asthmatic
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ALT normalisation | up to 8 weeks | To determine the effect of IV NAC on the time to normalization of liver function in patients with TB DIH |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of hospitalization | up to 8 weeks | To determine the effect of IV NAC on duration of hospitalization |
| Recovery from liver failure | up to 8 weeks | To determine the effect of IV NAC on the rate of recovery from liver failure |
| All-cause mortality | up to 8 weeks | To determine the effect of IV NAC on all-cause mortality in patients with TB DIH |
| TB Drug Rechallenge | up to 8 weeks | To determine the effect of IV NAC on success of TB drug rechallenge. |
| Rechallenge duration | up to 8 weeks | To determine the effect of IV NAC on duration of rechallenge |
| Adverse Events | up to 8 weeks | To determine the adverse event profile of IV NAC when administered to patients with TB DIH |
Other
| Measure | Time frame | Description |
|---|---|---|
| Biomarkers | — | To store blood, urine and biopsy specimens (if biopsies were taken as part of patient management),bank serum, to enable us to conduct future sub studies exploring mechanisms, predictors and biomarkers of TB DIH, genetic associations with TB DIH and improved diagnostic strategies |
Countries
South Africa
Outcome results
None listed