- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00405301
Study of Safety and Efficacy of Different Regimes of Reintroduction of Anti-TB Drugs in Anti-TB Drugs Induced Liver Damage
Study of Safety and Efficacy of Different Regimes of Reintroduction of Anti-TB Drugs in Antituberculosis Treatment Induced Hepatotoxicity
Study Overview
Status
Conditions
Detailed Description
Tuberculosis continues to be a major health problem in both the developing and developed countries because of its resurgence in the immunosuppressed patients. Short course chemotherapy containing isoniazid, rifampicin and pyrazinamide has proved to be highly effective in the treatment of tuberculosis. One of its adverse effect is liver damage which is the most common side effect leading to interruption of therapy.
There is lack of consensus guidelines for treatment of anti-TB drug induced liver damage Whether the re-introduction should take place with all the drugs given together in full doses (which reduces the chance of resistance and cost to the patient) or in a phased manner. There is lack of studies which compared different regimens of re-introduction of anti-TB drugs.
In this study, we will study three regimes of re-introduction of hepatotoxic anti-tuberculosis drugs (Rifampicin, Isoniazide, Pyrazinamide). These are potent anti-tuberculosis medications and need to be restarted in patients who developed liver toxicities attributed to these medications and became normal when these medicines were stopped. At the time of re-introduction the patients will be randomized in 3 groups.
- First group will receive Isoniazide(5mg/kg/day), Rifampicin(10mg/kg/day) and Pyrazinamide(25mg/kg/day) in full doses on day 1 and continued further.
- second group will receive Rifampicin(10mg/kg/day) in full dose on day 1 and continued, Isoniazide(5mg/kg/day)in full dose on day 8 and continued, Pyrazinamide(25mg/kg/day)on day 15 and continued.
- Third group will receive 100 mg/day of Isoniazide on day 1 which is gradually increased to maximum dose (5mg/kg/day) by day 4 and continued. Rifampicin is introduced on day 8 in a dose of 150 mg/day which is gradually increased to maximum dose (10mg/kg/day) by day 11 and continued. Pyrazinamide is introduced on day 15 in a dose of 500mg/day which is gradually increased to maximum dose (25mg/kg/day) by day 18 and continued.
All the three groups will be monitored for three months by analyzing weekly liver function tests. Any difference in the morbidity, deranged liver function or any other adverse effects will be monitored and treated appropriately.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
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Andhra Pradesh
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Tirupati, Andhra Pradesh, India, 517507
- Sri Venkateswara Institute of Medical Sciences
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Delhi
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New Delhi, Delhi, India, 110029
- All India Institute of Medical Sciences
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- A rise of five times the upper limit of the normal levels (50 IU/L) of serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)
- A rise in the level of serum total bilirubin level > 1.5mg/dl
- Any increase in serum AST and or ALT above pretreatment values together with anorexia, nausea, vomiting and jaundice
- Absence of serological evidence of infection with hepatitis viruses A,B,C,or E
- Normalization of liver function tests after withdrawal of antituberculosis drugs For diagnosis of anti-TB drugs induced hepatitis, criteria 1 or 2 or 3 should be present along with criteria 4 and 5.
Exclusion Criteria:
- Patients with serological evidence of acute viral hepatitis A,B,C,or E and carriers for HBV & HCV
- Age < 15 year and age > 65 years
- HIV positive patients
- Presence of chronic liver disease or cirrhosis
- Co-administration of other potential hepatotoxic drugs (methotrexate, phenytoin, valproate)
- Chronic alcoholics who consume > 48 g of alcohol/day for at least one year
- Pregnant women
- Subjects not giving consent
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: Arm 1
Arm 1: will receive Isoniazide(5mg/kg/day), Rifampicin(10mg/kg/day) and Pyrazinamide(25mg/kg/day) in full doses on day 1 and continued further
|
Patients who develop ATT drug induced hepatotoxicity will be divided into 3 arms .Arm 1,2,3 will be given drugs as described in detailed description of the title.
|
Other: Arm 2
Arm 2 : will receive Rifampicin(10mg/kg/day) in full dose on day 1 and continued, Isoniazide(5mg/kg/day)in full dose on day 8 and continued, Pyrazinamide(25mg/kg/day)on day 15 and continued
|
Patients who develop ATT drug induced hepatotoxicity will be divided into 3 arms .Arm 1,2,3 will be given drugs as described in detailed description of the title.
|
Other: Arm 3
Arm 3 will receive 100 mg/day of Isoniazide on day 1 which is gradually increased to maximum dose (5mg/kg/day) by day 4 and continued.
Rifampicin is introduced on day 8 in a dose of 150 mg/day which is gradually increased to maximum dose (10mg/kg/day) by day 11 and continued.
Pyrazinamide is introduced on day 15 in a dose of 500mg/day which is gradually increased to maximum dose (25mg/kg/day) by day 18 and continued.
|
Patients who develop ATT drug induced hepatotoxicity will be divided into 3 arms .Arm 1,2,3 will be given drugs as described in detailed description of the title.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
To compare the safety of different regimens of re-introduction of anti-TB drugs in drug induced liver damage.
Time Frame: 24 months
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24 months
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
To study the predictors of recurrence of drug induced liver damage
Time Frame: 24 months
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24 months
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To study the risk factors for development of drug induced liver injury
Time Frame: 24 months
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24 months
|
Collaborators and Investigators
Publications and helpful links
General Publications
- Tahaoglu K, Atac G, Sevim T, Tarun T, Yazicioglu O, Horzum G, Gemci I, Ongel A, Kapakli N, Aksoy E. The management of anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung Dis. 2001 Jan;5(1):65-9.
- Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med. 2002 Oct 1;166(7):916-9. doi: 10.1164/rccm.2108091.
- Singh J, Garg PK, Tandon RK. Hepatotoxicity due to antituberculosis therapy. Clinical profile and reintroduction of therapy. J Clin Gastroenterol. 1996 Apr;22(3):211-4. doi: 10.1097/00004836-199604000-00012.
- Singh J, Arora A, Garg PK, Thakur VS, Pande JN, Tandon RK. Antituberculosis treatment-induced hepatotoxicity: role of predictive factors. Postgrad Med J. 1995 Jun;71(836):359-62. doi: 10.1136/pgmj.71.836.359.
- Sharma SK. Antituberculosis drugs and hepatotoxicity. Infect Genet Evol. 2004 Jun;4(2):167-70. doi: 10.1016/j.meegid.2003.01.001. No abstract available.
- Sharma SK, Singla R, Sarda P, Mohan A, Makharia G, Jayaswal A, Sreenivas V, Singh S. Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. Clin Infect Dis. 2010 Mar 15;50(6):833-9. doi: 10.1086/650576.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Infections
- Bacterial Infections
- Bacterial Infections and Mycoses
- Gram-Positive Bacterial Infections
- Actinomycetales Infections
- Mycobacterium Infections
- Tuberculosis
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Anti-Bacterial Agents
- Leprostatic Agents
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 CYP3A Inducers
- Antitubercular Agents
- Antibiotics, Antitubercular
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2C8 Inducers
- Cytochrome P-450 CYP2C19 Inducers
- Cytochrome P-450 CYP2C9 Inducers
- Rifampin
- Pyrazinamide
Other Study ID Numbers
- AIIMS/MED/2006/10
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