NAC in TB DIH: A Trial Of Intravenous N-Acetylcysteine In The Management Of Antituberculous Drug-Induced Hepatitis

Sponsor

University of Cape Town (Other)

Overall Status

Completed

CT.gov ID

NCT02182167

Collaborator

Medical Research Council, South Africa (Other)

102

Enrollment

Locations

Arms

57.1

Actual Duration (Months)

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Drug-Induced Liver Injury	Drug: IV N-acetylcysteine (NAC) Drug: Water	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

102 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 1, 2014

Actual Primary Completion Date :

Feb 1, 2019

Actual Study Completion Date :

Feb 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IV NAC 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) Other Names: Paradote
Placebo Comparator: Placebo Water	Drug: Water

Arm

Intervention/Treatment

Experimental: IV NAC

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)

Other Names:

Paradote

Placebo Comparator: Placebo

Water

Drug: Water

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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
Adverse Events [up to 8 weeks]
To determine the adverse event profile of IV NAC when administered to 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

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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