HepatitisNCT01456845
Anti-tuberculosis (TB) Drug Levels and Correlation With Drug Induced Hepatotoxicity
An observational study of Hepatitis and Tuberculosis, run by All India Institute of Medical Sciences at 1 site in India.
Trial summary
The purpose of the study is to estimate plasma drug levels ( free and total drug levels ) of rifampicin and other antituberculosis drugs and compare these drug levels in patients who develop drug induced hepatotoxicity versus those who do not .The study hypothesis is that the ATT drug induced hepatotoxicity is related… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Hepatitis, Tuberculosis
- How many people
- 110 participants
- Where
- 1 siteIndia
- Study dates
- Aug 2010to Jun 2012
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Subjects: Patients with diagnosis of pulmonary/extrapulmonary 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 - patients who do not develop DIH while on regular treatment with anti-TB drugs
Who may be able to join
- Age: patients in the range between 18 to 65 years
- Patients of either gender
- Probable or confirmed cases of TB
- Patients receiving daily antituberculosis drugs
Who cannot join
- Patients with serological evidence of acute viral hepatitis A, B, C, or E and carriers of HBV and/or HCV
- HIV positive patients
- Presence of chronic liver disease or cirrhosis
- Cognitive dysfunction
- Terminally sick patients and unlikely to survive for 6-9 months
- Concomitant administration of other potentially hepatotoxic drugs(Methotrexate, Phenytoin, phenobarbitone, carbamazepine ,valproate Atenolol, labetalol, Salicylates , allopurinol, quinine, quinidine, fluconazole, cimetidine, ethionamide, verapamil, probenecid, TCA, halothane)
- Chronic alcoholics consuming >48 g/day for more 1 year
- Patients not willing to give informed consent
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Estimation of Plasma Free and Total Drug Levels of Rifampicin, Isoniazid and Pyrazinamide in Patients on Antituberculosis Therapy and Its Correlation With Development of Drug Induced Hepatotoxicity
The purpose of the study is to estimate plasma drug levels ( free and total drug levels ) of rifampicin and other antituberculosis drugs and compare these drug levels in patients who develop drug induced hepatotoxicity versus those who do not .The study hypothesis is that the ATT drug induced hepatotoxicity is related to free drug levels of rifampicin and other antituberculosis drugs .
Read the 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. Rifampicin is highly protein bound and hypoalbuminemia is a known risk factor for DIH ,so free drug levels in plasma has more significance than total drug levels in plasma.
Present study is done to estimate free and total drug levels of rifampicin and other antituberculosis drugs in patients on ATT and to compare it between patients who develop DIH vs those who do not and to assess the predicting ability of these drug levels in the subsequent development of drug induced hepatoxicity.
- Conditions
- Hepatitis, Tuberculosis
- Keywords
- Plasma levels, isoniazid, rifampicin, pyrazinamide, hepatoxicity
- Medical subject headings
- Hepatitis, Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Evaluation of plasma levels of isoniazid, rifampicin, pyrazinamide among cases and controls
Measured: 21 months
Secondary outcomes (1)
Evaluation of plasma drug levels and its correlation among cases and controls and to assess the ability of these drug levels to predict subsequent development of drug induced hepatoxicity
Measured: 21 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Oct 2011 (estimated)
- Study startAug 2010
- Primary completionJun 2012
- Study completionJun 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HepatitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 110 participants (actual)
Sponsor and investigators
- Lead sponsor
- All India Institute of Medical Sciences
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, S.K.SHARMA, All India Institute of Medical Sciences
- Investigators
- Surendra K Sharma, MD,Ph.D, Principal investigator, All India Institute of Medical Sciences, New Delhi-110029, India
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01456845
- Sponsor's protocol ID
- SKS/DIH/2011
- Status last verified
- Aug 2012
- First submitted
- 20 Oct 2011
- Last updated
- 31 Aug 2012
- Results posted
- No
- Data monitoring committee
- No
Publications
Satyaraddi A, Velpandian T, Sharma SK, Vishnubhatla S, Sharma A, Sirohiwal A, Makharia GK, Sinha S, Biswas A, Singh S. Correlation of plasma anti-tuberculosis drug levels with subsequent development of hepatotoxicity. Int J Tuberc Lung Dis. 2014 Feb;18(2):188-95, i-iii. doi: 10.5588/ijtld.13.0128.
