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

Tuberculosis Clinical Trial

Official title:

Study of Safety and Efficacy of Different Regimes of Reintroduction of Anti-TB Drugs in Antituberculosis Treatment Induced Hepatotoxicity

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00405301
• Other study ID #: AIIMS/MED/2006/10
• Status: Completed
• Phase: Phase 4
• First received: November 27, 2006
• Last updated: February 14, 2012
• Start date: December 2006
• Est. completion date: December 2008

Study information

• Verified date: February 2012
• Source: All India Institute of Medical Sciences, New Delhi
• Contact: n/a
• Is FDA regulated: No
• Health authority: India: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 175
• Est. completion date: December 2008
• Est. primary completion date: June 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years to 65 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Drug Induced Hepatotoxicity
• Drug-Induced Liver Injury
• Tuberculosis

Intervention

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.

Locations

Country	Name	City	State
India	All India Institute of Medical Sciences	New Delhi	Delhi
India	Sri Venkateswara Institute of Medical Sciences	Tirupati	Andhra Pradesh

Sponsors (1)

Lead Sponsor	Collaborator
All India Institute of Medical Sciences, New Delhi

Country where clinical trial is conducted

India, 

References & Publications (5)

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. — View Citation

Sharma SK. Antituberculosis drugs and hepatotoxicity. Infect Genet Evol. 2004 Jun;4(2):167-70. — View Citation

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. — View Citation

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. — View Citation

Tahaoglu K, Ataç G, Sevim T, Tärün 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To compare the safety of different regimens of re-introduction of anti-TB drugs in drug induced liver damage.		24 months	Yes
Secondary	To study the predictors of recurrence of drug induced liver damage		24 months	Yes
Secondary	To study the risk factors for development of drug induced liver injury		24 months	Yes