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

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ClinicalTrials.gov Identifier: NCT02182167
Recruitment Status : Recruiting
First Posted : July 8, 2014
Last Update Posted : October 11, 2018
Sponsor:
Collaborator:
Medical Research Council, South Africa
Information provided by (Responsible Party):
Dr Karen Cohen, University of Cape Town

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 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 2014
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : August 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hepatitis

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 Name: Paradote

Placebo Comparator: Placebo
Water
Drug: Water



Primary Outcome Measures :
  1. ALT normalisation [ Time Frame: 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 :
  1. Duration of hospitalization [ Time Frame: up to 8 weeks ]
    To determine the effect of IV NAC on duration of hospitalization

  2. Recovery from liver failure [ Time Frame: up to 8 weeks ]
    To determine the effect of IV NAC on the rate of recovery from liver failure

  3. All-cause mortality [ Time Frame: up to 8 weeks ]
    To determine the effect of IV NAC on all-cause mortality in patients with TB DIH

  4. Adverse Events [ Time Frame: up to 8 weeks ]
    To determine the adverse event profile of IV NAC when administered to patients with TB DIH

  5. TB Drug Rechallenge [ Time Frame: up to 8 weeks ]
    To determine the effect of IV NAC on success of TB drug rechallenge.

  6. Rechallenge duration [ Time Frame: up to 8 weeks ]
    To determine the effect of IV NAC on duration of rechallenge


Other Outcome Measures:
  1. 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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02182167


Contacts
Contact: Nicole Kramer nicky.kramer@uct.ac.za
Contact: Karen Cohen karen.cohen@uct.ac.za

Locations
South Africa
Groote Schuur Hospital Recruiting
Cape Town, Western Province, South Africa, 7925
Sub-Investigator: Farouk M Chughlay         
Sub-Investigator: Mashiko Setshedi         
Sub-Investigator: Gary Maartens         
Sub-Investigator: Mark Sonderup         
Sub-Investigator: Wendy Spearman         
Principal Investigator: Karen Cohen         
Sub-Investigator: Hannah Gunter         
New Somerset Hospital Recruiting
Cape Town, Western Province, South Africa, 8005
Sub-Investigator: Shiraz Moosa         
Sub-Investigator: Dave Stead         
Sponsors and Collaborators
University of Cape Town
Medical Research Council, South Africa
Investigators
Principal Investigator: Karen Cohen University of Cape Town

Responsible Party: Dr Karen Cohen, University of Cape Town
ClinicalTrials.gov Identifier: NCT02182167     History of Changes
Other Study ID Numbers: 20130808
DOH-27-0414-4719. ( Registry Identifier: SANCTR )
First Posted: July 8, 2014    Key Record Dates
Last Update Posted: October 11, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Dr Karen Cohen, University of Cape Town:
Drug Induced Hepatitis (DIH)
Toxic Liver
Drug Induced Liver Injury (DILI)

Additional relevant MeSH terms:
Hepatitis
Chemical and Drug Induced Liver Injury
Liver Diseases
Digestive System Diseases
Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Poisoning
Acetylcysteine
N-monoacetylcystine
Antitubercular Agents
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes
Anti-Bacterial Agents