PubMed 24429311
Study at a glance
From the registry record, last updated by the sponsor on 31 Aug 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Estimation of Plasma Free and Total Drug Levels of Rifampicin, Isoniazid and Pyrazinamide in Patients on Antituberculosis Therapy and Its Correlation With Development of Drug Induced Hepatotoxicity
- ClinicalTrials.gov ID
- NCT01456845
- Acronym / sponsor ID
- SKS/DIH/2011
- Conditions
- Hepatitis, Tuberculosis
- Keywords
- Plasma levels, isoniazid, rifampicin, pyrazinamide, hepatoxicity
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 110 participants (actual)
- Lead sponsor
- All India Institute of Medical SciencesUniversity, hospital or other
- Study start
- Aug 2010
- Primary completion
- Jun 2012 (actual)
- Study completion
- Jun 2012 (actual)
- First posted
- 21 Oct 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of the study is to estimate plasma drug levels ( free and total drug levels ) of rifampicin and other antituberculosis drugs and compare these drug levels in patients who develop drug induced hepatotoxicity versus those who do not .The study hypothesis is that the ATT drug induced hepatotoxicity is related to free drug levels of rifampicin and other antituberculosis 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. Rifampicin is highly protein bound and hypoalbuminemia is a known risk factor for DIH ,so free drug levels in plasma has more significance than total drug levels in plasma.
Present study is done to estimate free and total drug levels of rifampicin and other antituberculosis drugs in patients on ATT and to compare it between patients who develop DIH vs those who do not and to assess the predicting ability of these drug levels in the subsequent development of drug induced hepatoxicity.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Subjects: Patients with diagnosis of pulmonary/extrapulmonary 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 - patients who do not develop DIH while on regular treatment with anti-TB drugs
Key inclusion criteria (4 listed)
- Age: patients in the range between 18 to 65 years
- Patients of either gender
- Probable or confirmed cases of TB
- Patients receiving daily antituberculosis drugs
Key exclusion criteria (8 listed)
- Patients with serological evidence of acute viral hepatitis A, B, C, or E and carriers of HBV and/or HCV
- HIV positive patients
- Presence of chronic liver disease or cirrhosis
- Cognitive dysfunction
- Terminally sick patients and unlikely to survive for 6-9 months
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Evaluation of plasma levels of isoniazid, rifampicin, pyrazinamide among cases and controls
Time frame: 21 months
1 secondary outcome
Evaluation of plasma drug levels and its correlation among cases and controls and to assess the ability of these drug levels to predict subsequent development of drug induced hepatoxicity
Time frame: 21 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Aug 2012.
- Derived from this study: PubMed 24429311Satyaraddi A, Velpandian T, Sharma SK, Vishnubhatla S, Sharma A, Sirohiwal A, Makharia GK, Sinha S, Biswas A, Singh S. Correlation of plasma anti-tuberculosis drug levels with subsequent development of hepatotoxicity. Int J Tuberc Lung Dis. 2014 Feb;18(2):188-95, i-iii. doi: 10.5588/ijtld.13.0128.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Surendra K Sharma, MD,Ph.D principal investigator
All India Institute of Medical Sciences, New Delhi-110029, India
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Hepatitis and Tuberculosis, run by All India Institute of Medical Sciences at 1 site in India.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Aug 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Evaluation of plasma levels of isoniazid, rifampicin, pyrazinamide among cases and controls (time frame: 21 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01456845, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Aug 2012.