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

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

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.

Study Overview

• Status: Completed
• Conditions: Drug-Induced Liver Injury
• Intervention / Treatment: Drug: IV N-acetylcysteine (NAC); Drug: Water

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 Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• South Africa
  • Western Province
    • Cape Town, Western Province, South Africa, 7925
      • Groote Schuur Hospital
    • Cape Town, Western Province, South Africa, 8005
      • New Somerset Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure 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

Collaborators and Investigators

• Sponsor: University of Cape Town
• Collaborators: Medical Research Council, South Africa
• Investigators: Principal Investigator: Karen Cohen, University of Cape Town

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2014
• Primary Completion (ACTUAL): February 1, 2019
• Study Completion (ACTUAL): February 1, 2019

Study Registration Dates

• First Submitted: June 18, 2014
• First Submitted That Met QC Criteria: July 7, 2014
• First Posted (ESTIMATE): July 8, 2014

Study Record Updates

• Last Update Posted (ACTUAL): February 19, 2019
• Last Update Submitted That Met QC Criteria: February 18, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Drug Induced Hepatitis (DIH); Toxic Liver; Drug Induced Liver Injury (DILI)
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Liver Diseases; Drug-Related Side Effects and Adverse Reactions; Poisoning; Hepatitis; Chemical and Drug Induced Liver Injury; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: 20130808; DOH-27-0414-4719. (REGISTRY: SANCTR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No