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Anti-tuberculosis (TB) Drug Levels and Hepatotoxicity

This study has been completed.
Sponsor:
Information provided by:
All India Institute of Medical Sciences, New Delhi
ClinicalTrials.gov Identifier:
NCT00929786
First received: June 29, 2009
Last updated: November 9, 2009
Last verified: November 2009
  Purpose

The purpose of this study is to evaluate plasma levels of hepatotoxic anti-tuberculous drugs (isoniazid, rifampicin, pyrazinamide plus significant metabolites) among patients on antituberculosis treatment (ATT) and compare the same among those who develop drug induced hepatitis on follow up versus those who do not.


Condition
Hepatitis
Tuberculosis

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: Measurement of Drug Levels and Their Correlation With Hepatotoxicity During Antituberculosis Treatment

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Evaluation of plasma levels of isoniazid, rifampicin, pyrazinamide among cases and controls [ Time Frame: 20 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Evaluation of plasma levels of any significant metabolites among cases and controls [ Time Frame: 20 months ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples Without DNA

Plasma


Enrollment: 72
Study Start Date: November 2007
Study Completion Date: June 2009
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Groups/Cohorts
2

Cases - those patients who develop DIH while on regular treatment with anti-TB drugs.

Controls - patients who do not develop DIH while on regular treatment with anti-TB drugs.


Detailed Description:

Tuberculosis (TB) is a major health problem in both the developing and developed countries because of its resurgence in the immunosuppressed patients. World Health Organization (WHO) in 1993 declared tuberculosis to be a 'global emergency' with more than a third of the world's population infected. Globally 8.9 million new cases of tuberculosis occur annually, of which 1.8 million (20%) occur in India.

Short-course chemotherapy containing isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) has proved to be highly effective in the treatment of tuberculosis. One of its adverse effects is hepatotoxicity. It is the most common side effect leading to interruption of therapy. It is associated with mortality of 6-12% if these drugs are continued even after the onset of symptoms. Risk of hepatotoxicity is increased when these drugs are combined.

The time interval between the start of anti-TB drugs and appearance of hepatotoxicity varies from 3 to 135 days. In most cases hepatitis is evident within three months of start of antituberculosis treatment (ATT).

The pathogenesis of drug-induced hepatotoxicity (DIH) is still not entirely clear for most anti TB drugs including rifampicin. Hypersensitivity is a definite possibility Rifampicin induced hepatitis has been postulated to occur as a part of systemic allergic reaction and, due to unconjugated hyperbilirubinaemia as a result of competition with bilirubin for uptake at hepatocyte plasma membrane. DIH caused by rifampicin occurs earlier as compared to isoniazid. While a dose related toxicity may exist, a direct correlation between serum drug levels and hepatotoxicity has not been well reported. Thus the clinical relevance of therapeutic monitoring of serum rifampicin concentrations in managing DIH is still being explored.

Present study done to observe serum rifampicin, isoniazid, pyrazinamide level in patients on ATT and to compare it retrospectively between patients who develop drug induced hepatitis vs those who do not.

  Eligibility

Ages Eligible for Study:   16 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Subjects: Patients with diagnosis of CatI/CatIII Tuberculosis attending the out-patient department of the All India Institute of Medical Sciences, New Delhi, will form the study population.

Cases - those patients who develop DIH while on regular treatment with anti-TB drugs Controls - age, sex matched patients who do not develop DIH while on regular treatment with anti-TB drugs

Criteria

Inclusion Criteria:

  1. Patients diagnosed to be suffering from CatI/CatIII tuberculosis by a physician
  2. Age: 16-65 years
  3. Patient having normal baseline Liver function (AST/ALT1 < 50/50, serum bilirubin < 1.5 mg/dl)

Exclusion Criteria:

  1. Patients receiving any other drug known to be metabolized by liver by cytochrome P450 3A4 or P-glycoprotein
  2. Patients diagnosed to have acute viral hepatitis A, B, C, or E or carrier for HBV & HCV
  3. Known HIV positive patients
  4. Presence of chronic liver disease or renal insufficiency
  5. Concomitant administration of other potential hepatotoxic drugs (methotrexate, phenytoin, valproate)
  6. Chronic alcoholics who consume > 48 g of alcohol/day for at least one year
  7. Pregnant women
  8. Subjects not willing to participate
  9. Known patients with malabsorption or drug abuse
  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: NCT00929786

Locations
India
All India Institute of Medical Sciences
New Delhi, Delhi, India, 110029
All India Institute of Medical Sciences
New Delhi, India, 110029
Sponsors and Collaborators
All India Institute of Medical Sciences, New Delhi
Investigators
Principal Investigator: Surendra K Sharma, MD,Ph.D All India Institute of Medical Sciences, New Delhi-110029, India
  More Information

No publications provided

Responsible Party: Dr. S K Sharma, Department of Medicine, AIIMS, New Delhi-110029
ClinicalTrials.gov Identifier: NCT00929786     History of Changes
Other Study ID Numbers: SKS/DIH/01, sksharma@aiims.ac.in
Study First Received: June 29, 2009
Last Updated: November 9, 2009
Health Authority: India: Institutional Review Board

Keywords provided by All India Institute of Medical Sciences, New Delhi:
Plasma levels isoniazid rifampicin pyrazinamide

Additional relevant MeSH terms:
Tuberculosis
Actinomycetales Infections
Bacterial Infections
Gram-Positive Bacterial Infections
Mycobacterium Infections

ClinicalTrials.gov processed this record on November 19, 2014