A Trial Of Intravenous N-Acetylcysteine In The Management Of Antituberculous Drug-Induced Hepatitis

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomised Controlled Trial of Intravenous N-acetylcysteine in the Management of Antituberculous Drug-induced Hepatitis

Conditions
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Drug-Induced Liver Injury

Intervention / Treatment
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* Drug: IV N-acetylcysteine (NAC)
* Drug: Water


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV NAC<br>Participants will receive IV N-acetylcysteine or placebo. The dosing regimen is based on the regimens used in paracetamol poisoning . Initial dose: 150 mg/kg body mass of N-acetylcysteine/WFI infused in 200 mL of 5% dextrose intravenously over 60 minutes, followed by continuous infusion: 50 mg/kg body mass in 500 mL of 5% dextrose over next 4 hours, followed by 100 mg/kg body mass in 1 litre of 5% dextrose over 16 hours. | Drug: IV N-acetylcysteine (NAC)<br> <br> * Other names: Paradote;|
| Placebo Comparator: Placebo<br>Water | Drug: Water<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ALT normalisation | To determine the effect of IV NAC on the time to normalization of liver function in patients with TB DIH | up to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of hospitalization | To determine the effect of IV NAC on duration of hospitalization | up to 8 weeks | 
| Recovery from liver failure | To determine the effect of IV NAC on the rate of recovery from liver failure | up to 8 weeks | 
| All-cause mortality | To determine the effect of IV NAC on all-cause mortality in patients with TB DIH | up to 8 weeks | 
| Adverse Events | To determine the adverse event profile of IV NAC when administered to patients with TB DIH | up to 8 weeks | 
| TB Drug Rechallenge | To determine the effect of IV NAC on success of TB drug rechallenge. | up to 8 weeks | 
| Rechallenge duration | To determine the effect of IV NAC on duration of rechallenge | up to 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Induced Hepatitis (DIH), Toxic Liver, Drug Induced Liver Injury (DILI)