Study of Safety and Efficacy of Different Regimes of Reintroduction of Anti-TB Drugs in Anti-TB Drugs Induced Liver Damage

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
S.K.SHARMA, All India Institute of Medical Sciences, New Delhi
ClinicalTrials.gov Identifier:
NCT00405301
First received: November 27, 2006
Last updated: February 14, 2012
Last verified: February 2012
  Purpose

Purpose of the study is to evaluate the safety and efficacy of different re-introduction regimens in anti-TB drug induced liver damage. There is no consensus how best to treat such patients who developed drug induced liver damage.


Condition Intervention Phase
Drug Induced Hepatotoxicity
Tuberculosis
Drug: Rifampicin(max dose 10 mg/kg/day), Isoniazide (max dose 5 mg/kg/day) and Pyrazinamide (max dose 25 mg/kg/day)
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Study of Safety and Efficacy of Different Regimes of Reintroduction of Anti-TB Drugs in Antituberculosis Treatment Induced Hepatotoxicity

Resource links provided by NLM:


Further study details as provided by All India Institute of Medical Sciences, New Delhi:

Primary Outcome Measures:
  • To compare the safety of different regimens of re-introduction of anti-TB drugs in drug induced liver damage. [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To study the predictors of recurrence of drug induced liver damage [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
  • To study the risk factors for development of drug induced liver injury [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]

Enrollment: 175
Study Start Date: December 2006
Study Completion Date: December 2008
Primary Completion Date: June 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Drug: Rifampicin(max dose 10 mg/kg/day), Isoniazide (max dose 5 mg/kg/day) and Pyrazinamide (max dose 25 mg/kg/day)
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.
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
Drug: Rifampicin(max dose 10 mg/kg/day), Isoniazide (max dose 5 mg/kg/day) and Pyrazinamide (max dose 25 mg/kg/day)
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.
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.
Drug: Rifampicin(max dose 10 mg/kg/day), Isoniazide (max dose 5 mg/kg/day) and Pyrazinamide (max dose 25 mg/kg/day)
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.

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.

  Eligibility

Ages Eligible for Study:   16 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00405301

Locations
India
Sri Venkateswara Institute of Medical Sciences
Tirupati, Andhra Pradesh, India, 517507
All India Institute of Medical Sciences
New Delhi, Delhi, India, 110029
Sponsors and Collaborators
All India Institute of Medical Sciences, New Delhi
Investigators
Principal Investigator: Surendra K Sharma, MD, PhD All India Institute of Medical Sciences, New Delhi
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: S.K.SHARMA, Professor and Head, All India Institute of Medical Sciences, New Delhi
ClinicalTrials.gov Identifier: NCT00405301     History of Changes
Other Study ID Numbers: AIIMS/MED/2006/10
Study First Received: November 27, 2006
Last Updated: February 14, 2012
Health Authority: India: Ministry of Health

Keywords provided by All India Institute of Medical Sciences, New Delhi:
Tuberculosis
Drug Induced Hepatotoxicity
Anti-tuberculosis drugs
India

Additional relevant MeSH terms:
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Antitubercular Agents
Pyrazinamide
Rifampin
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antibiotics, Antitubercular
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on July 20, 2014